Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C2C(=CC=C(N[C:14](=[O:27])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)C=2)C(C)(C)C1)(=O)C.C(N1C2C(=CC=C([N+]([O-])=O)C=2)C(C)(C)C1)(=[O:32])C.O.O.[Sn](Cl)Cl.Cl>C(OCC)C>[C:23]([C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:14]([OH:27])=[O:32])=[CH:22][CH:21]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(=O)N1CC(C)(C)c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)/C=C/c3ccc(C(C)(C)C)cc3)cc21
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2E)-N-(1-Acetyl-3,3-dimethylindolin-6-yl)-3-[4-(tert-butyl)phenyl]prop-2-enamide. To a solution of 1-acetyl-3,3-dimethyl-6-nitroindoline, Example 31(c), (110 mg, 0.47 mmol) in ethyl ether (3 mL), magnetically stirred in a round-bottomed flask at 0° C., was added tin (II) chloride dihydrate (0.67 g, 2.96 mmol, Aldrich) and cond HCl (0.3 mL). The reaction mixture was stirred at 0° C. for 10 min, allowed to warm to 25° C. then stirred at that temperature overnight. The reaction mixture was washed with 10 N NaOH (10 mL), extracted with EtOAc and concentrated in vacuo. Analogous to the procedure used to prepare Example 1, the crude product and 4-tert-butyl-trans-cinnamic acid (92 mg, 0.45 mmol, EMKA-Chemie) provided, after purification by silica gel chromatography (2:3 hexane:EtOAc), the title product. MP 121° C. MS (ESI, pos. ion) m/z: 391 (M+1).
Reaction SMILES: P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:20]Br.[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35]O)=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:22]([CH:28]([O:39][SiH:40]([CH3:42])[CH3:41])[CH2:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][Br:20])=[CH:32][CH:31]=1)([CH:25]([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: BrBr
Reactant: CC(C)C(C)(C)C(Cc1ccc(CCO)cc1)O[SiH](C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)C(C)(C)C(Cc1ccc(CCBr)cc1)O[SiH](C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
To a stirred solution of (C6H5)3P (9.03 g, 34.4 mmol) in 220 ml of toluene at 0° C. was added bromine (1.76 ml, 34.4 mmol) over 10 minutes. To this stirred slurry was then added a solution of p-(2-thexyldimethylsilyloxyethyl)phenethyl alcohol (10.6 g, 34.4 mmol) and pyridine (2.78 ml, 34.4 mmol) in 50 ml of toluene over 10 minutes. This mixture was stirred at room temperature for 4 hours and diluted with 300 ml of saturated NaHCO3 solution. The resulting mixture was extracted with ether (4×300 ml). The combined ether extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated in 200 ml of hexane-ether 4:1 and filtered. The filtrate was concentrated and distilled under vacuum to give 9.9 g of p-(2-thexyldimethylsilyloxyethyl)phenethyl bromide (78%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-methoxy-propan-1-ol (300 g, 3.3 mol) in anhydrous CH2Cl2 (3 L) was added triethylamine (790 mL, 5.7 mol). The mixture was cooled to 0° C. and methanesulfonyl chloride (376 mL, 4.8 mol) in anhydrous CH2Cl2 (1 L) added dropwise. After stirring for 2 h at rt, the mixture was washed with water and brine, dried and evaporated to give the crude product as an oil (540 g, yield 96%) that was used in the next step without purification. 1H NMR (400 MHz, CDCl3): δ 3.40-3.37 (t, J=6.0 Hz, 2H), 2.55-2.52 (t, J=6.0 Hz, 2H), 2.40 (s, 3H), 2.06 (s, 3H), 1.08-1.02 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.C([Li])CCC.[C:21]1(=[O:26])[O:25][CH2:24][CH2:23][CH2:22]1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][OH:26])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: O=C1CCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(cc1OC)CCN(C(=O)CCCO)CC2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 6.0 g (29 mmol) of 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine in 30 mL of THF, at 0° C., there are added, dropwise, over 15 minutes, 11.6 mL (29 mmol/1 eq.) of 2.6M n-butyl lithium solution in hexane. The mixture is then cooled to about −78° C. and poured dropwise, over 10 minutes, into a solution of 2.7 mL (34.8 mmol/1.2 eq.) of gamma-butyrolactone in 15 mL of THF. Stirring is carried out at −78° C. for 30 minutes and the temperature is then brought to −30° C. and held there for 1 hour; the temperature is then allowed to return to ambient temperature, where stirring is carried out for 48 hours. The mixture is poured into 75 mL of saturated aqueous ammonium chloride solution and is then extracted twice with 120 mL of ethyl acetate. The combined organic phases are washed with 150 mL of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is taken up in 300 mL of ethyl acetate and washed twice with 75 mL 1M aqueous hydrochloric acid solution. The combined aqueous acid phases are re-extracted twice with 100 mL of dichloromethane. The organic phases are combined, dried over magnesium sulphate and concentrated to yield the desired product.