Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[NH:5][S:4]1(=[O:13])=[O:12].[P:14]([O-:22])([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH2:17]([O:16][P:14]([O:19][CH2:20][CH3:21])([O:22][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][CH3:11])[NH:5][S:4]1(=[O:13])=[O:12])=[O:15])[CH3:18]
Reactant: CCOP(=O)([O-])OCC
Reactant: CCCC1NS(=O)(=O)N(CCl)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1NS(=O)(=O)N(COP(=O)(OCC)OCC)C1=O
Yield: 35 %

Procedure:
2-Chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1 g; 4.42 mmol) was added to a solution of diethyl phosphate (Formula III: A=B=Et) (1.02 g; 6.62 mmol) in methylene chloride (5 ml) containing triethylamine (0.67 g; 6.63 mmol), and the mixture was allowed to reflux for 24 hours and then cooled. The mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography (50% ethyl acetate/hexane) to afford 0.54 g (35%) of 2-(diethoxyphosphinyloxymethyl)-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =H; R2=propyl; R3 =H; A=B=Et) as an oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]#[N:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[N-:30]=[N+:31]=[N-:32].[Na+].CN(C)C=O.[Cl-].[NH4+]>O>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]3[NH:32][N:31]=[N:30][N:27]=3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC#N)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCc3nnn[nH]3)c2c1
Temperature: 80 °C
Yield: 17.8 %

Procedure:
A mixture of 3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propanenitrile (100 mg, 0.25 mmol), sodium azide (48 mg, 0.98 mmol), dimethyl formamide (2 ml) and ammonium chloride (52.6 mg, 0.98 mmol) was heated at 80° C. in an oil bath overnight. The resulting mixture was diluted with water and extracted with dichloromethane (10 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 10% methanol in dichloromethane) to afford 20 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (m, 1 H), 7.92 (t, 1 H), 7.86 (s, 1 H), 7.60 (m, 1 H), 7.58-7.52 (m, 3 H), 5.89 (s, 1 H), 5.27 (s, 2 H), 4.52 (brs, 2 H), 3.86 (t, 2 H), 3.72 (t, 2 H), 3.33 (t, 2 H), 2.47 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[CH2:25](O)[CH3:26]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O:11][CH2:25][CH3:26])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1
Reactant: CCO
Reactant: CC(C(=O)O)c1ccc(-c2ccc(F)cc2)c(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(-c2ccc(F)cc2)c(F)c1
Temperature: 0 °C

Procedure:
2-(2,4'-Difluoro-4-biphenylyl)propionic acid (830 mg.), ethanol (10 ml.) and concentrated sulphuric acid (0.5 ml.) were refluxed for 16 hours. The solution was diluted with ice-water (200 ml.) and extracted with ether. After the usual washing, evaporation of the ether and distillation of the residue gave ethyl 2-(2,4'-difluoro-4-biphenylyl)-propionate, b.p. 145°-146°C./0.8 mm.
Reaction SMILES: [NH2:1][C:2]1[C:20]([Br:21])=[CH:19][C:5]2[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]([C:9]3[CH2:13][CH2:12][CH2:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].Cl>C(Cl)Cl>[Br:21][C:20]1[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:3][C:4]2[O:8][C:7]([C:9]3[CH2:13][CH2:12][CH2:11][CH:10]=3)=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(C2=CCCC2)oc2cc(N)c(Br)cc12
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C2=CCCC2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of ethyl 6-amino-5-bromo-2-(cyclopent-1-en-1-yl)benzofuran-3-carboxylate (3.63 g, 10.37 mmol) and pyridine (2.46 g, 31.1 mmol) in DCM (30 mL) was added dropwise methanesulfonyl chloride (2.37 g, 20.7 mmol) at 0° C., then the mixture was stirred at 25° C. overnight. 10% HCl(a.q.) was added, then the mixture was extracted with DCM (50 mL*3), dried over Na2SO4, and concentrated to give the product of ethyl 5-bromo-2-(cyclopent-1-en-1-yl)-6-(methylsulfonamido)benzofuran-3-carboxylate (4.3 g, yield: 96%). 1H-NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.80 (s, 1H), 7.22 (t, J=2.0 Hz, 1H), 6.84 (s, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.99 (s, 3H), 2.89˜2.94 (m, 2H), 2.62˜2.67 (m, 2H), 2.06 (t, J=7.6 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H). MS (M+H)+: 428/430.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]4[O:31][C:30]([CH3:33])([CH3:32])[CH:29](O)[C:28]=4[C:35]=3[CH3:36])[CH2:20][CH2:19]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>CO>[C:2]1([NH:1][CH:29]2[C:28]3[C:35]([CH3:36])=[C:24]([N:21]4[CH2:20][CH2:19][CH:18]([C:12]5[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=5)[CH2:23][CH2:22]4)[C:25]([CH3:38])=[C:26]([CH3:37])[C:27]=3[O:31][C:30]2([CH3:33])[CH3:32])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1OC
Reactant: Nc1ccccc1
Solvent: CO
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(Nc3ccccc3)C(C)(C)O4)CC2)cc1OC
Yield: 60 %

