Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:11][O:12][CH:13]([O:18][CH3:19])[C:14](OC)=[O:15].C(N(CC)CC)C.CO>CCOC(C)=O>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:14](=[O:15])[CH:13]([O:18][CH3:19])[O:12][CH3:11]
Reactant: NCc1cccc(F)c1Cl
Reactant: COC(=O)C(OC)OC
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(OC)C(=O)NCc1cccc(F)c1Cl
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-3-fluorobenzylamine (575 mg, 3.53 mmol), methyl dimethoxyacetate (512 mg, 3.78 mmol), triethylamine (0.62 mL, 4.4 mmol) and MeOH (1 mL, 20 mmol) in a sealed tube was heated at 80° C. for 20 h. After cooling to rt, the mixture was diluted with EtOAc (40 ml), washed with HCl (2N, 2×30 ml), water (2×30 ml), brine (30 ml), dried over MgSO4, filtered, and concentrate vacuo to give the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ=3.40 (s, 6H), 4.59 (d, J=6.0 Hz, 2H), 4.74 (s, 1H), 6.99 (brs, 1H), 7.07-7.12 (m, 1H), 7.17-7.25 (m, 2H). MS(ES+): m/z=262.06/264.04 (100/62) [MH+]. HPLC: tR=2.91 min (ZQ3, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=O)=[CH:5][NH:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:11])=[CH:5][NH:6]2
Reactant: O=Cc1c[nH]c2cccc(Br)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c[nH]c2cccc(Br)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-1H-indole-3-carbaldehyde (7.5 g, 66.9 mmol) in THF (125 mL) was added LiAlH4 (40 mL, 1.0 M THF) dropwise at rt. The mixture was then heated at reflux for 2 h and was then cooled to 0° C. At that point 15% NaOH (2 mL) and water (7 mL) were added in sequence and the mixture was stirred vigorously for 1 h. At that point the suspension was filtered over Celite® and the filtrate was concentrated to provide crude 4-bromo-3-methyl-1H-indole, which was taken to the next step. A solution of crude 4-bromo-3-methyl-1H-indole (14.0 g, 66.9 mmol) in THF (50 mL) was added to a suspension of NaH (2.94 g, 73.6 mmol, 60% in mineral oil) in THF (200 mL) at 0° C. The mixture was stirred for 0.5 h at that temperature before a solution of p-toluene sulfonylcholoride (13.4 g, 70.2 mmol) in THF (50 mL) was added. After stirring for an additional 1 h sat aq NH4Cl was added slowly. The reaction mixture was then diluted with EtOAc and sat aq NH4Cl and the layers were separated. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was then purified by FCC (0-50% EtOAc/heptane) to give 4-bromo-3-methyl-1-tosyl-1H-indole.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][C:3]1=[O:14].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][C@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:3]1=[O:14]
Reactant: CCOC(=O)CBr
Reactant: C[C@H]1OC[C@@H](c2ccccc2)NC1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)[C@@H](C)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (2R,5R)-2-methyl-5-phenylmorpholin-3-one from Step B (500 mg, 2.62 mmol) in DMF (15 mL) at 0° C. was added NaH (113 mg of a 60% dispersion in oil, 2.83 mmol). After 10 min, ethyl bromoacetate (437 mg, 2.62 mmol) was added and the mixture was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (3 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=278 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[CH3:17].[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CS(C)=O>[C].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:17][C:3]1[CH:4]=[C:5]([O:9][CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[C:7]([CH3:8])[C:2]=1[C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:18]=[O:19])[CH:25]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1Br
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(C=O)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
2-Bromo-1,3-dimethyl-5-[3-(methylsulfonyl)propoxy]benzene (15.00 g), 3-formylphenylboronic acid (7.38 g), tripotassium phosphate (19.83 g), palladium carbon (3.0 g) and 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (1.16 g) were added to dimethyl sulfoxide (150 mL) and water (75 mL), and the mixture was stirred at 80° C. for 5 hr. Activated carbon (1.5 g) was added, and the mixture was filtered with heating at 80° C. to remove the insoluble material. The filtrate was cooled to room temperature and stirred for 5 hr. The filtrate was cooled to 10° C. or below and stirred for 2 hr. Water (120 mL) was added dropwise, and the mixture was