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].O>CS(C)=O>[CH3:13][C:11]1[N:12]=[C:5]2[C:4]([O:3][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)=[CH:9][CH:8]=[CH:7][N:6]2[CH:10]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1cn2cccc(O)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn2cccc(OCc3ccc([N+](=O)[O-])cc3)c2n1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.3 g) was added portionwise to a suspension of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (1.0 g) in dimethyl sulfoxide (10 ml) at room temperature over a period of 15 minutes. After being stirred for 30 minutes, 4-nitrobenzyl bromide (1.6 g) was added in one portion to the mixture and then the resultant mixture was stirred for 24 hours at room temperature. The mixture was poured into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel (30 g) with methylene chloride as an eluent to afford a solid, which was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-methyl-8-(4-nitrobenzyloxy)imidazo[1,2-a]pyridine (0.77 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][CH2:23][CH2:24][OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:22][CH2:23][CH2:24][OH:25])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NCCO)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 3 (100 mg, 0.35 mmol) was reacted with 2-aminoethanol (CAS 141-43-5) (43 mg, 0.7 mmol), HATU (276 mg, 0.7 mmol) and DIPEA (0.30 mL, 1.8 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(2-hydroxyethyl)benzamide 7. LC/MS (ESI+): m/z 328 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])[CH2:4][CH:3]1[NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[H-].[Na+].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>O1CCCC1>[C:39]([O:38][C:36]([CH2:35][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]([CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH2:4][CH:3]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:2]1=[O:1])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(NC1CN(C(=O)C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)CN(C(=O)C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Under ice-cooling, 2-oxo-3-benzyloxycarbonylamino-5-cyclohexylcarbonyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (800 mg) was added to a suspension of 60% sodium hydride (152 mg) in tetrahydrofuran (50 ml), the mixture was stirred at room temperature for one hour. Subsequently, tert-butyl bromoacetate (390 mg) was added and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, Water was added to the residue and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodiun sulfate, and the mixture was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 640 mg of the title compound (Yield: 63%).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[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].Cl.[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=1)([CH3:50])([CH3:49])[CH3:48].C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C)C=O>[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[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])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:58][CH:57]=1)([CH3:49])([CH3:50])[CH3:48]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (210 mg), 4-(aminomethyl)benzoyl-glutamic acid di-t-butyl ester hydrochloride (144 mg), diethylphosphorocyanidate (75 mg) and triethylamine (93 mg) in dimethylformamide (10 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:2) to yield the title compound (328 mg, yield 99%) as a colorless wax-like substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)([O-:3])=[O:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27].N1C=CC=CC=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[CH:16]1[O:20][CH2:19][CH2:18][O:17]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1C1OCCO1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(c3ccc([N+](=O)[O-])c(C4OCCO4)c3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-Nitro-5-piperazinylphenyl)-1,3-dioxolane (6.63 g, 24 mmol) was added portionwise over 1 hour to a stirred solution of 3,4-dimethoxybenzoyl chloride (4.76 g, 24 mmol) and pyridine (4.04 g, 48 mmol) in dry dichloromethane (200 mL). The mixture was stirred overnight at room temperature, washed twice with water and concentrated in vacuo to provide 2-[2-nitro-5-[4-(3,4-dimethoxybenzoyl)piperazinyl]phenyl]-1,3-dioxolane used without further purification below.