Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:21]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1.O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:21]1[N:26]=[C:25]([Cl:27])[CH:24]=[CH:23][N:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc(CSc2cccc3[nH]ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccnc(-n2ccc3c(SCc4ccccc4)cccc32)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.9 %

Procedure:
4-Benzylsulfanyl-1H-indole (5.00 g, 21 mmol) (Can. J. Chem. 1962, 40, 511) was slowly added to a suspension of NaH (60% dispersion in mineral oil, 1.37 g, 34 mmol) in DMF (40 mL) at 0° C. The reaction mixture was stirred for 15 min until the gas evolution ceased, then 2,4-di-chloropyrimidine (3.03 g, 20 mmol) was added portionwise, followed by an additional aliquot of DMF (10 mL). The resulting mixture was slowly warmed to RT, then poured onto a slurry of ice and water and extracted with EtOAc. The organic layer was washed twice with a mixture of water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexanes, gradient from 10:90 to 50:50) to give 4-benzylsulfanyl-1-(4-chloropyrimidin-2-yl)-1H-indole (979 mg, 14% yield) as a pale-yellow waxy solid and a mixture of 4-benzylsulfanyl-1-(2-chloropyrimidin-4-yl)-1H-indole and the bisubstituted product (691 mg) after precipitation from DCM/EtOAc. This mixture was repurified by flash chromatography (EtOAc/hexanes, 20:80) to give 4-benzylsulfanyl-1-(2-chloropyrimidin-4-yl)-1H-indole (270 mg, 4% yield) as an off-white solid. MS=352 [M+H]+; MP=159.0-161.2° C.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([NH:36][CH2:37][CH:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[C:28]([N+:33]([O-])=O)[CH:29]=[N:30]2)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.ClCCl.CC[N+]1C=CC(C2C=C[N+](CC)=CC=2)=CC=1.[Br-].[Br-]>[CH2:15]([O:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27]([NH:36][CH2:37][CH:38]3[CH2:42][O:41][C:40]([CH3:44])([CH3:43])[O:39]3)=[C:28]([NH2:33])[CH:29]=[N:30]2)=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)OCC(CNc2c([N+](=O)[O-])cnc3cc(OCc4ccccc4)ccc23)O1
Agent: CC[n+]1ccc(-c2cc[n+](CC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)OCC(CNc2c(N)cnc3cc(OCc4ccccc4)ccc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of sodium dithionite (85% pure, 135.07 g, 659.42 mmol) and potassium carbonate (101.27 g, 732.73 mmol) in water (450 mL) was added dropwise to a mechanically stirred mixture of ethyl viologen dibromide (1.1 g, 2.93 mmol) and (7-benzyloxy-3-nitro-quinolin-4-yl)[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]amine (60.0 g, 146.54 mmol) in dichloromethane (500 mL) and water (50 mL). The reaction mixture was stirred at ambient temperature overnight and then diluted with water (600 mL) and stirred for an additional 10 minutes. The organic phase was separated and the aqueous layer was reextracted with dichloromethane (400 mL). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford 55.60 g of 7-benzyloxy-N4-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]quinoline-3,4-diamine as a brown foam. 1H-NMR (300 MHz, CDCl3) δ 8.38 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.51-7.28 (m, 6H), 7.18 (dd, J=9.2, 2.5 Hz, 1H), 5.16 (s, 2H), 4.35 (br s, 1H), 4.30-4.18 (m, 1H), 4.02 (dd, J=8.3, 6.5 Hz, 1H), 3.81 (br s, 2H), 3.68 (dd, J=8.3, 6.1 Hz, 1H), 3.60-3.46 (m, 1H), 3.40-3.25 (m, 1H), 1.52 (s, 3H), 1.37 (s, 3H); MS (APCI) m/z 380.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[N:8][C:7]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]=[CH:12][C:6]=2[C:5]=1O.FC(F)(F)S(N(C1C=CC=CC=1)S(C(F)(F)F)(=O)=O)(=O)=O.[N:44]1([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[C:5]([N:47]2[CH2:46][CH2:45][N:44]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:49][CH2:48]2)=[C:6]2[CH:12]=[N:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(Cn2ncc3c(O)c(Br)cnc32)cc1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
NaH (0.144 g, 3.59 mmol) in DMF (5 mL) was added dropwise to a solution of 5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-ol (1.00 g, 2.99 mmol) in dimethylformamide (“DMF”) (10 mL). The reaction mixture was warmed to 40° C. and stirred for 30 minutes. After cooling to room temperature, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.28 g, 3.59 mmol) was added and stirred at room temperature for 1 hour. tert-Butyl piperazine-1-carboxylate (1.23 g, 6.58 mmol) was then added. The mixture was warmed to 80° C. and stirred for 1 hour. The reaction was then cooled to room temperature, and a saturated ammonium chloride solution (30 mL) was added. The reaction mixture was extracted with ethyl acetate (2×20 mL) and dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (hexane:ethyl acetate, 5:1) to give tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.23 g, 82%) as a solid. MS ESI (+) m/z 504.3 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.42 (s, 1H), 8.28 (s, 1H), 7.17 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 5.48 (s, 2H), 3.66 (s, 3H), 3.49 (m, 8H), 1.40 (s, 9H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:21]2[N:25]3[CH2:26][CH2:27][CH2:28][C:29]([C:39]([OH:42])([CH3:41])[CH3:40])([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=4)[C:24]3=[N:23][N:22]=2)[CH:12]=[CH:13][C:14]=1[C:15]1[O:19][C:18]([CH3:20])=[N:17][CH:16]=1)C1C=CC=CC=1>CO.[C].[Pd]>[F:38][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[F:37])[O:30][C:29]1([C:39]([OH:42])([CH3:41])[CH3:40])[CH2:28][CH2:27][CH2:26][N:25]2[C:21]([C:11]3[CH:12]=[CH:13][C:14]([C:15]4[O:19][C:18]([CH3:20])=[N:17][CH:16]=4)=[C:9]([OH:8])[CH:10]=3)=[N:22][N:23]=[C:24]12
Reactant: Cc1ncc(-c2ccc(-c3nnc4n3CCCC4(Oc3ccc(F)c(F)c3)C(C)(C)O)cc2OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: Cc1ncc(-c2ccc(-c3nnc4n3CCCC4(Oc3ccc(F)c(F)c3)C(C)(C)O)cc2O)o1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 69 %

