Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH:15]([CH2:16][NH:17][CH2:18]2)[CH2:14]1)=[O:12].Cl[C:22]1[CH:31]=[C:30]([CH3:32])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([N:13]1[CH2:20][CH:19]2[CH2:18][N:17]([C:22]3[CH:31]=[C:30]([CH3:32])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:16][CH:15]2[CH2:14]1)=[O:12]
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: COc1ccc(C(=O)N2CC3CNCC3C2)c(OC)c1
Product: COc1ccc(C(=O)N2CC3CN(c4cc(C)c5ccccc5n4)CC3C2)c(OC)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 38 and 2-chloro-4-methyl-quinoline. MS (ESI) mass calcd. for C25H27N3O3, 417.51; m/z found, 418.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32]>>[C:31]([C:33]1[CH:38]=[C:37]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[C:3]=2[CH2:1][CH3:2])[CH:36]=[CH:35][CH:34]=1)#[N:32]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccc(C#N)c2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3-cyanophenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H19N2O3 (M+H): 359.1390. Found 359.1394
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]([OH:12])=O)=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:28][CH2:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33]>O1CCCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]([C:4]1[C:9]([C:10]([NH:28][CH2:29][CH2:30][CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:5]=1)([CH3:2])[CH3:3]
Reactant: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)O
Reactant: NCCC(O)C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCCC(O)C(F)(F)F
Reaction time: 18 h
Yield: 60 %

Procedure:
To a solution of 2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid (synthesized similar to the methods described in sections a) to d) of example X1) (1.40 g, 5.30 mmol) in tetrahydrofuran (40 ml) are added triethylamine (2.9 ml, 21.2 mol) and 0-(7-azabenzotriazol-1-yl)N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.9 g, 5.3 mmol). The mixture is stirred for 15 min at RT, before 4-amino-1,1,1-trifluorobutan-2-ol hydrochloride (1.05 g, 5.8 mmol) is added and stirring is continued for 18 h. After completion of the reaction, the mixture is diluted with ethyl acetate and 10% aqueous ammonium chloride. The organic layer is separated and washed with saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 50% ethyl acetate/cyclohexane) to yield 2-Isopropyl-4-methyl-6-morpholin-4-yl-N-(4,4,4-trifluoro-3-hydroxy-butyl)-pyridine-3-carboxylic acid amide (example X6) (1.24 g, 3.18 mmol, 60%). [M+H]+390.2.
Reaction SMILES: [S:1]1[C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.S1C(C(O)=O)=CC2C=CC=CC1=2.C(Cl)(=O)C(Cl)=O.[NH2:31][CH:32]([P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.N1C=CC=CC=1>[S:1]1[C:5]([C:6]([NH:31][CH:32]([P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(NC(=O)c1cc2ccccc2s1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzo[b]thiophenecarbonyl chloride prepared from 2-benzo[b]thiophenecarboxylic acid (356 mg) and oxalyl chloride (0.35 ml) in methylene chloride (2 ml) was added dropwise a mixture of tetraethyl (aminomethylene)bis(phosphonate) (606 mg), pyridine (316 mg) and trace amounts of 4-(dimethylamino)pyridine in methylene chloride (8 ml) at 5° C. The mixture was stirred for 2 hours at ambient temperature followed by the addition of ethyl acetate. The mixture was washed with water, 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was treated with diisopropyl ether to give tetraethyl [(2-benzo[b]thiophenecarboxamido)methylene]bis(phosphonate) (790 mg) as a white powder which was recrystallized from a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [Na].[NH2:2][OH:3].Cl.[F:5][C:6]([F:11])([F:10])[CH2:7][C:8]#[N:9]>CO>[F:5][C:6]([F:11])([F:10])[CH2:7][C:8](=[N:2][OH:3])[NH2:9]
Reactant: NO
Reactant: N#CCC(F)(F)F
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(CC(F)(F)F)=NO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a flask containing sodium (45.87 mmol, 2.5 g) in MeOH (10 ml), a suspension of NH2OH.HCl (45.87 mmol, 3.2 g) in MeOH (11 ml) was added using a dropping funnel. After addition, the mixture was stirred for 15 min. The suspension was filtered to remove the precipitated NaCl. The filtrate was cooled to 0° C. and 3,3,3-trifluoropropionitrile (45.87 mmol, 5 g) was added. The reaction mixture was stirred for 1 h. The solvent was evaporated under reduced pressure. The crude product was proceeded to the next step without purification. Yield 3.0 g.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:5])[CH3:4].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[S:32])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[OH2:5].[ClH:1].[ClH:1].[ClH:1].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C:31]2[S:32][CH:2]=[C:3]([CH3:4])[N:33]=2)[CH2:24][CH2:23]1
Reactant: CC(=O)CCl
Reactant: NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccco2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1csc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccco3)CC2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.3 parts of 1-chloro-2-propanone, 5 parts of N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea, 3 parts of potassium carbonate and 68 parts of N,N-dimethylacetamide was stirred overnight at room temperature. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried overnight in vacuo at 100° C., yielding 3.8 parts of 1-(2-furanylmethyl)-N-[1-[2-[(4-methyl-2-thiazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine trihydrochloride monohydrate; mp. 238.5° C. (compound 88).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]([CH2:16][CH3:17])[C:11]([N:13]([CH3:15])[CH3:14])=[N:12][C:8]=2[CH:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[Cl:22])([O-])=O.C(COC)OC>[Pt]=O.CO>[NH2:1][C:4]1[C:9]2[N:10]([CH2:16][CH3:17])[C:11]([N:13]([CH3:14])[CH3:15])=[N:12][C:8]=2[CH:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[C:5]=1[Cl:22]
Reactant: CCn1c(N(C)C)nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Agent: O=[Pt]
Solvent: COCCOC
Solvent: CO
Product: CCn1c(N(C)C)nc2cc(C(F)(F)F)c(Cl)c(N)c21
Reaction time: 3 h

