Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[N:10]([CH2:17][CH:18]=C)[CH:11](C)[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH2:1]([O:8][C:9]([N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH:17]1[CH3:18])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(C)N(CC=C)C(=O)OCc1ccccc1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CC1CCC=CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19 mmol) was dissolved in CH2Cl2 (10 ml) and a stream of argon gas was bubbled into the reaction mixture for 10 minutes. Then bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added and the reaction mixture was refluxed for 2 h. Additional bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (mg, 0.0108 mmol) was added and the reaction mixture was refluxed for an additional 1.5 hours. The reaction was cooled to RT under argon overnight, then was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 5% EtOAc/hexanes) to give the title compound (0.72 g, 92%): 1H NMR: 7.35-7.20 (m, 5H), 5.65 (1H, m), 5.13 (2H, AB), 4.45-4.05 (m, 2H), 3.56 (1H, d), 2.25-2.10 (m, 2H), 1.90-1.60 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=246.2.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:19][NH:20][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1]
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Reactant: NCc1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Yield: 42.6 %

Procedure:
A mixture of 2,2,2,2′,4′-pentafluoroacetophenone (1.05 g, 5.0 mmol), 3,5-dichlorobenzylamine (0.88 g, 5.0 mmol), N,N-diisopropylethylamine (1.7 mL, 10.0 mmol) and acetonitrile (25 mL) was heated at reflux for 18 h, cooled and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes as eluent to yield the title compounds as a yellowish solid (0.78 g, 43%). 1H NMR (400 MHz, CDCl3): δ 9.28 (br s, 1H), 7.88 (m, 1H), 7.34 (s, 1H), 7.22 (s, 2H), 6.44 (m, 1H), 6.30 (dd, 1H), 4.43 (d, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13](=O)[CH2:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na].C(O)(=O)C.[NH3:22]>>[N:1]1([C:7]2[CH:8]=[C:9]([CH:13]([NH2:22])[CH2:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N
Reactant: CCC(=O)c1cccc(N2CCOCC2)c1
Agent: [Na]
Solvent: CC(=O)O
Product: CCC(N)c1cccc(N2CCOCC2)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-morpholin-4-yl-phenyl)propan-1-one (4.06 g, 18.5 mmol), powdered 3A molecular sieves (4 g), in ammonia (2.0 M solution in methanol) (61.2 mL) was stirred in sealed vessel at 65° C. for 2 hours, at which time sodium cyanoboronhydride (2.33 g, 37 mmol) and glacial acetic acid (8.47 mL) was added and the mixture was stirred at 65° C. for another 2 hours. After cooling down, the reaction mixture was filtered to remove molecular sieves and the filtrate was concentrated under vacuum. Solids was re-dissolved in dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (15 mL). The aqueous layer was extracted with dichloromethane (2×25 mL) and the combined organic layer was dried over magnesium sulfate, and concentrated under vacuum. The crude pale yellow oil was purified by Biotage flash chromatography with 90:10:10 dichloromethane:methanol:triethylamine to afford the title compound as a pale yellow clear oil (2.56 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.[Br:32]CCBr>CCOCC>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][C:15]=2[Br:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCBr
Reactant: COc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: COc1cc(Br)c2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
To 1-(tert-Butoxycarbonyl)-5-methoxyindoline (2.0 g) and TMEDA (1.57 mL, 1.3 eq.) in ether (40 mL) at −78° C. was added sec-BuLi (7.4 mL, 1.2 eq.). The reaction was warmed to −40° C. for 2 hours and then cooled to −78° C. 1,2-dibromoethane (2.07 mL, 3 eq.) was added and the reaction stirred for 45 minutes at −78° C. The bath was then removed and the reaction was stirred for 1 hour. The reaction was quenched with water and extracted with ether. The ether was washed with brine, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel, using hexane/ethyl acetate (19:1) as eluent, affording 1-(tert-butoxycarbonyl)-7-bromo-5-methoxyindoline (1.16 g).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25](=[O:28])[CH:26]=[CH2:27])[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[BrH:29].C(OC(C)C)(C)C>C(O)(=O)C>[Br:29][CH2:27][CH2:26][C:25]([C:23]1[N:22]=[CH:21][NH:20][CH:24]=1)=[O:28]
Reactant: C=CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Br
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: O=C(CCBr)c1c[nH]cn1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
1-(1-Trityl-1H-imidazol-4-yl)-2-propen-1-one (29.0 g) was dissolved in acetic acid (130 ml) and the mixture was cooled to 10° C. A 25% solution of hydrogen bromide in acetic acid (100 ml) was added and the mixture was stirred at room temperature for 2 h. Isopropyl ether was added to the reaction mixture and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (22.3 g) as a pale yellow powder.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH2:24])[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11]1.CC(C)([O-])C.[Na+].CCOCC>C1COCC1>[O:10]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)=[CH:11]1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Reactant: O=C(O)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
A solution of nicotinic acid (74 mg, 0.6 mmol, 1.2 eq.) and 1,1-carbonyldiimidazole (122 mg, 0.75 mmol, 1.5 eq.) in dry THF (1 mL) was stirred for 45 min. at rt. In parallel, a solution of 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and sodium tert-butoxide (96 mg, 1.0 mmol, 2.0 eq.) in dry THF (2 mL) was stirred for 45 min. at rt. The two solutions were then combined and the reaction mixture was stirred overnight at rt. Et2O was then added and the precipitate obtained was filtered, washed with Et2O, THF, a 5N solution of NaOH and water. It was resuspended in an acidic aqueous solution (pH 1) and filtered to give the title compound as a white powder (52.4 mg, 31%). HPLC, Rt: 1.98 min. (purity 95.1%). LC/MS, M+(ESI): 306.1, M−(ESI): 304.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]([Cl:22])=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:22].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1ccccc1F
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Fc1ccccc1/C=C/c1nc2ccccc2n1-c1ccccn1