Procedure:
Using aniline and 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 19, the title compound was synthesized in the same manner as in Example 58. Yield 60%. mp. 138–140° C. (methanol).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:5]=1[CH2:4][CH2:1][OH:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Yield: 92.4 %

Procedure:
A mixture of 2-carboxymethyl-4-nitrobenzoic acid (13 g, 57.7 mmol), acetic anhydride (5.45 mL, 57.7 mmol) and toluene (130 mL) were heated to reflux for 5 hrs. The solvent was removed under vacuum to yield 6-nitro-isochroman-1,3-dione (compound (10) in Scheme 2) as a yellow solid (10.51 g, 88%). Borane tetrahydrofuran complex (35.6 mL, 1M in THF) was added dropwise over 40 min to a solution of 6-nitro-isochroman-1,3-dione (2 g, 9.66 mmol) in THF (40 mL) at 0° C. The contents were then stirred for 18 hrs at 25° C., cooled to 0° C., quenched with methanol (30 mL), and stirred for 1 hr. The solvents were removed under vacuum, ethyl acetate (30 mL) was added and the organic phase was washed with 10% aqueous hydrochloric acid. The aqueous acidic layer was backwashed with ethyl acetate (30 mL), the combined organic layers were dried with magnesium sulfate, and evaporated under vacuum until approximately 2 mL of ethyl acetate remained. This solution was filtered through silica gel washing with methylene chloride (30 mL) to remove impurities. The silica gel was flushed with ethyl acetate, the solvent was removed under vacuum to give a solid which was slurried in methylene chloride and filtered to afford the title diol as a white solid, 1.38 g , 73%.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:2]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([C:24]5[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=5)=[CH:9][CH:10]=4)[C:5]4([CH2:20][O:19][C:18]([NH2:21])=[N:17]4)[C:4]=3[CH:3]=2)[CH:23]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=NC2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: NC1=NC2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Resealable tube was charged with 2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (100 mg, 0.219 mmol), pyridin-3-ylboronic acid (81 mg, 0.656 mmol), Pd(PPh3)4 (50.6 mg, 0.044 mmol). DME (1 ml) and sodium carbonate (0.328 ml, 0.656 mmol) were added and the reaction mixture was capped with argon, sealed, and stirred at 95° C. for 16 hrs. The mixture was partitioned between DCM and water. The aqueous layer was removed and the organic layer was washed with brine, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (12 g column, 15-100% DCM/MeOH/NH4OH in DCM) to give material with impurity followed by second FC on silica (12 g column, 50-85% DCM/MeOH/NH4OH) to give 2′,7′-di(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [F:1][C:2]([F:31])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH2:22][C:23]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].CO.[BH4-].[Na+].O>C(Cl)Cl>[F:31][C:2]([F:1])([O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH:23]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[OH:24])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C(CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1)C1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=S(=O)(CC(O)C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Crude 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanone (3.60 g, 0.008M) was dissolved in DCM (120 ml) and methanol (40 ml) at ambient temperature and sodium borohydride (334 mg, 0.0088 mol) was added. Stirred for 2 hours, added H2O (250 ml) and extracted with DCM. Collected the organic phase, dried over MgSO4, filtered and evaporated to dryness to yield 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanol (3.6 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[C:24]([F:32])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CO.[OH-].[Li+]>C1COCC1>[NH2:1][C:2]1[C:3]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:32])[CH:23]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3CCC(NC(=O)OC(C)(C)C)CC3)cnc2N)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(c2cnc(N)c(-c3ccc(C(=O)O)c(F)c3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To methyl 4-(3-amino-6-(4-((tert-butoxycarbonyl)amino)cyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (230 mg, 0.517 mmol) was added MeOH (2 mL), THF (2 mL) and then lithium hydroxide 1M aqueous solution (1.552 mL, 1.552 mmol). The reaction was stirred at room temperature for 1 h. The solvent was concentrated to residue, then THF (20 mL) was added and concentrated to residue. Then THF (20 mL) was added again and re-concentrated to residue to constant mass to give the desired product (which is 2:1 trans to cis ratio), used as is. Assume quantitative yield (0.517 mmol). LCMS (m/z): 431.2 (MH+), 0.78 min for both.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=2)=[CH:4][C:3]=1[C:18]1[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=1.[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1>CS(C)=O.CCOC(C)=O>[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:2]2[O:6][C:5]([C:7]3[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:8]=3)=[CH:4][C:3]=2[C:18]2[N:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:19]=2)[CH2:34]1
Reactant: CN(C)C1CCCNC1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(Br)o2)c(C)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(N3CCCC(N(C)C)C3)o2)c(C)cn1
Temperature: 120 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
To a solution of N-{-4-[5-bromo-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.19 g, 0.38 mmol) in DMSO (3 mL) was added N,N-dimethylpiperidin-3-amine (0.25 g, 1.9 mmol). The mixture was allowed to stir at 120° C. for 48 h. The reaction mixture was diluted with EtOAc and washed with water. The organic solution was separated, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-{5-[3-(dimethylamino)piperidin-1-yl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.15 g, 72%). LCMS (FA): m/z=540.7 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](Cl)=[O:29])[C@H:24]([CH2:31][CH3:32])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][O:5][C:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][C@H:24]1[CH2:31][CH3:32])=[O:29]
Reactant: CCCOc1cc(F)c(CO)c(F)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CCCOc1cc(F)c(COC(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2CC)c(F)c1
Yield: 78 %