Procedure:
A mixture of 2-{3-[3-(benzyloxy)-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-8-(3,4-difluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol (100 mg) and 5% palladium-carbon (100 mg) in methanol (1.5 mL) was stirred at room temperature for 45 min under a hydrogen atmosphere. The mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (58.1 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9](=O)[N:8]=[C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:6][C:5]=2[N:19]=1.P(Cl)(Cl)([Cl:22])=O.CN(C)C1C=CC=CC=1>CO.ClCCl>[Cl:22][C:9]1[C:4]2[S:3][C:2]([NH2:1])=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc2[nH]c(SCc3ccccc3)nc(=O)c2s1
Solvent: CO
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reaction time: 2 h

Procedure:
The product from step (b) (0.89 g), phosphorus oxychloride (12 ml) and N,N-dimethylaniline (1.2 ml) were heated at reflux for 2 hours. The cooled reaction mixture was poured onto ice water and stirred for 2 hours. Chromatography (SiO2, methanol/dichloromethane as eluant) gave the sub-title compound.
Reaction SMILES: CC1C2C(C)(C)C(C2)CC=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:12][CH3:13].C(=O)C.OC(C(O)(C)C)(C)C.[Cl:29][C:30]1[N:35]=[C:34](Cl)[CH:33]=[CH:32][N:31]=1.[F-].[Cs+].C(=O)([O-])O.[Na+]>C1COCC1.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([O:15][C:11](=[O:14])[CH2:12][CH2:13][C:32]1[CH:33]=[CH:34][N:35]=[C:30]([Cl:29])[N:31]=1)[CH3:17]
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(O)C(C)(C)O
Agent: CC1=CCC2CC1C2(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a stirred solution of borane dimethyl sulphide complex (1.42 ml, 15 mmol) in THF at 0° was added dropwise α-pinene (5 ml, 31.5 mmol). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to −35° and ethyl propionate (1.47 g, 1.52 ml, 15 mmol) added dropwise. The reaction mixture was stirred at room temperature for 2 h and then cooled to 0°. Acetaldehyde (5 ml, 3.94 g, 89 mmol) was added dropwise. The reaction mixture was heated to reflux for 1 h. Upon cooling the solvent and volatiles were removed by evaporation in vacuo. The residue was dissolved in THF (50 ml) and pinacol (1.8 g, 18 mmol) added. The reaction mixture was stirred for 1 h at room temperature. The solvent and volatiles were removed by evaporation in vacuo. To the crude product was added 2,4-dichloropyrimidine (2.24 g, 15 mmol) followed by cesium fluoride (4.56 g, 30 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.88 g, 0.75 mmol). The reaction mixture was diluted with dioxane (50 ml) and heated under reflux for 3 h. Upon cooling the reaction mixture was poured into saturated sodium hydrogen carbonate solution (100 ml) and extracted twice with dichloromethane (100 ml). The combined organic fractions were dried over magnesium sulphate, filtered and the solvent removed by evaporation in vacuo. Purification by flash column chromatography (diisopropylethersilica) gave the title compound (1.59 g, 50%). 1H NMR (CDCl3) δ 6.78 (1H, d, J 12 Hz), 6.62 (1H, d, J 12 Hz), 4.22 (2H, q, J 8 Hz) and 1.21 (3H, t, J 8 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].S(Cl)([Cl:35])=O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:35])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Solvent: CN(C)C=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12

Procedure:
The 3-halo-3-cephem esters represented by the above formula II when Y is chloro or bromo are also prepared with the 3-hydroxy-3-cephem esters as described by R. R. Chauvette et al., J. Amer. Chem. Soc., 96, 4986 (1974). For example, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate is reacted with thionyl chloride in dry DMF to yield p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-chloro-3-cephem-4-carboxylate.
Reaction SMILES: Cl.[C:2]([CH2:7][NH2:8])(=[O:6])[CH:3]([CH3:5])[CH3:4].C(=O)(O)[O-].[Na+].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:8][CH2:7][C:2](=[O:6])[CH:3]([CH3:5])[CH3:4])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)C(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C(=O)CNC(=O)c1ccc(F)cc1
Yield: 89.4 %

Procedure:
4.0 g of isobutyrylmethylamine hydrochloride, 6.1 g of sodium bicarbonate and 5.1 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(4). 5.8 g of N-(4-fluorobenzoyl)isobutyrylmethylamine are thereby obtained. Yield: 89.2%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([N+:14]([O-])=O)[CH:13]=1>[Pd].C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C:11]([NH2:17])=[C:12]([NH2:14])[CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(-c2ccncc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A suspension of 3″-fluoro-5′-nitro-3,2′:3′,4″-terpyridin-6′-amine (2.25 g, 7.23 mmol) and 10% palladium on carbon (0.4 g) in a mixture of THF/ethanol 40:60 (100 mL) was stirred under hydrogen atmosphere. After 3 h, the mixture was filtered through Celite® and the filter cake was washed with ethanol. The combined filtrate and washings were evaporated to give the title compound as a solid (2.01 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([O:13][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:11]=[CH2:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=C[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
A solution of (3S,4S)-N-[(tertbutyloxy)carbonyl]-4-amino-3-hydroxy-5-phenyl pentene [prepared by the method of Hanson et al, J. Org. Chem., 50, 5399 (1985)] (10.0 g, 64.5 mmol), imidazole (9.14g, 13 mmol), and chlorotriisopropylsilane (12.44 g, 43.3 mmol) in anhydrous DMF (40 mL) was stirred for 5 days at room temperature under an N2 atmosphere. The solution was poured into H2O (500 mL) and extracted with Et2O (2×25 mL). The combined organic layers were washed with H2O (250 mL), a 0.5M citric acid solution (2×120 mL), a 5% KHCO3 solution (2×100 mL), and brine (2×100 mL). After the organic layer was dried over MgSO4, the filtrate was concentrated and purified by medium pressure column chromatography (silica gel, 10% ethyl acetate in hexane, Rf 0.23) to give 12.9 g (82 % yield) of the title compound as a clear, colorless oil. 1H and 13C NMR spectral data were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([O:23]CC4C=CC(OC)=CC=4)[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]=[O:35])[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:36]1([C:42]#[C:43][Mg]Br)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>C1COCC1>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[C:13]([N:17]3[CH:22]=[C:21]([OH:23])[C:20](=[O:33])[CH:19]=[C:18]3[CH:34]([OH:35])[C:43]#[C:42][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:14]=[CH:15][CH:16]=2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(COc2cn(-c3cccc(-c4c(Cl)cnc5[nH]ccc45)c3)c(C=O)cc2=O)cc1
Reactant: Br[Mg]C#Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1cc(C(O)C#Cc2ccccc2)n(-c2cccc(-c3c(Cl)cnc4[nH]ccc34)c2)cc1O
Reaction time: 0.08 h