Procedure:
7-nitro-6-chloro-2-dimethylamino-1-ethyl-5-trifluoromethylbenzimidazole (2 g.) in 50 ml. of a 50:50 mixture of dimethoxyethane and methanol was hydrogenated in the presence of 100 mg. of platinum oxide catalyst at an initial pressure of 40 psi. for 3 hours. Filtration to remove the catalyst was followed by solvent removal by evaporation under reduced pressure. The residue was passed through a silica gel column with chloroform as eluent to give 1.1 g. of the desired product melting at 99° - 100°C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[NH4+:21].[OH-].CCOC(C)=O.O>C1COCC1>[NH2:21][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 150 °C
Yield: 76.4 %

Procedure:
Tert-butyl (1-(4-fluoro-3-nitrophenyl)ethyl)carbamate (500 g, 1.75 mmol) was stirred in THF (2 ml). NH4OH (0.978 ml, 7.0 mmol) was added and the reaction mixture was heated at 150° C. for 30 minutes using microwave (Biotage Initiator). NH4OH (0.6 00 ml) was added and then heated at 180° C. After cooling to room temperature, the reaction mixture was poured into EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 0% to 50% EtOAc/Hexane to afford the title compound (376 mg, yield: 76%) 1H-NMR (400 MHz, CDCl3) δ 1.43-1.48 (m, 12H) 4.71 (br. s., 2H) 6.79 (d, 1H) 7.34 (dd, 1H) 8.05 (d, 1H).
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:15])=[O:9])[CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylic acid hydrochloride (1.0 g, 7.6 mmol) in methanol (25 mL) at 0° C. was added thionyl chloride (0.83 mL, 11.4 mmol). The reaction was warmed to room temperature and heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated to dryness to give the title compound (1.2 g, 92%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C([N+]([O-])=O)=NC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][C:34]=1F>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][C:34]1[CH:33]=[CH:32][C:31]([C:36](=[O:38])[CH3:37])=[CH:30][C:29]=1[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(O)c(OCc2ccccc2)c1
Reactant: CC(=O)c1ccc(F)c(F)c1
Agent: O=[N+]([O-])c1ncccc1F
Product: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OCc2ccccc2)c1
Yield: 96 %

