Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH3:10][CH:4]([CH2:3][CH2:2][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C1COCCN1
Reactant: CCOC(=O)C(C)CCBr
Solvent: c1ccccc1
Product: CCOC(=O)C(C)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 40.0 g. (0.19 mole) of ethyl 4-bromo-2-methylbutyrate (Tetrahedron 21, 2966 (1965)), 66.0 g. (0.76 mole) of morpholine and 750 ml. of benzene was heated at 60°C. for 5 hours and stirred at room temperature for a total of 40 hours. A colorless solid was removed by filtration, and the mother liquor was evaporated to give a colorless, mobile residue. This material was combined with 250 ml. of ether and filtered to remove a small amount of additional solid. The solution was concentrated and the residue distilled to give the desired material as 38.0 g. (93%) of colorless liquid (b.p. 71°-73°C. at 0.10 mm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[N+:20]([O-])=O)[C:5]([NH:7][CH2:8][C:9]([O:11]CC(Cl)(Cl)Cl)=[O:10])=[O:6].CC(O)=O>CCOC(C)=O.[Zn]>[NH2:20][C:19]1[CH:18]=[CH:17][C:4]([C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: O=C(CNC(=O)c1ccc([N+](=O)[O-])c(F)c1)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)NCC(=O)O)cc1F
Temperature: 87.5 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl 2-(3-fluoro-4-nitrobenzamido)acetate (40 mg, 0.1 mmol), zinc dust (105 mg, 1.61 mmol) and AcOH (3 mL) was stirred at 85-90° C. for 15 min. The reaction mixture was attained to rt and diluted with EtOAc (30 mL). The solution was filtered through super cell and washed with EtOAc (2×5 mL). The residue obtained after evaporation of the solvent was chromatographed using chloroform:methanol (60:40) as eluents to give the product as an off-white color solid (17 mg, 75%), mp 198-200° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3].[CH3:44][NH:45][CH2:46][CH:47]([OH:50])[CH2:48][OH:49]>ClCCl>[OH:50][CH:47]([CH2:48][OH:49])[CH2:46][N:45]([CH3:44])[S:2]([C:5]1[CH:6]=[C:7]([CH:41]=[CH:42][CH:43]=1)[C:8]([NH:10][C:11]1[S:12][C:13]2[CH2:40][CH2:39][CH2:38][CH2:37][C:14]=2[C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)=[O:17])=[O:9])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CNCC(O)CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)N(C)CC(O)CO)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 83 mg of 3-(methylamino)propane-1,2-diol, and 2.5 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 241 mg of methyl 4-{2-[4-({[2-({3-[(2,3-dihydroxypropyl)(methyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a pale yellow foamed solid.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]2[CH2:24][CH2:23][O:22][CH:21]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:20]2)[CH:14]=1)[CH3:12])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:30]([O:29][C:27](=[O:28])[NH:26][CH2:25][C@@H:21]1[O:22][CH2:23][CH2:24][N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:11]([NH2:10])[CH3:12])[CH:14]=2)[CH2:20]1)([CH3:32])([CH3:31])[CH3:33]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1cccc(N2CCOC(CNC(=O)OC(C)(C)C)C2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(N)c1cccc(N2CCO[C@@H](CNC(=O)OC(C)(C)C)C2)c1
Yield: 89 %

Procedure:
The mixture of (S)-(1-{3-[2-(tert-butoxycarbonylaminomethyl)-morpholin-4-yl]-phenyl}-ethyl)-carbamic acid benzyl ester (600 mg, 1.3 mmol), palladium on C (10 wt %) (300 mg), and methanol (10 ml) was put onto hydrogenator and shaken at 50 psi of hydrogen for 2 days and one night. The mixture was filtered through Celite pad and washed with methanol. The filtrate was concentrated under vacuum. The sticky oil (89% yield) was used for next step without purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:35](Br)[CH:36]=[CH2:37]>CN(C)C=O>[CH2:37]([C:24]([CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:14][C:5]1[C:6]([C:10]([F:11])([F:12])[F:13])=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH:36]=[CH2:35]