Procedure:
To a solution of 0.05 g (0.01 mmol) 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-phenyl]-5-(4-methoxy-benzyloxy)-4-oxo-1,4-dihydro-pyridine-2-carbaldehyde in 3 mL THF at −40° C. was added 1 mL phenylethynylmagnesium bromide (1.0 M in THF). The reaction mixture was stirred at −40° C. for 30 min before 1 mL of water was added. The reaction was gravity filtered through an Isolute HM-N tube, which was rinsed with 4 mL EtOAc and the combined organics were concentrated. The resulting residue was dissolved in 1 mL TFA and allowed to stand at room temperature for 5 min before being concentrated. Purification by automated mass-guided HPLC afforded 1-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]-5-hydroxy-2-(1-hydroxy-3-phenylprop-2-yn-1-yl)pyridin-4(1H)-one. Compound exhibits equilibrating rotational isomerism in solution. Reported NMR data correlates to the major rotational isomer. 1H NMR (500 MHz, CD3OD, 0° C.): δ 8.26 (s, 1H); 7.96 (s, 1H); 7.89-7.78 (m, 3H); 7.71 (t, J=8.59 Hz, 1H); 7.50 (d, J=3.49 Hz, 1H); 7.41-7.36 (m, 5H); 6.34 (d, J=3.46 Hz, 1H); 5.45 (s, 1H). HRMS (FT/ICR) Calc (M+H)+ 468.1109. Found 468.1109.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[C:35](F)=[N:36][CH:37]=[CH:38][CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH:21]1[C:22]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[C:35]([N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[N:36][CH:37]=[CH:38][CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:15]4[C:24]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: C1CCNC1
Reactant: OC1(c2cccnc2F)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2N2CCCC2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled solution (0° C.) of pyrrolidine (0.417 mL, 5.00 mmol, 5 eq) in tetrahydrofuran (10 mL) under nitrogen was added n-butyllithium (2.5M in hexane, 1.92 mL, 4.80 mmol, 4.8 eq). This was followed by 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)-piperidin-4-ol (described in example 58) (0.400 g, 1.00 mmol) in tetrahydrofuran (10 mL). The bath was removed and the solution warmed to room temperature over 1.5 h. No reaction was evident after stirring for 18 h. To accelerate the reaction, 18-crown-6 (0.528 g, 2.00 mmol, 2.0 eq) was added and the solution was heated to 60° C. for 5 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (35 mL, eluent: 50% ethyl acetate in hexane) to yield 0.450 g (quantitative) of the title compound. TLC analysis (Rf 0.23, 50% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 8.35 (dd, J=1.7, 4.6 Hz, 1H), 7.63 (dd, J=1.8, 7.9 Hz, 1H), 7.22 (m, 4H), 7.12 (dd, J=7.9, 4.6 Hz, 1H), 6.93 (m, 4H), 4.27 (br s, 1H), 3.48 (s, 2H), 3.21 (m, 4H), 2.85 (m, 2H), 2.76 (m, 2H), 2.63 (d, J=1.3 Hz, 2H), 2.01 (m, 6H), 1.70 (m, 2H) MS (CI, CH4) m/z 452 (M+1,100), 480 (M+29,12), 434 (16). The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (60° C., 16 pascal, 18 h) to yield a white solid, mp 249°-253° C.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11]2=[O:18].O1CCCC1>C(N(CC)CC)C>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:12](=[O:17])[C:11]2=[O:18]
Reactant: CCOC(=O)Cl
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)C(=O)c2cc(Cl)ccc21