Procedure:
This compound was prepared from 2,6-difluoro-4-propoxy-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (257 mg; 78%); MS (ISP): 465.4 (M+Na)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].[H-].[Na+]>CN(C)C=O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCO
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1

Procedure:
1,4,5-Triphenyl-2-chloroimidazole was treated with 8-hydroxyoctanoic acid and sodium hydride in dimethylformamide to give the title compound, m.p. 158°-159° C., Found: C, 75.3; H, 6.6;N, 6.0%; C29H30N2O3.0.43H2O Requires: C, 75.3;H, 6.7; N, 6.0%
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH3:23]I.O>CN(C=O)C>[CH3:23][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:15][CH2:14][CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[CH:20]=2)[NH:4]1
Reactant: CI
Reactant: COC(=O)C1=Cc2cc(-c3nnn[nH]3)ccc2OCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(C3=NNN(C)N3)ccc2OCC1
Reaction time: 0.25 h
Yield: 79.6 %

Procedure:
In DMF (6 ml) was dissolved methyl 7-(1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (400 mg, 1.47 mmol), and to the mixture was added at 0° C. sodium hydride (60%, 90 mg, 2.3 mmol). The mixture was stirred at the same temperature for 15 minutes, and to the mixture was added at 0° C. methyl iodide (0.28 ml, 4.4 mmol). While the temperature of the mixture was warmed from 0° C. to room temperature, the mixture was stirred for 3 hours. To the mixture was added at 0° C. water (30 ml), and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (silica gel 40 g, ethyl acetate/hexane=1/8→1/2), and the first eluted desired fraction was concentrated under reduced pressure to give methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (334 mg, 1.17 mmol, 79%). The second eluted desired fraction was concentrated under reduced pressure to give methyl 7-(1-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate (76 mg, 0.27 mmol, 18%). Methyl 7-(2-methyl-1H-tetrazol-5-yl)-2,3-dihydro-1-benzoxepine-4-carboxylate; IR (KBr): 1705 cm−1.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[C:24]([CH:30]([F:32])[F:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:27]([C:25]3[C:24]([CH:30]([F:32])[F:31])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CC(C)(C)c2cccc(NC(=O)c3cn(C)nc3C(F)F)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.17 g of 1-methyl-3-difluoromethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.20 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-difluoromethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (2)) (optical purity: 99% ee).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]2[C:20](F)=[N:21][CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[CH:24]=2)[C:13]=1[CH:39]=[CH2:40]>C1COCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[Cl:11][C:12]1[N:17]=[CH:16][C:15]2[NH:18][C:20]3[N:21]=[CH:22][C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:27][CH:26]=4)=[CH:24][C:19]=3[C:14]=2[C:13]=1[CH:39]=[CH2:40]
Reactant: C=Cc1c(Cl)ncc(N)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(Cl)ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c12
Yield: 24.8 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.3 mL, 1.3 mmol) was added to a solution of 6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-5′-vinyl-[3,4′]bipyridinyl-3′-ylamine (53 mg, 0.13 mmol) in anhydrous THF (1 mL) and the resultant solution stirred at ambient temperature for 20 min. The reaction mixture was diluted with brine (5 mL) and ethyl acetate (5 mL). The resultant precipitate was collected by filtration to afford the title compound as a beige powder (13 mg, 26%). 1H NMR (CDCl3, 400 MHz): 8.85 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.61 (s, 1H), 7.58-7.55 (m, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.22-7.14 (m, 1H), 6.03-6.01 (m, 1H), 5.99-5.97 (m, 1H), 3.56 (s, 2H), 2.47-2.37 (m, 4H), 1.64-1.59 (m, 4H), 1.52-1.44 (m, 2H). LCMS (Method A): RT=6.81 min, M+H+=403/405.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19])[CH:3]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(=Cc1cccc(Br)c1)[N+](=O)[O-]

