Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[S:23][C:13]=3[N:14]=2)=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccccc1
Product: FC(F)(F)c1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O-]Cl.[Na+].[Na+].[Br-].C([O-])(O)=O.[Na+].[Cl:11][CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1.O>[Cl:11][CH2:12][C:13](=[O:26])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1
Reactant: OC(CCl)COc1cccc(C(F)(F)F)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)COc1cccc(C(F)(F)F)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
10% aq. NaOCl (900 mL) was added dropwise to a stirred mixture of NaBr (30.9 g, 0.30 mol), NaHCO3 (50.4 g, 0.60 mol), water (200 mL) and a solution of 1-chloro-3-[3-(trifluoromethyl)phenoxy]-2-propanol (80.0 g from Example 1) and TEMPO (0.94 g, 6 mmol) in CH2Cl2 (100 mL) at 0 to 5° C. The mixture was stirred for 0.5 h at the same temperature and 10% aq. Na2S2O3.5H2O (150 mL) was added. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered trough thin layer of silica gel and concentrated in vacuo. A mixture of the residue and hexane (300 mL) was stirred for 1 h at rt and for 1 h at 0 to 5° C. The precipitate was filtered, washed on the filter with cold hexane and dried in vacuo to give 60.5 g of 1-chloro-3-[3-(trifluoromethyl)phenoxy]-2-propanone as off-white crystals: mp 38–39° C. 1H NMR (CDCl3) δ: 7.41 (t, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 7.0 (d, J=8.0 Hz, 1H), 4.82 (s, 2H), 4.37 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH:16]([CH2:27][O:28]C(=O)C)[CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].C(O)=[O:33]>>[OH:28][CH2:27][CH:16]([CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][O:14][N:6]1[CH:5]=[N:4][C:3]2[C:2](=[O:33])[NH:10][C:9]([NH2:11])=[N:8][C:7]1=2
Reactant: CCOP(=O)(CCC(COC(C)=O)COn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: O=CO
Product: CCOP(=O)(CCC(CO)COn1cnc2c(=O)[nH]c(N)nc21)OCC
Temperature: 90 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
A solution of 6-chloro-9-[2-(acetoxymethyl)-4-(diethoxyphosphoryl)butoxy]-2-formamidopurine (0.128 g, 0.268 mmol) in 80% formic acid (5 ml) was stirred at 80° C. for 5 hours. The solvent was evaporated under reduced pressure and the residue coevaporated with toluene (2×10 ml). The residue was redissolved in a 0.02 M solution of hydrochloric acid in ethanol (4ml) and the resulting mixture stirred at 90° C. for 2 hours. The solvents were evaporated under reduced pressure and the residue coevaporated with ehtanol (2×15 ml). The product was purified by column chromatography on silica gel (eluting with chloroform:ethanol 92:8) to give the title compound (64 mg, 61%). 1H NMR: δH [(CD3)SO] 1.22 (6H, t, J=7Hz, (CH3CH2 ()2), 1.75 (5H, m, CHCH2CH2P), 3.5 (2H, m, CH2OH), 4.0 (4H, m, (OCH2CH3)2), 4.24 (2H, m, NOCH2), 4.64 (1H, t, J=5.2Hz, D2O exchangeable, CH2OH), 6.55 (2H, br.s, D2O exchangeable, NH2), 7.92 (1H, s, H-8), 10.52 (1H, br.s, D2O exchangeable, NH).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)=[N:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)s2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4O)s2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (120 mg, 0.24 mmol) in THF (30 mL) was added 10% Pd(OH)2/C (200 mg). The mixture was stirred under H2 atmosphere at rt for 3 h, filtered and concentrated to afford tert-butyl 4-(5-((2S,5R)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate as a yellow solid, which was directly used in the next step. ESI-MS (EI+, m/z): 410.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>O1CCCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:14][CH2:13][CH2:11][OH:12]
Reactant: Clc1nc2ccccc2o1
Reactant: NCCO
Solvent: C1CCOC1
Product: OCCNc1nc2ccccc2o1