Procedure:
Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-2-fluorocinnamoyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull, 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate/ethanol yielded the titled compound. MW: 351.81; mp: 226.0-228.0° C.; 1H-NMR (DMSO) δ: 8.92-8.87 (1H, m), 8.39-8.29 (1H, m), 8.29 (1H, d, J=16.1 Hz), 7.99-7.79 (4H, m), 7.70-7.51 (4H, m), 7.44-7.31 (3H, m).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+].O>CO>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)ncc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (17.82 g, 78.2 mmol) in methanol (100 mL) stirred at 0° C. was added solid sodium methoxide (4.22 g, 78 mmol) portionwise during 5 minutes. The reaction mixture was stirred at 23° C. overnight. To the organic phase was added water (25 mL) and the methanol was removed. Then it was extracted with dichloromethane. The organic phase was dried over sodium sulphate and evaporated in vacuo to give the title compound as a white solid (17.2 g, 67.6 mmol, 86 yield). LC/MS [M+H]+=223/225.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:34])([F:33])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C(Cl)Cl>[F:34][C:9]([F:8])([F:33])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][CH2:18][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(C(F)(F)F)cc3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(N2CCC3(CCNC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(4-(trifluoromethyl)phenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.47 mmol, 1.0 eq.) in methylene chloride (3 ml) and the reaction mixture was stirred at 25° C. for 1 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-23).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1)[CH3:22]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][N:23]([CH2:21][CH3:22])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1)[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: CCNc1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN(CC)c1cccc(C)c1
Temperature: 95 °C
Reaction time: 17 h

Procedure:
4-Bromobutyric acid ethyl ester (17.1 ml), potassium carbonate (20.5 g), and DMF (80 ml) were added to N-ethyl-m-toluidine (8 g), and the mixture was stirred at 95° C. for 17 hours. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (14.1 g).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:20][NH2:21])[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:28][CH2:29][CH2:30][CH2:31][S:32](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:34])=[O:33]>>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:21][CH2:20][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:18][S:17][CH2:1][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])(=[O:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)n1nnc(C)n1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1

Procedure:
3-Hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)propylamine IVh1 is allowed to react and worked up by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: CC([NH2:9])C1C=CC=CC=1.[OH:10][C:11]([CH:13]([C:15]1[CH:28]=[CH:27][CH:26]=[C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:16]=1)[CH3:14])=O>>[CH3:14][CH:13]([C:11]([NH2:9])=[O:10])[C:15]1[CH:16]=[C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Reactant: CC(N)c1ccccc1
Product: CC(C(N)=O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
The basic phase is acidified and is then extracted with chloroform. After forming the R (+) α-methylbenzylamine derivative of ketoprofen, analysis of the mixture of the two diastereoisomers by high performance liquid chromatography shows that the enantiomeric excess of S (+) ketoprofen is 93%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:10]2[CH2:33][NH:34][C:35]([CH3:37])([CH3:36])[C:9]2=[N:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[F:47][C:48]1[CH:49]=[C:50]([S:55](Cl)(=[O:57])=[O:56])[CH:51]=[C:52]([F:54])[CH:53]=1>ClCCl>[CH2:2]([O:4][C:5]([N:7]1[C:11]([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[C:10]2[CH2:33][N:34]([S:55]([C:50]3[CH:49]=[C:48]([F:47])[CH:53]=[C:52]([F:54])[CH:51]=3)(=[O:57])=[O:56])[C:35]([CH3:36])([CH3:37])[C:9]2=[N:8]1)=[O:6])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CNC2(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc2c(c1NC(=O)c1ccccc1CN1C(=O)c3ccccc3C1=O)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride (1.24 g, 2.4 mmol) in dry dichloromethane (30 mL) was added N,N-diisopropylethylamine (1.67 mL, 9.6 mmol) and 3,5-difluorobenzenesulfonyl chloride (0.77 g, 3.6 mmol). After stirring at room temperature for 3 hours the mixture was diluted with dichloromethane (50 mL), washed with 1N HCl, water, saturated solution of NaHCO3, brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel eluting with ethyl acetate and then with dichloromethane/methanol 98:2 affording the title compound as white solid (1.4 g).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23.C([Li])CCC.CN(C)[CH:47]=[O:48]>O1CCCC1.CCCCCC>[CH:47]([C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23)=[O:48]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(CCC)[C@@H]1Cc2c(C=O)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (-)(2aR,4S)-6-bromo-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (6.8 g, 12 mmol) in 100 ml of tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 1 hour. Dimethylformamide (3 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and then extracted with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to provide 5.6 g of the above-titled compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:15]2[C:10](=[N+:11]([O-])[CH:12]=[CH:13][CH:14]=2)[S:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])[CH3:2].P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][C:12]1[N:11]=[C:10]2[S:9][C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])[C:15]2=[CH:14][CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc[n+]2[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1c(C(=O)OC)sc2nc(Cl)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate 7-oxide (245.4 mg) and toluene (7.9 mL) was added phosphoryl chloride (0.367 mL). The mixture was stirred at 80° C. for 3 h. After cooling, the mixture was concentrated. The residue was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (147 mg).
Reaction SMILES: C1(C)C=CC(S([O-])=O)=CC=1.[Na+].[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](C=O)=[C:15]1[CH3:25])[CH3:13]>>[CH2:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH3:25])[CH3:13]
Reactant: CCn1c(C)c(C=O)c2ccccc21
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Product: CCn1c(C)cc2ccccc21