Procedure:
According to the procedure of example 21(a3) except substituting 4-Ethyl-2-methoxy phenol by 2-(benzyloxy)-4-ethylphenol (1.3 g, 5.7 mmol) and 3-Fluoro-2-nitropyridine by 1-(3,4-difluorophenyl)ethanone (0.98 g, 6.27 mmol), the title compound was prepared as a clear oil in 96% yield (2 g) and used without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:13]=[C:14]([F:22])[CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[CH2:17]2.N1CCCCC1>O1CCCC1>[F:22][C:14]1[CH:13]=[C:12]([NH:11][CH:1]=[O:3])[C:20]2[C:16](=[CH:17][C:18](=[O:21])[N:19]=2)[CH:15]=1
Reactant: Nc1cc(F)cc2c1NC(=O)C2
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: O=CNc1cc(F)cc2c1=NC(=O)C=2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of acetic anhydride (0.8 ml) and formic acid (0.6 ml) was stirred for 1 hour at room temperature, and added with 7-amino-5-fluoro-1,3-dihydro-indol-2-one 20b (2.0 g, 12 mmol) in 30 ml of tetrahydrofuran to the above mixture, followed by piperidine (0.02 ml). The resulting mixture was stirred for 3 hours until precipitates were formed, filtered to provide the crude product (1.95 g), and recrystallized from methanol to obtain the title compound 5-fluoro-7-formamido-indol-2-one 20c (700 mg, yield 30.4%) as a white solid.
Reaction SMILES: [CH:1]1([C:5](=O)[CH2:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.[NH2:10][NH2:11]>CCO>[CH:1]1([C:5]2[NH:11][N:10]=[C:7]([NH2:8])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: N#CCC(=O)C1CCC1
Solvent: CCO
Product: Nc1cc(C2CCC2)[nH]n1
Temperature: 75 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
To an aliquot of the crude 3-cyclobutyl-3-oxo-propionitrile (10.0 g, 81.3 mmol) prepared above in EtOH (300 mL) was added hydrazine. The resulting mixture was heated to 75° C. (oil bath). After 14 hr, the reaction was cooled to room temperature and concentrated under reduced pressure. The resulting oil was taken up in EtOAc and washed with saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure. Purification of this material was accomplished by flash column chromatography on a Biotage® 75S MPLC system (A Dynax Corp., Charlottesville, Va.), eluting with 100 EtOAc (2 L) and 10% MeOH/CH2Cl2 (2 L). The product-containing fractions were collected and concentrated to give the title compound (10.0 g, 91% yield) as a brown oil. 400 MHz 1H NMR (CDCl3) d 5.47 (s, 1H), 5.25 (bs, 3H), 3.40 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.34-2.27 (m, 2H), 2.16-1.88 (m, 4H). LRMS m/z (APCI+) 138 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:22])=[CH:17][CH:16]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCCCN2CCOCC2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 4-(3-aminopropyl)morpholine (22.5 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanoltriethylamine (96:2:2). Concentration of the product fractions under vacuum N-(6-methyl-4′-{[(3-morpholin-4-ylpropyl)amino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (59.5 mg, 83%). NMR; δH [2H6]-DMSO 9.94,(1H, s), 8.55,(1H, t), 8.36,(1H, s), 7.90,(2H, d), 7.78,(1H, t), 7.67,(1H, dd), 7.60,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.98,(1H, m), 3.56,(4H, t), 3.30,(2H, m), 2.35–2.32,(6H, m), 2.19,(3H, s), 1.69,(2H, m). LCMS: retention time 2.42 min, MH+448.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1C=CC=C[CH:3]=1.[NH2+:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N:10]1([C:18]2[CH:23]=[CH:22][C:21]3[CH:2]([CH3:3])[C:1](=[O:8])[O:9][C:20]=3[CH:19]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C([O-])c1ccccc1
Reactant: c1ccccc1
Reactant: C1CCC[NH2+]CC1
Solvent: O
Product: CC1C(=O)Oc2cc(N3CCCCCC3)ccc21

Procedure:
A mixture of 18.2 g (0.1 mole) of 4-methyl-3-(3-oxobutyl)-maleic acid anhydride and 23.2 g (0.105 mole) of hexahydroazepinium benzoate in 400 ml of benzene is heated under reflux for 48 hours using a water separator. The benzene is removed in vacuo and the residue remaining is partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product remaining after drying and after removal of the methylene chloride is chromatographed over silica gel with petroleum ether/ether. Subsequent recrystallisation from ether/petroleum ether yields 6-(hexahydroazepin-1-yl)-3-methylbenzofuran-2(3H)-one having a melting point of 57°-59° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[C:5](F)=[CH:4][N:3]=1.[NH2:12][NH2:13]>C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:8]([CH3:9])=[N:13][NH:12][C:5]2=[CH:4][N:3]=1
Reactant: CC(=O)c1cc(Br)ncc1F
Reactant: NN
Solvent: OCCO
Product: Cc1n[nH]c2cnc(Br)cc12
Temperature: 165 °C
Reaction time: 3.5 h