Procedure:
A solution of 2-chlorobenzoxazole (12.78 g) in dry tetrahydrofuran (50 ml) was added, over 10 minutes, to a stirred, ice-cooled solution of ethanolamine (15.3 g) in dry tetrahydrofuran (400 ml). The mixture was heated at reflux overnight, cooled, and the solvent evaporated. The residue was partitioned between water (500 ml) and dichloromethane (500 ml), and the resulting white solid filtered off, washed with dichloromethane and dried in vacuo to afford the title compound m.p. 162°-4° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1C=CC([C@@H](N2CC[C@](CC(C)=C)(C3C=CC=CC=3)OC2=O)C)=C[CH:29]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:9]2[CH2:29][CH2:28]2)[N:10]2[CH2:15][CH2:14][C:13]([CH2:22][C:23]([CH3:25])=[CH2:24])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])=[CH:6][CH:7]=1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C=C(C)CC1(c2ccccc2)CCN(C(c2ccc(Br)cc2)C2CC2)C(=O)O1

Procedure:
The stereochemical assignments of the diastereomers are based on the comparison of the 1H NMR data with the data of the known analogs 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one and 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C@@H:19]1[CH2:23][O:22]C(C)(C)[O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO.Cl>[CH2:1]([O:17][CH2:18][C@@H:19]([OH:20])[CH2:23][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOC[C@@H]1COC(C)(C)O1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CO
Reaction time: 12 h
Yield: 81.1 %

Procedure:
A mixture of 28.2 g of (R)-4-[(hexadecyloxy)methyl]-2,2-dimethyl-1,3-dioxolane in 189 ml of methyl alcohol and 21 ml of IN hydrochloric acid is stirred at reflux for 2.5 hours followed by 12 hours at ambient temperature. The reaction is cooled, filtered and the cake washed with cold methyl alcohol then dried to give 20.3 g of the desired product as white plates, m.p. 63°-64° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:33][CH2:34]Cl)[CH2:31][CH3:32])[CH3:29]>>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:29][CH2:28][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[CH2:16][CH:15]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(CN3CCNCC3c3ccccc3)cc2)cc1
Reactant: CCN(CC)CCCl
Product: CCN(CC)CCN1CCN(Cc2ccc(OCc3ccccc3)cc2)C(c2ccccc2)C1

Procedure:
1-(4'-Benzyloxy benzyl)-2-phenyl piperazine prepared according to Example 16, is alkylated by means of diethylamino ethylchloride by following the procedure described in Example 3c. The resulting reaction product is obtained in the form of a light yellow oil boiling at 235° C./0.01 mm. Hg.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OCC(C)OC(C)=O

Procedure:
0.5 g of rhenium-V-chloride, 1 g copper-II-chloride and 1 g iron-III-chloride are dissolved in 500 ml of glacial acetic acid and 50 ml of acetic acid anhydride and then treated as in the earlier Examples. On working up, 20.2 g of propylene glycol diacetate are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1>[Ni].C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Ni]
Solvent: CCO
Product: Cc1ccc(C(=O)Oc2ccc(O)cc2)cc1

Procedure:
16.9 g (0.042 mol) of 4-benzoxyphenyl 4-methylbenzoate are added to 250 ml of ethanol and hydrogenated at room temperature using Raney nickel under a hydrogen atmosphere at atmospheric pressure. The catalyst is subsequently filtered off with suction and destroyed using ethanol. The filtrate is evaporated, and the product is purified by filtration through silica gel.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[C:7]#[N:8].C1C(=O)N([Br:21])C(=O)C1>ClC1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:10][C:5]1[CH:4]=[C:3]([N+:11]([O-:13])=[O:12])[C:2]([Cl:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: N#Cc1cc(Cl)c([N+](=O)[O-])cc1CBr
Temperature: 130 °C
Yield: 108.9 %

Procedure:
A mixture of 5-chloro-4-nitro-2-methylbenzonitrile (32.0 g, 0.16 mol), NBS (54.0 g, 0.30 mol) and benzoyl peroxide (200 mg, catalytic amount) in chlorobenzene was heated at 130° C. and irradiated with a sunlamp for 15 h. More NBS (30.0 g, 0.17 mol) and benzoyl peroxide (200 mg) were added. The mixture was further reacted for 24 h. After cooling, the precipitate formed was filtered off and washed with CH2Cl2. The combined filtrates were washed with H2O (2×), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was then chromatographed over silica gel and eluted with hexanes:EtOAc (9:1) to give 2-bromomethyl-5-chloro-4-nitrobenzonitrile (48 g, contaminated with starting material and dibrominated product) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:12]>CCO>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1c(O)ccc([N+](=O)[O-])c1C
Solvent: CCO
Product: Cc1c(N)ccc(O)c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 972 %