stirred for 1 hr. Water (150 mL) was added dropwise, and the mixture was stirred for 1 hr. The crystallized solid was collected by filtration, and the solid was washed with water (150 mL), and dried under reduced pressure to give 2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-carbaldehyde (15.43 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO>[I:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=Cc1ccc(OC2CCCCO2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: Ic1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (9.07 g, 43.96 mmol) and 4-iodoaniline (8.87 g, 40.49 mmol) in 200 mL methylene chloride was added magnesium sulfate (26.7 g, 221.82 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated. The residue was dissolved in 150 mL ethanol and 75 mL methanol and sodium borohydride (6 g, 158.60 mmol) was added in portions over a period of 2 hr. The reaction mixture was stirred at room temperature for an additional 2 hr. The reaction mixture was quenched with water and the aqueous solution was washed three times with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (10% hexanes/ethyl acetate) followed by crystallization from methylene chloride/methanol afforded the title compound of Step A.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:31]#[N:32])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[C:31]([C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[CH:6][N:1]=1)#[N:32]
Reactant: CC(C)(C)OC(=O)CCc1ccncc1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
tert-Butyl 3-(4-pyridyl)propionate (0.58 g, 2.8 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.65 g, 2.9 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (3:1, v/v) were collected and concentrated. The residue was dissolved in nitroethane (4 ml), and trimethylsilyl cyanide (0.50 g, 5.1 mmol) and N,N-dimethylcarbamoyl chloride (0.54 g, 5.1 mmol) were added thereto. The reaction mixture was stirred at room temperature for 16 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.52 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](SC)=[CH:10][N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][NH2:17]>CCO.CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][CH3:16])=[CH:10][N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])Nc1ccc(Cl)nc1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNC(=C[N+](=O)[O-])Nc1ccc(Cl)nc1

Procedure:
In 25 ml of EtOH was dissolved 0.42 g (0.00171 mole) of 1-(6-chloro-3-pyridyl)amino-1-methylthio-2-nitroethylene, followed by addition of 0.2 g of a 40% solution of methylamine in methanol. The mixture was refluxed for 1.5 hours. The solvent was distilled off and the crystalline residue was washed with AcOEt and dried to recover 0.33 g of the title compound as white crystals.
Reaction SMILES: [C:1]([C:3](=[CH:9]OCC)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Cl.[CH:14]([NH:17][NH2:18])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C.CO>[NH2:2][C:1]1[N:17]([CH:14]([CH3:16])[CH3:15])[N:18]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(C)NN
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1cnn(C(C)C)c1N
Yield: 93.7 %

Procedure:
A mixture of ethyl 2-cyano-3-ethoxyacrylate (84.4 g, 0.50 mol), isopropyl hydrazine hydrochloride (55.2 g, 0.50 mol) and potassium carbonate (68.8 g, 0.50 mol) in 90% ethanol/methanol (1.5 L) was heated under reflux for 16 hours. The solvent was then removed in vacuo and water and ethyl acetate were added. The mixture was separated and the organic layer was dried over magnesium sulfate, filtered and the solvent was removed in vacuo to yield ethyl 5-amino-1-isopropyl-1H-pyrazole-4-carboxylate (92.4 g, 94%). +ESI (M+H) 198.1; 1H NMR (400 MHz, CDCl3, δ): 7.63 (s, 1H), 4.97 (br.s., 2H), 4.28 (q, 2H), 4.18 (m, 1H), 1.45 (d, 6H), 1.31 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([CH3:30])=[N:25]3)=[CH:14][C:15]=1[C:16]([O:18]C)=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>O1CCOCC1>[C:32]([NH:31][C:23]1[C:24]([CH3:30])=[N:25][C:26]2[C:21]([N:22]=1)=[C:20]([C:13]1[NH:12][C:11]3[CH:9]([CH3:10])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16](=[O:18])[C:15]=3[CH:14]=1)[CH:29]=[CH:28][CH:27]=2)([CH3:34])([CH3:33])[CH3:35]
