Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Mg].[O:11]1[CH2:15][CH2:14][NH:13]C1.Cl.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>C1(C)C=CC=CC=1.II>[OH:11][CH2:15][CH2:14][N:13]1[CH2:17][CH2:21][O:20][CH2:19][CH:18]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C1CCOC1
Reactant: CCCCCCCCBr
Reactant: C1COCN1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: Cc1ccccc1
Product: CCCCCCCCC1COCCN1CCO
Temperature: 5 °C
Reaction time: 2 h

Procedure:
25 g of 1-Bromooctane were slowly added to a suspension of 3.5 g of magnesium and 7.5 mg of iodine in 41 ml of THF at 65° C. The reaction mixture was stirred at the same temperature for 2 h. When the corresponding Grignard compound was prepared, the mixture was cooled down at 5° C. and a solution of 16.7 g of Oxazolidine (II) in 40 ml of toluene was added in 1 hour. The mixture was stirred at 5° C. for 30 min. and the reaction was warmed up until room temperature. The mixture was added to an aqueous solution of 5% HCl and stirred for 30 min. The organic layer was decanted, dried and concentrated until dryness to obtain 19 g of the desired compound as a brown oil. MS (EI), (m/z, %): 243 (M+., 5), 242 (M-H, 5), 212 (M-CH2OH, 50), 198 (M-(CH2)2OH, 8), 130 (M-C8H17, 100), 112 (M-C8H17-H2O, 8), 100 (M-73, 30), 86 (8), 71 (8), 56(9), 41 (14).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH:6]([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=O)[CH3:2].BrC1C=C(C(=O)CC)C=CC=1.C(OCC)(=O)C(OCC)=O.O.[NH2:41][NH2:42]>CCO>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:16])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[NH:42][N:41]=1)=[O:18])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1cccc(Br)c1
Agent: CCC(=O)c1cccc(Br)c1
Solvent: CCO
Solvent: O
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1n[nH]c(-c2cccc(Br)c2)c1C
Yield: 46 %

Procedure:
In analogy to the procedure described in example 16A], 4-(3-bromo-phenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester (synthesized from 3′-bromopropiophenone and diethyl oxalate, following a procedure described in Ksander, Gary M.; McMurry, John E.; Johnson, Mark. A method for the synthesis of unsaturated carbonyl compounds. Journal of Organic Chemistry (1977), 42(7), 1180-5) and hydrazine monohydrate were heated at 90° C. in EtOH for 1 h to give after crystallization (Et2O/n-penatane) the title compound in 46% yield as off-white powder. MS: 308.1 (M+, 1 Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15](O)=[O:16])[S:14][C:7]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:66][N:67]1[CH2:72][CH2:71][N:70]([CH2:73][CH2:74][CH2:75][NH2:76])[CH2:69][CH2:68]1>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[F:32])=[O:23])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:76][CH2:75][CH2:74][CH2:73][N:70]3[CH2:69][CH2:68][N:67]([CH3:66])[CH2:72][CH2:71]3)=[O:16])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)O)sc34)cc2F)c1
Reactant: CN1CCN(CCCN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCN(C)CC5)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylic acid (100 mg, 0.22 mmol), HATU (90 mg, 0.24 mmol) and N,N-diisopropylethylamine (55 mg, 0.43 mmol) in anhydrous acetonitrile (10 ml) was stirred at room temperature for 30 minutes, followed by addition of 3-(4-methylpiperazin-1-yl)propan-1-amine (40 mg, 0.25 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-[3-(4-methylpiperazin-1-yl)propyl]thieno[3,2-b]pyridine-2-carboxamide as brown solid. Yield: 110 mg, 84%.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH3:27])[C:14]2[CH:18]([CH2:19][C:20]([O:22]CC)=[O:21])[O:17][B:16]([OH:25])[C:15]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O.O>[C:1]([O:5][C:6]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH3:27])[C:14]2[CH:18]([CH2:19][C:20]([OH:22])=[O:21])[O:17][B:16]([OH:25])[C:15]=2[CH:26]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(OCCC(=O)OC(C)(C)C)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCCC(=O)OC(C)(C)C)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
To a solution of ethyl 2-(6-(2-(tert-butoxycarbonyl)ethoxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (80 mg, 0.2 mmol) in 16 mL of THF/H2O (1/1) was added LiOH (42 mg, 1.0 mmol) in 5 mL of H2O at 0° C. The reaction mixture was stirred at room temperature for 1.5 h and acidified by 1 N HCl to pH=5. The resulting mixture was extracted with EtOAc (3×20 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as an off-white powder (60 mg, yield: 82.2%). 1H NMR (400 MHz, DMSO) δ12.23 (s, 1H), 9.09 (s, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.01-6.98 (m, 1H), 6.85 (d, J=2.0 Hz, 1H), 5.45-5.42 (m, 1H), 3.96-3.93 (m, 2H), 3.27-3.31 (m, 2H), 3.00-3.04 (m, 1H), 2.25 (s, 3H), 2.08-2.02 (m, 1H), 1.39 (s, 9H); MS (ESI) m/z=366 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:33])[C:20]=2[CH2:21]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-:36].C([N+](CCCC)(CCCC)CCCC)CCC>>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][S:10][C:11]2[O:12][C:13]3[C:18]([C:19](=[O:33])[C:20]=2[CH2:21][F:36])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)oc3ccccc3c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)c1ccc(CSc2oc3ccccc3c(=O)c2CF)cc1