Procedure:
A mixture of 2,3-dimethyl-4-nitrophenol (2 g, 1.2 mmol) and Pd(C) (10%) (1.83 g) in EtOH (80 mL) was stirred at room temperature under H2 atmosphere for 5 hours. The crude mixture was then filtered using celite and washed with DCM. After evaporating the solvent, the title compound (1.60 g, 97%) was obtained as a brown powder. 1H-NMR (6, ppm, DMSO-d6): 1.94 (s, 3H, HMe), 2.01 (s, 3H, HMe), 4.06 (s, 2H, NH2), 6.32 (d, 1H, Harom 6, J6-5=8.1 Hz), 6.40 (d, 1H, Harom 5, J6-5=8.1 Hz), 6.61 (s, 1H, Harom 2), 8.10 (broad s, 1H, OH).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[Cu][C:35]#[N:36]>CN1C(=O)CCC1>[C:35]([C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8])#[N:36]
Reactant: N#C[Cu]
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: CN1CCCC1=O
Product: Cc1c(C#N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 24.5 %

Procedure:
A mixture of 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 120 mg, 0.20 mmol) and copper (I) cyanide (66.7 mg, 0.74 mmol) in NMP (2.5 ml) was stirred overnight at 140° C. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was first purified by preparative HPLC and then by flash chromatography eluting with dichloromethane/methanol (10:0.2) to give the title compound as a white solid (24 mg, 24%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(OC(C)C)(C)C>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:8]2=[O:36])[CH2:40][CH2:39]1
Reactant: CN1CCNCC1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCCl)C1=O)c1cc2ccccc2[nH]1
Solvent: CC(C)OC(C)C
Product: CN1CCN(CCOCCN2C(=O)C(NC(=O)c3cc4ccccc4[nH]3)N=C(c3ccccc3)c3ccccc32)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of (3RS)-1-[2-(2-chloroethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one (500 mg) and 1-methylpiperazine (5.0 ml) was stirred at 70° C. for 5.0 hours. Then diisopropyl ether (30 ml) was added to the reaction mixture. After the resultant precipitate was filtered off, the filtrate was evaporated. The residue was washed with water and dried to give (3RS)-1-[2-[2-(4-methyl-1-piperazinyl)ethoxy]ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.43 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A mixture of 1.93 g (7.8 mmol) of ethyl 2-(4-[trifluoromethyl]phenyl)propionate, 10 mL of 1N NaOH, and 10 mL of absolute ethanol was heated to reflux for 3 hours, allowed to cool to room temperature, and poured into 50 mL of 1N HCl. The resulting aqueous mixture was extracted with three 10 mL portions of dichloromethane. Combination, drying (MgSO4), and concentration of the organic layers afforded an oil which was crystallized from hexanes to give 0.90 g (50% yield) of the acid as a white, crystalline solid: mp 56°-58° C.; 1H NMR (CDCl3) 1.47 (d, 3H, J=7 Hz), 3.73 (q, 1H, J=7 Hz), 7.36 (d, 2H, J=8 Hz), 7.52 (d, 2H, J=8 Hz); 19F NMR (CDCl3, relative to CFCl3)-63.2 ppm (s); IR (neat) 2963, 1712, 1619, 1419, 1327, 1264, 1232, 1166, 1124, 1072, 1019, 843 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:26]C)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC3C=CC=CC=3)=[C:13]([F:25])[CH:12]=1)[N:6]=[CH:5]2.B(Br)(Br)Br.O.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:25])[CH:12]=3)[N:6]=[CH:5][C:4]=2[C:3]=1[OH:26]
Reactant: COc1c(Br)ccc2c1cnn2-c1ccc(OCc2ccccc2)c(F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(-n2ncc3c(O)c(Br)ccc32)cc1F
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A solution of 5-bromo-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-4-(methyloxy)-1H-indazole (D20) (71 mg) in dry dichloromethane (2 mL) was cooled to −78° C. under argon and treated dropwise with boron tribromide solution (0.75 mL of 1M solution in dichloromethane, 0.75 mmol). The mixture was allowed to reach room temperature and was stirred overnight. Water and ethyl acetate were added and the pH of the aqueous layer was adjusted to 7 and the product was extracted into ethyl acetate. The extracts were dried (Na2SO4), concentrated and chromatographed (silica gel, 0-100% ethyl acetate in hexane) to give the title compound (E11) as a beige solid (40 mg)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[C:25]([O:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:33])[CH2:31][NH:32][C:19]([C:18]1[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)=[O:21])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC(=O)OC(C)(C)C)cn1
Yield: 81 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using glycine tert-butylester hydrochloride instead of 3-methoxypropylamine, to the title compound (111 mg, 81%) which was obtained as an off white foam. MS: m/e=424.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]#[C:23][CH3:24])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([C:5]2([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][N:8]([C:37]([C:33]3[S:32][CH:36]=[CH:35][CH:34]=3)=[O:38])[CH2:7][CH2:6]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)c3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
To a solution of 4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester (500 mg, 1.29 mmol) in methylene chloride (10 ml) was added triethylamine (261 mg, 2.58 mmol), thiophenylcarbonyl chloride (227 mg, 1.55 mmol) followed by a catalytic amount of dimethylaminopyridine. The resulting mixture was stirred for 15 hours at room temperature, quenched with water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 480 mg (81%) of the product as a solid. HR-MS: m/z Calculated for C22H23NO6S2 462.1040; Found 462.1039.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17]>C(O)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:17][C:16]2[CH:15]=[C:14]([Cl:13])[CH:20]=[C:19]([Cl:21])[CH:18]=2)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: CCO
Product: COC(=O)c1ccc(C=Nc2cc(Cl)cc(Cl)c2)cc1
Reaction time: 0.25 h