Procedure:
A suspension of 3-bromo-benzaldehyde (2.5 g, 13.5 mmol), ammonium acetate (1.09 g, 14.2 mmol), and nitroethane (250 mL) was heated to reflux overnight. Solvent removed under vacuum then residue partitioned between ethyl acetate and saturated sodium chloride. Concentrated organic purified on silica and isolated as a yellow oil. 1H NMR (CDCl3) s (3H, 2.44 ppm), m (2H, 7.35 ppm), m (2H, 7.55 ppm) s (1H, 8.00 ppm).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C@H:7]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:8]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:9]([O:11]CC2C=CC=CC=2)=[O:10])=[CH:5][O:4][N:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:28]([O:27][C:25](=[O:26])[C@H:7]([C@@H:8]([CH2:19][CH2:20][C:21]([F:24])([F:22])[F:23])[C:9]([OH:11])=[O:10])[C:6]1[C:2]([CH3:1])=[N:3][O:4][CH:5]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1nocc1[C@H](C(=O)OC(C)(C)C)[C@@H](CCC(F)(F)F)C(=O)O
Yield: 46.9 %

Procedure:
In a 200 mL round-bottomed flask a colorless solution of (2R,3R)-1-benzyl 4-tert-butyl 3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinate (2.4 g, 5.44 mmol) in MeOH (Volume: 50 mL) was treated with Pearlman's Catalyst (0.076 g, 0.544 mmol) and hydrogenated using a hydrogen-filled balloon at room temperature for 1 hour until the reaction was complete (monitored by HPLC). The mixture was filtered through a 0.45 μm membrane and rinsed with MeOH. The filtrated was concentrated to give 2.03 g of crude solid. The solid was purified on Prep HPLC [C18 Luna 30×100 eluting with a gradient from 10% B to 100% B (15 min)] to afford 99% pure Intermediate (896 mg, 46% yield) as a white solid. MS(ES):m/z=352 [M+H+], m/z=350[M−H−]. 1H NMR (500 MHz, chloroform-d) δ 8.40 (s, 1H), 3.62 (d, J=10.0 Hz, 1H), 3.08 (td, J=10.0, 3.6 Hz, 1H), 2.34 (s, 3H), 2.33-2.14 (m, 2H), 2.03-1.89 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH2:10][C:9]1=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:24](Cl)=[O:25])[S:23][CH:22]=[CH:21][CH:20]=1.O.Cl>CN(C1C=CN=CC=1)C.CN(C)C=O>[C:1]([NH:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]([C:24](=[O:25])[C:19]2[S:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)NC(=O)N1C(=O)Cc2ccc(Cl)cc21
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)N1C(=O)C(C(=O)c2cccs2)c2ccc(Cl)cc21
Reaction time: 0.5 h

Procedure:
A solution of 667 mg (2.5 mmole) of N-t-butyl-6-chloro-2-oxindole-1-carboxamide and 684 mg (5.6 mmole) of 4-(N,N-dimethylamino)pyridine in 8 ml of N,N-dimethylformamide was cooled in an ice-bath, and then a solution of 410 mg (2.8 mmole) of 2-thenoyl chloride in 2 ml of N,N-dimethylformamide was added dropwise, with stirring. Stirring was continued for ca. 30 minutes, and then the reaction mixture was poured into a mixture of 60 ml of water and 2.5 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath, and then the solid was recovered by filtration and recrystallized from ca. 30 ml of acetic acid. This afforded 425 mg of the title compound as yellow crystals, mp 160.5°-161.5° C. (slight decomposition).