Procedure:
Ethoxycarbonyl chloride (10.5 ml) is added dropwise to a mixture of 5-chloroisatin (18.16 g), tetrahydrofuran (180 ml) and triethylamine (15.3 ml) with stirring, and the mixture is stirred at room temperature for 5 minutes. The mixture is concentrated under reduced pressure to remove solvent, and water is added to the residue. Crystalline precipitates are collected by filtration, washed with isopropanol and isopropyl ether and then dried, whereby 5-chloro-1-ethoxycarbonylisatin (23.3 g) is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=O.Cl.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([C:13](=[O:15])[CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:27][CH2:26]1
Reactant: Cc1ccc2[nH]cc(CCC(=O)O)c2c1
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Product: COc1ccccc1N1CCN(C(=O)CCc2c[nH]c3ccc(C)cc23)CC1

Procedure:
Prepared from 5-methyl-1H-indole-3-propanoic acid (Description 24) and-(2-methoxyphenyl)piperazine hydrochloride according to the method of Description 25. 1H NMR (360 MHz, CDCl3) δ7.89 (1H, br s), 7.40 (1H, s), 7.24 (1H, d, J 8.3 Hz), 7.04-7.00 (3H, m), 6.94-6.81 (3H, m), 3.86 (3H, s), 3.81 (2H, t, J 5.0 Hz), 3.53 (2H, t, J 5.0 Hz), 3.13 (2H, t, J 7.6 Hz), 2.96 (2H, t, J 5.0 Hz), 2.80 (2H, t, J 5.0 Hz), 2.77-2.73 (2H, m), and 2.46 (3H, s).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH3-]C#[N:29].[Na+].[BH4-].[Na+]>CO.O.C(O)=O>[NH2:29][CH2:1][C:3]1[S:7][C:6]([C:8]2[N:9]=[N:10][O:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2conn2)s1
Reactant: [BH3-]C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: NCc1ccc(-c2conn2)s1
Reaction time: 16 h

Procedure:
To a solution of the 5-formyl-thiophen-2-yl-oxadiazol derivative (1 eq., usual scale 0.02-0.25 mmol) and the appropriate amine (2-40 eq.) in methanol (24 mL/mmol), sodium triacetoxy borohydride (NaBH(OAc)3) (10 eq.) is added. The mixture is stirred for 2 h before NaBH3CN (10 eq.) is added. Stirring of the suspension is continued for 16 h before NaBH4 (20 eq.) is added and stirring is continued for another 16 h at rt. The reaction mixture is diluted with water (4 mL/mmol) and formic acid (4 mL/mmol) and the resulting solution is separated by prep. HPLC (Waters Symmetry C18 19×50 mm, 5 μm, 10 to 95% acetonitrile in water containing 0.5% HCOOH) to give the desired 5-aminomethyl-thiophen-2-yl-oxadiazol derivative as a colourless to pale yellow resin.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=O)[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:34]1([CH2:40][SH:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([C:10](=[O:12])[S:41][CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3]2
Reactant: SCc1ccccc1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(SCc1ccccc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.1 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (55 mg, 0.29 mmol), EDC (83 mg, 0.43 mmol), and HOBT (65.9 mg, 0.43 mmol) were dissolved in dry THF (5 ml) under a nitrogen atmosphere. Triethylamine (140 μl, 1.00 mmol) and phenylmethanethiol (37.1 μl, 0.32 mmol) were dissolved in dry THF (2 ml) and then added to the reaction mixture. The resulting suspension was stirred at room temperature overnight. The mixture was evaporated, and the crude partitioned between EtOAc and water. The organic phase was washed with saturated NaHCO3, dried over sodium sulfate, filtered, and evaporated under vacuum to obtain S-benzyl quinuclidine-3-carbothioate (110 mg, crude), which was used in the next step without any further purification.