Procedure:
p-Carbomethoxybenzaldehyde (0.20 moles) was treated with 3,5-dichloroaniline (0.20 moles) with vigorous stirring in a 1 liter Erlenmeyer Flask. After 15 mins., 33 cc. of 95% ethanol was added and the reaction mixture was stirred vigorously for an additional 5 minutes. The reaction mixture was left standing at room temperature for 10 min.; then it was placed in an ice bath for 0.5 hours. The crystals which formed were collected, washed with 95% ethanol, and air-dried. Recrystallization from 85% ethanol gave N-(p-carbomethoxybenzylidene)-3,5-dichloroaniline.
Reaction SMILES: [OH-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[C:16]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]1[CH2:12][N:13]([CH3:23])[CH2:14][CH2:15]2>C(O)CO>[OH:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14][N:13]([CH3:23])[CH2:12]1
Reactant: CN1CCC2(c3ccccc3)OC2C1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: CN1CCC(Sc2ccccc2)(c2ccccc2)C(O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
9.6 Ml of 10% sodium hydroxide solution was added to a solution of 2.46 ml (0.024 mole) of thiophenol in 15 ml of ethylene glycol and the resulting solution stirred at room temperature for five minutes. 1.9 G (0.01 mole) of 3,4-epoxy-1-methyl-4-phenyl-piperidine was added with stirring to the above solution and the resulting solution stirred at room temperature for a further one hour. A solid began to separate after five minutes. The solid was filtered and suspended in acetone. Filtration of the solid gave 2.6 g of 3-hydroxy-1-methyl-4-phenyl-4-phenylthio-piperidine as a white solid having a melting point of 217°-9° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]([OH:22])[CH2:20][OH:21])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1.COC(OC)(C)C>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:20][O:21][C:23]([CH3:28])([CH3:24])[O:22]4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C(O)CO)cnc21
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CC1(C)OCC(c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)O1
Yield: 785.9 %

Procedure:
A solution of 1-(1-benzenesulfonyl-pyrrolo[2,3-b]pyridine-5-yl)-ethane-1,2-diol (2.1 g, 6.61 mmol), p-toluene sulfonic acid (134 mg, 0.71 mmol) and 2,2-dimethoxy-propane (10 mL) in dichloromethane (20 mL) was stirred at 25° C. for 12 h. The solution was then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (2.0 g, 85%) as a white solid: LC/MS m/e calcd for C18H19N2SO4 [M+H]+ 359.42, observed 359.3; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 3H), 1.56 (s, 3H), 3.73 (dd, J=7.5 Hz, 8.3 Hz, 1H), 4.35 (dd, J=6.4 Hz, 8.3 Hz, 1H), 5.16 (dd, J=6.4 Hz, 7.5 Hz, 1H), 6.60 (d, J=4.0 Hz, 1H), 7.49 (m, 2H), 7.58 (m, 1H), 7.75 (d, J=4.0 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 8.19 (d, J=7.6 Hz, 2H), 8.42 (d, J=2.0 Hz, 1H).