Procedure:
2-(4-Tert-butylbenzyl)thio-3-tosyloxymethyl chromen-4-one (3 g, 5.9 mmol) is introduced into a 15 mL round bottom flask and tetrabutylammonium fluoride solution (5.9 mmol; 1M in THF) is added to it. The solution is heated to reflux for 3 hours after which all volatiles are removed and the residue obtained is purified by silica gel flash chromatography (ethyl acetate:hexanes).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=[O:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:47]1COCC1>C[Mg]Br.CCOC(C)=O.Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]([OH:46])[CH3:47])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixture of benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.200 g, 0.320 mmol) in THF (5.0 mL), methylmagnesium bromide in THF (3.0 M, 0.43 mL, 1.3 mmol) was added slowly at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature. The reaction mixture was then diluted with EtOAc (10 mL), and 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic extracts were combined, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (201 mg, 98%). LCMS calc. for C35H41N6O6 (M+H)+: m/z=641.2. Found: 641.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:13][N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCN2c1ccccc1
Agent: [Li+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CN(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C

Procedure:
A solution of 4-oxo-1-phenyl-1,3,7-triaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester (130 mg, 0.45 mmol) in dry THF (3 ml) under nitrogen was cooled to −78° C. and treated with 1M LHMDS in THF (0.55 ml, 0.55 mol). The reaction was allowed to warm to RT for 30 mins before cooling back to −78° C. and adding 2M MeI in THF solution (0.45 ml, 0.9 mmol). The reaction was left to warm to RT overnight. The reaction mixture was diluted with EtOAc (10 ml) and washed with brine (20 ml). The aqueous phase was extracted with EtOAc (10 ml). Organics portions were combined, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C)C=O.C(OCC)(=O)C>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCCCBr)cc1
Temperature: 60 °C
Yield: 89.8 %

Procedure:
A solution of 4-hydroxybenzoic acid methyl ester (100 g) and 1,6-dibromohexane (481 g) in N,N-dimethylformamide (500 ml) was treated with potassium carbonate (109 g) then heated at 60° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate (3 L) and washed with water (7×1 L). The organic layer was dried over magnesium sulfate, filtered, and evaporated to give a crude oil. Hexane (˜100 ml) was added and the resulting precipitate removed by filtration and discarded and the filtrate loaded onto a silica gel column (2 kg). Elution with hexane, followed by 9:1 hexane-ethyl acetate and 8:1 hexane-ethyl acetate afforded methyl 4-(6-bromo-n-hexyloxy)benzoate (186 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[CH3:57][S-:58].[Na+].[CH3:60]N(C)C=O>COC(C)(C)C>[CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41][CH2:57][S:58][CH3:60])=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: C[S-]
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCSC)cc1
Temperature: 25 °C

Procedure:
A solution of 0.50 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.55 g of sodium methanethiolate in 5 ml of N,N-dimethylformamide is stirred at 90° C. over 1 hour. The reaction mixture is cooled to room temperature, diluted with tert-butyl methyl ether, washed with saturated aqueous sodium bicarbonate solution, dried with sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a colourless oil from the residue. Rt=6.53.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:12][C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:28])=O.C(N(CC)CC)C.O>ClCCl>[Cl:28][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:12][C:13]=1[CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(O)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methanol (0.7 g) in dichloromethane (5 mL) were added oxalyl chloride (0.3 mL) and triethylamine (0.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.8 g, 100%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.P([O-])(OCC)(SCC)=[S:27]>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24](=[S:27])[NH2:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Reactant: CCOP([O-])(=S)SCC
Product: NC(=S)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Yield: 50 %