Reactant: COC(=O)C(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1c([N+](=O)[O-])cccc1C(F)(F)F)c1ccc(OC)cc1
Yield: 97.6 %

Procedure:
[2-(2-Nitro-6-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (14.55 g; 31.96 mmole) was dissolved in dry dimethylformamide (90 ml) under argon. Prewashed 50% sodium hydride (1.85 g; 38.5 mmole) was added with stirring and stirring was continued for 20 minutes before allyl bromide (19.33 g; 159.8 mmole; 13.8 ml; d=1.398; 5 eq.) was added dropwise. The mixture was quenched (1N hydrochloric acid) after a few minutes of reaction time, and extracted with ethyl acetate (two times). The organic extract was washed with saturated potassium carbonate (two times), saturated sodium chloride, and dried (magnesium sulfate). The solution was concentrated on a high vacuum pump leaving 23.0 g. This material was flash chromatographed (silica gel/9:1-hexane:ethyl acetate) and the appropriate fractions were combined and concentrated giving 15.45 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:24])([F:23])[F:22])([O:16][Si](C)(C)C)[C:8]([F:26])([F:25])[CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:22])([F:23])[F:24])([OH:16])[C:8]([F:25])([F:26])[CH2:7][CH2:6][C:5]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(Cl)cc3c2CCC1(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(Cl)cc3c2CCC1(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6,8-Dichloro-2,2-difluoro-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.12 g, 0.27 mmol) was dissolved in THF (5 mL) and KOH (0.055 g, 1.1 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure to give the crude material which was purified by column chromatography [EtOAc-hexane (1:9) as eluant] to furnish the title compound. (0.012 g, 12%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.41 (br s, 1H), 7.44 (s, 1H), 7.3 (s, 1H), 3.35 (br s, 1H), 2.97 (t, J=12.0 Hz, 2H), 2.61-2.54 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([O:33][C:34]2[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=2)[C:9]([NH:12][C:13]2[S:17][N:16]=[C:15]([CH:18]3[CH2:24][CH:23]4[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[N:14]=2)=[N:10][CH:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:20]12[NH:25][CH:23]([CH2:22][CH2:21]1)[CH2:24][CH:18]([C:15]1[N:14]=[C:13]([NH:12][C:9]3[N:10]=[CH:11][C:6]([S:5][CH2:4][C:3]([O:2][CH3:1])=[O:41])=[CH:7][C:8]=3[O:33][C:34]3[C:35]([CH3:40])=[N:36][CH:37]=[CH:38][CH:39]=3)[S:17][N:16]=1)[CH2:19]2
Reactant: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.7 %

Procedure:
tert-Butyl 3-(5-(5-(2-methoxy-2-oxoethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (461 mg, 0.770 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (5 mL) was added. The reaction was stirred at ambient temperature for 15 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to afford methyl 2-(6-(3-(8-azabicyclo[3.2.1]octan-3-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)acetate (402 mg, 0.806 mmol, 105% yield) as a pale yellow foam.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].C(#N)C.[F:9][C:10]([F:22])([F:21])[C:11]1[C:12]([S:17]([NH2:20])(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>C(N(CC)CC)C>[F:21][C:10]([F:9])([F:22])[C:11]1[C:12]([S:17]([NH:20][C:2](=[O:3])[O:4][CH3:5])(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)Cl
Reactant: NS(=O)(=O)c1ncccc1C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)NS(=O)(=O)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