Procedure:
Following a procedure similar to that described in 3A but employing 6.5 g. of 85.9% sodium p-toluenesulfinate, 4.6 g. of 1-ethyl-2-methyl-1H-indole-3-carboxaldehyde and 3.8 g. of 1-ethyl-2-methyl-1H-indole there was obtained 4.5 g. of 3-[(1-ethyl-2-methyl-1H-indol-3-yl)(4-methylphenylsulfonyl)methyl]-1-ethyl-2-methyl-1H-indole, m.p. 146°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]4)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH3:31])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1C=[N+]([C@@H]2[O:42][C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl-].[Mg+2].[Cl-].C(#N)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:24][CH2:25][S:26](=[O:30])(=[O:29])[CH2:27][CH2:28]4)=[O:22])=[CH:17][CH:16]=3)=[C:11]([CH2:31][OH:42])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1)N1CCS(=O)(=O)CC1
Yield: 18 %

Procedure:
A solution of {6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridin-3-yl}-(1,1-dioxo-1-thiomorpholin-4-yl)-methanone (44.5 mg, 0.096 mmol) in DMSO (2 mL) was added to a suspension of CYP3A4 (800 nmol)) and NADP in a total volume of 1000 mL reaction buffer (823 mL 0.1M K+ phosphate buffer pH 7.4, 50 mL 1M trisodium citrate, 10 mL 1M magnesium chloride, 2.5 mL 20 mM NADP). The mixture was shaken in a 2 L baffled Erlenmeyer flask at 220 rpm at 27° C. for 4 h, by which time the ratio of substrate:product (12:8 at 3 h, and 11:9 at 4 h) remained almost constant (reaction monitoring: 0.2 mL suspension was treated with 0.2 mL acetonitrile, centrifuged at 13,200 rpm for 2 min, and supernatant was analyzed by HPLC). The suspension (1000 mL) was extracted with 2 L ethyl acetate. The solvent was distilled off and the residue was dissolved in 100 mL water. This was applied to a 10 g reverse phase C18 cartridge which was eluted with a step gradient of acetonitrile in water (15 mL aliquots). Metabolite containing fractions eluting at 35% MeCN were pooled as appropriate and after removal of organic solvent by rotary evaporation were freeze dried to afford the title compound (8.4 mg, 18%) as a white solid. MS: m/e=536.1 [M+CH3COO]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[H-].[Na+].I[CH3:32].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][C:23]([CH3:32])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CI
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (5.0 g) in DMF (50 mL) was added sodium hydride (60%, 576 mg) at 0° C., and the mixture was stirred at 0° C. for 30 min. Iodomethane (978 μL) was added, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (3.40 g).
Reaction SMILES: C([O:3][CH2:4][CH3:5])C.[Br:6][C:7]1[CH:12]=[CH:11]C(Br)=[CH:9][N:8]=1.C([Li])CCC.CN(C)C=O>O>[Br:6][C:7]1[N:8]=[CH:9][C:5]([CH:4]=[O:3])=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 66 %

Procedure:
To a diethyl ether (60 mL) solution of 2,5-dibromopyridine (3.00 g, 12.7 mmol) was added n-butyl lithium (7.99 mL, 1.6 M hexane solution, 12.7 mmol) under nitrogen atmosphere at −78° C., which was stirred for 50 minutes at −78° C. Then, N,N-dimethylformamide (1.18 mL, 15.2 mmol) was added to the mixture, which was stirred for 35 minutes while the temperature was raised to room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain the title compound (1.56 g, 66%).