Reactant: COC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)C(C)N(C(=O)OC(C)(C)C)C4=O)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a stirred solution of methyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (326b) (0.13 g, 0.27 mmol) in p-dioxane (2 mL) was added LiHMDS (1.64 mL, 1.64 mmol) dropwise. After the addition, the mixture was stirred at RT in overnight, then heated at 60° C. in 1 h, cooled to RT, and quenched with saturated aq. NH4Cl, extracted with EtOAc (3×). The extracts were dried over MgSO4, filtered, concentrated and purified by ISCO (0-70% EtOAc/Hexanes) to give the title compound (43 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (1H, s), 7.78 (1H, dd, J=7.4, 1.4 Hz), 7.67 (1H, dd, J=8.2, 1.4 Hz), 7.38 (1H, t, J=7.7 Hz), 6.94 (1H, s), 6.00 (1H, s), 4.99 (1H, q, J=6.5 Hz), 2.56 (3H, s), 1.59 (3H, d, J=6.5 Hz), 1.52 (9H, s), 1.51 (9H, s). m/z (ESI, +ve) 450.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.NN.[O-]S([O-])(=O)=O.[Mg+2]>CO.[Ni]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)CCNc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: CN(C)CCNc1ccccc1N
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of N,N-dimethyl-N′-(2-nitrophenyl)ethane-1,2-diamine (3.83 g, 18.3 mmol) and Raney-Nickel (0.5 g) in methanol is treated dropwise with hydrazine (5 mL), stirred at room temperature until reaction is complete by TLC, treated with Celite and MgSO4 and filtered. The filtercake is washed with methanol. The combined filtrate is concentrated in vacuo to give the title compound as a brown oil, 3.11 g (94% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[C:14]1[CH:15]=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)(=[O:20])=[O:21])[CH:17]=[CH:18][C:13]=1[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:33]
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reaction time: 4 h

Procedure:
3-[2-Ethoxycarbonyl-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (71 mg, 0.149 mmol) was dissolved in 2 ml of CH2Cl2. TFA (0.5 ml) was added and the mixture was stirred for 4 hours. The solution was concentrated under reduced pressure to give 5-(3-Fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-benzoic acid ethyl ester, MS (M+H)=378.
Reaction SMILES: CN(C)C(=O)C.Br[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1.[CH2:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])(=O)C.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[N+:21]([C:10]1[CH:9]=[C:8](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O-:23])=[O:22]
Reactant: C=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 48 mL of N,N-dimethylacetamide solution containing 6.0 g of tert-butyl 4-bromo-2-nitrobenzoate, 2.7 mL of styrene, 2.5 g of sodium acetate, 3.2 g of tetrabutylammonium bromide and 0.22 g of palladium acetate (II) were added sequentially, and heated and stirred under nitrogen atmosphere at 90° C. for 3 hours. After the reaction mixture was cooled to room temperature, 0.45 mL of styrene and 0.22 g of palladium acetate (II) were added and heated and stirred at 110° C. for 3 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to obtain 3.8 g of tert-butyl 2-nitro-4-((E)-2-phenylvinyl)benzoate as white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:4].[C:16](#[N:18])[CH3:17]>>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:18]3[CH:11]=[CH:10][CH:9]=[CH:14][CH:17]=[CH:16]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1
Reactant: O=C(CCl)Nc1n[nH]c2cc(Cl)ccc12
Reactant: CC#N
Product: O=C(CN1C=CC=CC=C1)Nc1n[nH]c2cc(Cl)ccc12

Procedure:
The process is performed as in Example 75, starting with 500 mg of 2-chloro-N-(6-chloro-1H-indazol-3-yl)acetamide, 15 cm 3 of acetonitrile and 0.69 cm3 of hexamethyleneimine. The reaction medium is refluxed for 2 hours and then concentrated to dryness under reduced pressure (2 kPa; 50° C.); the crude product is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with ethyl acetate. The fractions containing the expected product are combined and the residue is taken up in 10 cm3 of diisopropyl ether, filtered off and dried under reduced pressure (90 Pa; 45° C.) to give 670 mg of N-(6-chloro-1H-indazol-3-yl)-1H-azepine-1-acetamide in the form of a yellow foam.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33](O)=[O:34])[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:47][C:48]1C=C[C:51]([C:52]([OH:54])=O)=[CH:50][CH:49]=1)=O>>[O:54]1[CH2:52][CH2:51][CH2:50][CH:49]1[CH2:48][NH:47][C:33]([CH:31]1[CH2:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)[CH2:32]1)=[O:34]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Agent: NCCCc1ccccc1