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C@H:11]([CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:17]([CH3:28])[CH:16]=1)=[O:13].CN1CCOCC1>C1COCC1>[NH:33]1[CH:34]=[C:30]([CH2:29][C@@H:11]([NH:10][C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)[N:31]=[CH:32]1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: Cc1cc(NC(=O)[C@H](N)Cc2c[nH]cn2)ccc1C(=O)N1CCCC1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1cc(NC(=O)[C@@H](Cc2c[nH]cn2)NC(=O)c2ccc(Br)s2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 10c from 5-bromo-thiophene-2-carboxylic acid and (R)-2-amino-3-(1H-imidazol-4-yl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propionamide with PPA and NMM in THF.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][C:13](=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(O)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Yield: 56.6 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (230 mg, 0.806 mmol) was dissolved in ethyl acetate (5 mL). Degussa wet (50 wt % water) 10% Pd/C (223 mg, 0.105 mmol) was added and the mixture was stirred in a hydrogenation reactor under 95 psi hydrogen for 3 h. The mixture was filtered through Celite®. The filtrate was concentrated and purified by silica gel flash chromatography to provide the title compound as a white solid (131 mg). LCMS m/z=288.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C@@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[C@@H:11]3[CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[O:22])[CH2:14][CH2:13][C@@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCC2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCC3)c1ccc(F)cc1
Temperature: 100 °C
Yield: 58.1 %

Procedure:
To a solution of (7aS,11aR)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.21 g, 1.0 mmol)) in 1,4-dioxane (7.0 mL) were added 4-chloro-4′-fluorobutyrophenone (0.40 g, 2.0 mmol), KI (catalytic amount) and K2CO3 (0.28 g, 2.0 mmol). The reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled to 20° C. then diluted with CHCl3. The solution was filtered to remove excess K2CO3 and the filtrate was concentrated in vacuo and chromatographed (silica gel, CHCl3:MeOH 98:2) to give the title compound (0.22 g, 58%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.75-2.20 (m, 7H), 2.20-2.35 (m, 1H), 2.35-2.48 (m, 2H), 2.48-2.60 (m, 1H), 2.60-2.78 (m, 3H), 2.78-2.90 (m, 1H), 2.99 (t, J=7.2 Hz, 2H), 3.05-3.15 (m, 1H), 3.18-3.32 (m, 2H), 6.62 (t, J=7.3 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.90-8.08 (m, 2H) ppm.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14](N)=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:25])=O.CN(C)C=O>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([Cl:25])=[O:15])=[CH:12][N:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Yield: 89 %

Procedure:
Heat 40 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide together with 290 ml of thionyl chloride and 1 ml of dimethylformamide for 16 hours at boiling point. Cool the resulting solution, draw off the formed precipitate and wash it with thionyl chloride and with carbon tetrachloride to obtain an 89% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxylic acid chloride [m.p. 208° to 210° C (from dioxane)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([OH:16])=O)[CH:4]=1.CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([NH:51][C:48]2[CH:49]=[CH:50][N:46]([CH3:45])[N:47]=2)=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)O)cc2c1OC(C)(C)C2
Reactant: Cn1ccc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2ccn(C)n2)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (24 g, 0.11 mol) in CH2Cl2(500 mL) were added EDCI (31.6 g, 1.08 mol), NMM (54.5 g, 0.54 mol), HOBt (22 g, 0.16 mol) and 1-methyl-1H-pyrazol-3-ylamine (11 g, 0.11 mol) sequentially. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/1) showed the reaction was complete. The mixture was washed with water (250 mL), sat. aq. citric acid (250 mL×2), sat. NaHCO3 (250 mL) and brine (250 mL) sequentially. The organic phase was dried over Na2SO4 and concentrated to give a white solid. The crude solid was purified by column chromatography (EtOAc/petroleum ether=1/10˜1/1) to give the title compound (9.6 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 7.49 (s, 1H), 7.44 (s, 2H), 6.48 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.96 (s, 2H), 1.35 (s, 6H).