Procedure:
To a 150 mL sealed flask containing 50 mL dry ethylene glycol was dissolved 1-(2-bromo-5-fluoro-4-pyridinyl)ethanone (8.2 g, 37.6 mmol). Added dropwise via syringe next was anhydrous hydrazine (1.24 mL, 39.5 mmol). The stirred light yellow mixture was sealed, and heated at 165° C. After 3.5 h, the orange-tan reaction mixture was removed from heating. After cooling to room temperature, the contents were poured onto a stirring mixture of 300 g ice/water (1:1), wherein solid precipitation occurred. After stirring for 10 min, the off-white precipitate was collected. This solid was dried in vacuo and collected 5-Bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine as an off-white solid (7.9 g, 99%). ESI MS m/z=212 (M+1).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: COc1ccc2ccc(C3(O)CCNCC3)cc2c1
Product: COc1ccc2ccc(C3(O)CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)cc2c1
Yield: 72.1 %

Procedure:
Beginning with 0.334 gm (1.77 mMol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.455 gm (1.77 mMol) of 4-hydroxy-4-(7-methoxynaphth-2-yl)piperidine, 0.570 gm (72%) of the title compound was recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: O.Cl.[O:3]=[C:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(OCC)C.Cl[C:16]([O:18][CH2:19][Cl:20])=[O:17].[OH-].[Na+]>O>[Cl:20][CH2:19][O:18][C:16]([N:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)=[O:17]
Reactant: O=C(Cl)OCCl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C1CCN(C(=O)OCCl)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of 1 g of 4-oxopiperidine hydrochloride monohydrate in 0.7 ml of water was added 2.2 ml of diethyl ether, and the mixture was stirred at 0° C. Chloromethyl chloroformate (0.3 ml) was added dropwise, and the mixture was stirred at 0° C. for 5 minutes. Next, 0.8 ml of a 17N aqueous sodium hydroxide solution and 0.3 ml of chloromethyl chloroformate were divided into three portions and alternately added dropwise, and the resulting mixture was stirred at 0° C. for additional 20 minutes. The reaction mixture was diluted with 5 ml of a saturated aqueous saline, and extracted three times with 5 ml of diethyl ether. The organic layer thus obtained was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to give 1.7 g (100%) of 1-chloromethoxycarbonyl-4-oxopiperidine.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C(O)C>[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7]
Reactant: C1CCC2OC2C1
Reactant: c1c[nH]cn1
Solvent: CCO
Product: OC1CCCCC1c1ncc[nH]1
Yield: 76.4 %

Procedure:
A mixture of cyclohexene oxide (Va) (9.81 g), ethanol (25 ml) and imidazole (13.6 g) was refluxed under heating for 70 hours. The ethanol was evaporated and after addition of a small amount of water, the residue was extracted with chloroform. The extract was washed with a small amount of water, dried and evaporated to give 2-imidazolylcyclohexanol (IVa) (12.7 g) as crystaline residue (Yield 76%). Mp. 133°-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@H:11]1[O:16][C@@H:15]([CH3:17])[CH2:14][NH:13][CH2:12]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH2:12][C@H:11]([CH3:10])[O:16][C@H:15]([CH3:17])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@@H]1CN(Cc2ccc(Br)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
To a mixture of 4-bromobenzaldehyde (3.70 g, 20 mmol) and cis-2,6-dimethylmorpholine (2.52 g, 22 mmol) in DCE (100 mL) was added NaBH(OAc)3 (5.30 g, 25 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with sat. NaHCO3 (30 mL) and H2O (30 mL), and was extracted with DCM (30 mL×2). Concentration of the solvents afforded the crude title compound as a pale yellow liquid (6.41 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=7.2 Hz, 2H), 7.21 (d, J=7.2 Hz, 2H), 3.64-3.55 (m, 2H), 3.44 (s, 2H), 2.68 (d, J=11.6 Hz, 2H), 1.75 (t, J=11.0 Hz, 2H), 1.54 (d, J=6.0 Hz, 6H); MS ESI 284.0 [M+H]+, calcd for [C13H18BrNO+H]+ 284.1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([OH:22])=[O:21]>>[CH3:18][CH:17]([S:14]([NH:13][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:27]=[CH:28][C:23]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:3][CH:4]=1)(=[O:16])=[O:15])[CH3:19]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1c1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 108.2 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (245 mg, 0.62 mmol, prepared in example 17) and 4-carboxybenzeneboronic acid (114 mg, 0.69 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with 4% methanol/methylene chloride to afford 260 mg of the title compound which was further purified by semiprep C18 reverse phase HPLC to give 96 mg (40%) of the title compound as a white solid.