Procedure:
The title compound (223 mg, 50%) was prepared from 4-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}tetrahydro-2H-pyran-4-carbonitrile and diethyl dithiophosphate similarly to the procedure used for intermediate 50. LRMS APCI+ m/z 375 [MH]+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]2)[CH2:2]1.[ClH:16].C(OCC)(=O)C>O1CCCC1>[ClH:16].[CH2:2]1[C:3]2([CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C1CC2(CCN1)CC2
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
Tert-butyl 6-azaspiro[2.5]octane-6-carboxylate (261 mg, 1.23 mmol) was dissolved in tetrahydrofuran (5 mL), 4N hydrochloric acid/ethyl acetate solution (2 mL, 8.00 mmol) was added, and the mixture was stirred at 50° C. for 24 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (155 mg, 85%) as white crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:13]=[C:14]([CH2:21][OH:22])[C:15]([CH2:19][OH:20])=[CH:16][C:17]=1[F:18].C(N(CC)CC)C>ClCCl.ClCCl.CS(C)=O>[F:11][C:12]1[CH:13]=[C:14]([CH:21]=[O:22])[C:15](=[CH:16][C:17]=1[F:18])[CH:19]=[O:20]
Reactant: OCc1cc(F)c(F)cc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cc(F)c(F)cc1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 85.2 %

Procedure:
To a solution of oxalyl chloride 2M in dichloromethane (DCM) (4.5 ml, 8.8 mmol, 2.2 molar equivalents) cooled to −78° C. was added dropwise a solution of dimethylsulfoxyde (DMSO) (1.25 ml, 17.7 mmol, 4.4 molar equivalents) in DCM (5 ml). The solution was stirred at −78° C. for 5 minutes and 4,5-difluorobenzene-1,2-dimethanol (compound 21) (0.70 g, 4.0 mmol, 1.0 molar equivalent) dissolved in a mixture of DCM/DMSO (1-2 ml) was added dropwise. The solution was stirred for 1 hour at −78° C. and triethylamine (15 ml) was slowly added at −78° C. The reaction mixture was stirred for 10 minutes at −78° C. and slowly warmed up to room temperature. Ice-cold water (25 ml) was added to the reaction mixture and the aqueous layer extracted with DCM (3 times 30 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated in vacuum to give a yellow oil. Purification by column chromatography on silica gel (eluent, hexane:DCM 2:8) gave the title compound as a light yellow solid (0.58 g, 85%). 1H NMR (300.13 MHz, CDCl3) δ(ppm) 7.83 (t, J=9.00 Hz, 2H) 10.49 (s, 2H). 19F NMR (282.38 MHz, CDCl3) δ(ppm) −127.10 (s).
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[CH2:30]([O:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36])[CH3:31]>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[O:32][CH2:30][CH3:31])=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc3c(c1)OCO3)NCC2
Reactant: O=C(Br)CBr
Reactant: CCOc1ccccc1CN
Product: CCOc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)cc2C1Cc1ccc2c(c1)OCO2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzylamine
Reaction SMILES: CO[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].[Na].[H-].[Na+].Br[C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].CN(C)[CH:41]=[O:42]>>[CH3:37][C:31]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:23]=[CH:24][C:25]([O:42][CH3:41])=[CH:26][CH:3]=3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)([CH3:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccc(OC)cc3)cc2)cc1

Procedure:
7.4 gm (21.2 millimols) of 4-[2-(4-methoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl (see Example I) were dissolved in 60 ml of absolute dimethyl formamide and converted into the sodium salt with 1.1 gm (about 25 millimols) of 55% sodium hydride suspension in oil, and the salt was reacted with 9.7 gm (51.5 millimols) of ethyl 2-bromo-2-methyl-propionate at room temperature over a period of 18 hours. After distilling off the dimethylformamide, the evaporation residue was dissolved in acetone, the solution was filtered, the acetone was distilled out of the filtrate, and the residue was purified on a silicagel column with toluene/ethyl acetate (4:1) as the eluant. Yield: 2 gm (20% of theory); m.p. 149°-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)=[C:11]([F:13])[CH:12]=1)=[O:5])[CH3:2].C[C:28](C)([O-:30])C.C(OC(=O)CCC)[C@@H]1OC1.CO>O1CCCC1>[F:13][C:11]1[CH:12]=[C:7]([N:6]2[CH2:2][C@H:1]([CH2:28][OH:30])[O:3][C:4]2=[O:5])[CH:8]=[CH:9][C:10]=1[N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Nc1ccc(N2CC[C@@H](NC(=O)OC(C)(C)C)C2)c(F)c1
Agent: CCCC(=O)OC[C@H]1CO1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Reaction time: 0.08 h