Product: O=C(NCC1CCCO1)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting (tetrahydrofuran-2-yl)methanamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.49 (d, J=5.0 Hz, 1H), 8.13 (s, 1H), 8.05 (t, J=5.8 Hz, 1H), 7.42 (d, J=5.1 Hz, 1H), 7.35-7.27 (m, 2H), 6.41-6.34 (m, 2H), 4.79-4.73 (m, 4H), 3.94-3.68 (m, 6H), 3.68-3.55 (m, 1H), 3.54-3.39 (m, 1H), 3.20-3.07 (m, 2H), 1.93-1.71 (m, 3H), 1.55-1.41 (m, 1H); MS (ESI(+)) m/e 422 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:18]1[CH2:19][CH3:20]
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 72.9 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (˜35.75 mmol) was cyclized using triethyl orthopropionate (7.56 g, 42.9 mmol) in the presence of pyridine hydrochloride (0.41 g). The crude product was purified by chromatography (silica gel eluting with 95/5 dichloromethane/methanol) to provide 7.5 g of 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH2:36])(=[O:35])=[O:34])=[CH:23][CH:22]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].ClC(OCCCC)=O>>[CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH:36][C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])(=[O:35])=[O:34])=[CH:25][CH:26]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Agent: CCCCOC(=O)Cl
Product: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(=O)(=O)NC(=O)OCc3ccccc3)cc2)c1C

Procedure:
The title compound was prepared from 7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-6-[(1-oxobutyl)amino]-3H-imidazo[4,5-b]pyridine as described in Example 30 substituting the reagent benzyl chloroformate for butyl chloroformate in Step 5. FAB MS for C35H37N5SO5 : M+ +1=640.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:13]=[O:14].O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:13][OH:14])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Fc1ccc(-c2c[nH]cn2)cc1
Solvent: O
Solvent: CCO
Product: OCn1cnc(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a stirred solution of 4-(4-fluorophenyl)-1H-imidazole (10 g, 62 mmol) in 95% ethanol (25 mL) was added aqueous formaldehyde solution (37%, 9 mL) slowly. The reaction mixture was stirred at RT for 1 hr before water (25 mL) was added. The reaction mixture was stirred at RT for an additional 3 hr. The solid that separated from solution out was filtered, washed with aqueous ethanol solution, and dried to give (4-(4-fluorophenyl)-1H-imidazol-1-yl)methanol (11.4 g, 59 mmol, 96% yield) as a solid. MS found: (M+H—CH2O)+=163.1.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]2[CH2:20][CH2:19]2)=[CH:9][CH:8]=1.C(O)(=O)C.[OH-].[Na+].C(OCC)(=O)C>C1COCC1.[Zn]>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:15][C@H:14]2[N:16]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
To a solution of 2,2,2-trichloroethyl(4-{trans-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]cyclopropyl}phenyl)-carbamate (15.9 g) in THF (166 mL) were added zinc powder (32.6 g) and acetic acid (5 mL). The reaction mixture was stirred at room temperature for 5 hr, 1N aqueous sodium hydroxide solution (100 mL) and ethyl acetate (500 mL) were added, and the mixture was filtered through celite. The organic layer was separated from the mother liquor, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (6.83 g).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:11](=[O:30])[CH2:12][CH2:13][N:14]([CH3:29])[C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.CO>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[C:1]([NH:9][CH:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:11](=[O:30])[CH2:12][CH2:13][N:14]([CH3:29])[C:15]([N:17]1[CH2:28][CH2:27][CH2:26][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(CCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The t-butyl ester product from part (d) (300 mg.) is treated for 1.5 hours with 3 ml. of trifluoroacetic acid, concentrated in vacuo and triturated to a solid with ether/hexane to give 250 mg. of (±)-1-[[[4-benzoylamino)-3-oxo-5-phenylpentyl]methylamino]carbonyl]-L-proline; m.p. 38°-68°; [α]D23 =-9.16° (c=1.2, methanol); Rf =0.71 [silica gel, chloroform:methanol:acetic acid (9:0.5:0.5)].