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][C:20]3[CH:33]=[CH:32][C:23]([CH:24]=[C:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:31])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:20]3[CH:33]=[CH:32][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:31])=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)c4ccccc4)cc3)cc2)S1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCCc3ccc(OS(=O)(=O)c4ccccc4)cc3)cc2)S1
Yield: 48.6 %

Procedure:
1.5 g (3.1 mmole) 5-(4-[2-(4-(benzenesulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated on 1 g Pd/C (5%) in ethyl acetate and acetic acid (2.5%) at atmospheric pressure for 24 hours. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The starting material was not completely consumed, therefore the hydrogenation was restarted twice with Pd/C (10%), followed by purification by chromatography on silica gel using dichloromethane:methanol (95:5) as eluent to give 0.728 g (yield 48.6%) of the desired product.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:12](=O)[C:13]([C:28]#[N:29])=[CH:14][N:15](CC3C=CC(OC)=C(OC)C=3)[CH:16]=2)[CH:8]=[CH:9][CH:10]=1.[Li+].[Cl-:32]>O=P(Cl)(Cl)Cl>[Cl:32][C:12]1[C:13]([C:28]#[N:29])=[CH:14][N:15]=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][Cl:1])[CH:6]=1
Reactant: COc1ccc(Cn2cc(C#N)c(=O)c(-c3cccc(OCCCl)c3)c2)cc1OC
Reactant: [Cl-]
Agent: [Li+]
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cncc(-c2cccc(OCCCl)c2)c1Cl
Yield: 75.2 %

Procedure:
A solution of 5-[3-(2-chloroethoxy)-phenyl]-1-(3,4-dimethoxybenzyl)-4-oxo-1,4-dihydro-pyridine-3-carbonitrile (2.5 g, 5.9 mmol) and LiCl (2.3 g, 53 mmol) in 22 mL of POCl3 was heated at reflux for 2.5 h. The excess POCl3 was removed by concentrating in vacuo. The residue was dissolved in 100 mL CH2Cl2 and washed with ice-cold 3 N NaOH. The organic layer was separated, dried over anhydrous MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography on silica gel eluting with 30% EtOAc in hexanes to yield 1.3 g (75% yield) of 4-chloro-5-[3-(2-chloroethoxy)phenyl]nicotinonitrile as an off-white solid.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1.C([O-])(=[S:28])C.[K+].O>CC(N(C)C)=O>[SH:28][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:25])[C:13]([N:22]([CH3:24])[CH3:23])([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])=[CH:8][CH:7]=1
Reactant: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCI)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)C(C)(Cc1ccccc1)C(=O)c1ccc(NCCCS)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6.6 g (0.015 mol) of 1-[4-(3-Iodopropylamino)phenyl]-2-dimethylamino-2-benzyl-propan-1-one are dissolved in 50 ml of dimethylacetamide. To the solution are added 2.42 g of potassium thioacetate and heated up to 50° C. After the reaction mixture is stirred at 50° C. for 2 h, it is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is dissolved in 70 ml of ethanol and the solution is bubbled by nitrogen for 30 min. to remove oxygen. To the solution are added 7 ml of 2 N sodium hydroxide solution and stirred at 0° C. for 30 min. After the reaction mixture is neutralized by adding 2 N hydrochloric acid solution, the resulting solution is poured into 100 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After ethyl acetate is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:2) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 1.14 (s, 3H), 1.43 (t, 1H), 1.97 (m, 2H), 2.33 (s, 6H), 2.68 (q, 2H), 2.96 (d, 1H), 3.34-3.39 (m, 2H), 3.42 (d, 1H), 4.18 (br, 1H), 6.57 (d, 2H), 6.89-6.92 (m, 2H), 7.10-7.12 (m, 3H), 8.46 (d, 2H).