Procedure:
5-Ethoxycarbonylamino-2-((3R)-3-t-butoxycarbonylamino-1-pyrrolidinyl)fluorobenzene (33.6 g, 0.092 M) was dissolved in dry tetrahydrofuran (300 ml) under nitrogen. cooled to −70°, and treated dropwise over 30 minutes with a solution of lithiun t-butoxide (1 M in tetrahydrofuran, 100.7 ml), keeping the temperature below −65°. After stirring for 5 minutes, (R)-glycidylbutyrate (14.52 g, 0.101 M) was added, and stirring continued at −65° for 1 hour, before allowing the temperature to rise to ambient over 16 hours. The mixture was treated with MeOH (50 ml), stirred at ambient temperature for 1 hour, and the precipitate collected and washed well with tetrahydrofuran to give the desired product (21.8 g).
Reaction SMILES: Cl.N[C:3]1[C:4]2[C:5](=[N:15][N:16]([CH3:18])[CH:17]=2)[NH:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[N:9]=1.C(=O)([O-])[O-:20].[K+].[K+]>C(O)C.O>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[NH:6][C:5]3=[N:15][N:16]([CH3:18])[CH:17]=[C:4]3[C:3](=[O:20])[NH:9][C:8]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc2c(n1)Nc1ccc(Cl)cc1N=C2N
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cn1cc2c(n1)Nc1ccc(Cl)cc1NC2=O

Procedure:
4-Amino-7-chloro-2,10-dihydro-2-methylpyrazolo[3,4-b][1,5]benzodiazepine hydrochloride (11.3 g) and potassium carbonate (16.8 g) were heated under reflux in a mixture of ethanol (200 ml) and water (20 ml) for 48 hours. Water (300 ml) was added and the solution cooled. The precipitate was crystallised from acetic acid to give the title compound m.p. >260° C.
Reaction SMILES: [CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][NH+:8]=1.CS(O)(=O)=O.[CH2:18]1[S:20][CH2:19]1>CC1C=CC=CN=1.O>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[SH:20][CH2:19][CH2:18][N+:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6]
Reactant: C1CS1
Reactant: Cc1cccc[nH+]1
Agent: CS(=O)(=O)O
Agent: CS(=O)(=O)[O-]
Solvent: Cc1ccccn1
Solvent: O
Product: Cc1cccc[n+]1CCS
Temperature: 55 °C
Reaction time: 21 h
Yield: 85 %

Procedure:
To a suspension of 2-methylpyridinium methanesulfonate in 2-methylpyridine prepared by the addition of methanesulfonic acid (0.65 mL, 0.010 mol) to cold 2-methylpyridine (2.17 mL, 0.022 mol) was added ethylene sulfide (0.655 mL, 0.011 mol). The reaction mixture was stirred under a nitrogen atmosphere at 55° C. for 21 h, cooled to 23° C. and diluted with water (5 mL). The aqueous solution was washed with ether (6×4 mL) pumped to remove traces of organic solvents and poured on top of a column (2.5×10.0 cm) of μ-bondapak C-18. The column was eluted with water and lyophilization of the appropriate fractions gave 2.13 g (85%) of the title compound, ir (film) νmax : 2520 (SH), 1623 (pyridinium) 1574, 1512, 1485, 1412, 1195 (sulfonate), 1038 cm-1, 1Hmr (DMSO-d6 +D2O) δ: 2.37 (3H, s, CH3SO3-), 2.83 (3H, s, CH3 on pyridinium), 3.09 (2H, J=6.9 Hz, CH2S), 4.71 (2H, t, J=6.9 Hz, CH2N+), 7.83 (2H, m, Hm of pyridinium), 8.44 (1H, m, Hp of pyridinium), 8.89 (1H, m, Ho of pyridinium), uv (H2O) λmax : 266 (ε3550) mμ.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[C:13]2[C:9](=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1)[C:3]#N.[OH-:20].[Na+].C([OH:24])C>O>[CH3:1][CH:2]([C:5]1[C:13]2[C:9](=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1)[C:3]([OH:24])=[O:20]
Reactant: CC(C#N)c1cccc2c(-c3ccccc3)onc12
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: CC(C(=O)O)c1cccc2c(-c3ccccc3)onc12
Yield: 31 %

Procedure:
A mixture of 7.7 g (0.031 mole) of α-methyl-3-phenyl-2,1-benzisoxazole-7-acetonitrile, 20 ml of 20% sodium hydroxide and 150 ml of 95% ethanol was heated at reflux and under an argon atmosphere for 21 hr. The reaction mixture was poured into 1.2 liters of water and filtered. The filtrate was treated with charcoal and filtered through Celite. The filtrate pH was adjusted to 7 with concentrated hydrochloric acid and filtered. The filtrate pH was adjusted to 2 with concentrated hydrochloric acid and allowed to stand at ambient temperature. The resulting solid was collected by filtration, air-dried, and recrystallized from cyclohexane-ethyl ether to give 2.6 g (31%) of light-tan solid, m.p. 140°-144° C.