Methyl chloroformate (3.31 g, 35 mmol) was added under cooling with ice to a dry acetonitrile (150 ml) solution containing 3-trifluoromethylpyridine-2-sulfonamide (7.91 g, 35 mmol) and triethylamine (16 ml), and the mixture was continuously stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure, and the residue was dissolved in 300 ml of water. A small amount of insoluble substances were removed by filtration, and the filtrate was adjusted to pH of 1 to 2 with concentrated hydrochloric acid under cooling with ice. Precipitated crystals were collected by filtration and thoroughly washed with water, then washed with a solvent mixture of ethyl ether/n-hexane and dried to obtain 4.4 g of desired methyl N-(3-trifluoromethylpyridine-2-sulfonyl)carbamate. Melting point: 128°-129° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[O:9])=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1.CO.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CCOC(C)=O>[C:18]1([C:5]2[CH:6]=[C:7]3[C:8](=[O:9])[C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[CH:12]=[CH:1][C:2]3=[N:3][CH:4]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ncc(-c2ccccc2)cc1C(=O)c1ccccc1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c2ccccc2ccc2ncc(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A flask was charged with 2-[(2-methyl-5-phenylpyridin-3-yl)carbonyl]benzaldehyde (6.2 mg, 0.02 mmol) and MeOH (1 mL). LiHMDS (25 μl, 1.0 M in THF) was added and the vessel was heated in the Biotage Initiator series microwave for 30 min. at 100° C. The mixture was then diluted with EtOAc, washed with water and brine, then dried over Na2SO4. The solution was concentrated in vacuo and purified by reverse phase HPLC (0-100% CH3CN/water with a 0.1% TFA modifier) to afford the title compound. 1H NMR (600 MHz, CD3OD) δ 9.15 (d, 1H), 8.76 (d, 1H), 8.25 (d, 1H), 7.77 (m, 4H), 7.66 (t, 1H), 7.54 (t, 21), 7.45 (m, 2H0, 7.36 (d, 1H). LRMS (APCI) calculated for C20H14NO [M+H]+, 284.1; found 283.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([CH2:26][CH2:27][C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[C:24]([CH3:36])[NH:23][C:22]=1[CH:37]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:37][C:22]4[NH:23][C:24]([CH3:36])=[C:25]([CH2:26][CH2:27][C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[O:29])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)N1CCOCC1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (86 mg, 0.31 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-3-oxo-propyl)-1H-pyrrole-2-carbaldehyde (83 mg, 0.31 mmol) and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound. MS 525 [M++1].
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:9](=O)[CH2:10][OH:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][N:4]([CH2:9][CH2:10][OH:11])[CH2:3]1
Reactant: O=CCO
Reactant: CC1(C)CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(C)CN(CCO)CCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dissolve 2,2-dimethylmorpholine (151 mg, 1.0 mmol) in 1,2-dichloroethane (3 mL) and add glycolaldehyde (60 mg, 1.0 mmol). Stir at room temperature for 30 min followed by addition of NaBH(OAc)3 (233 mg, 1.1 mmol). Stir 3 h, then quench by adding 30 mL of 1N NaOH. Pour into a separatory funnel and extract with EtOAc (2×50 mL). Wash the combined organic layers with brine (50 mL). The crude alcohol was used as is without further purification. MS (ES+) 160.2 (M+1)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:22])([CH3:21])[C:9]=3[O:23][C:4]=2[CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[F:39][C:40]1[CH:41]=[C:42]([SH:46])[CH:43]=[CH:44][CH:45]=1>[Cu]I>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:5]3[CH:6]=[CH:7][C:2]([S:46][C:42]4[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=4)=[CH:3][C:4]=3[O:23][C:9]=2[C:10]1([CH3:22])[CH3:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3cc(I)ccc23)C1(C)C
Reactant: Fc1cccc(S)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(oc3cc(Sc4cccc(F)c4)ccc23)C1(C)C
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To tert-butyl 7-iodo-1,1-dimethyl-3,4-dihydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P30 (0.505 g, 1.18 mmol) was added sodium tert-butoxide (341 mg, 3.55 mmol), copper(I) iodide (20 mg, 0.08 mmol), 1,2-ethanediol (132 μL, 2.38 mmol), N,N-dimethylformamide (17 mL, 210 mmol), and finally 3-Fluoro-benzenethiol (101 μL, 1.19 mmol). The reaction mixture was flushed with N2 and heated at 120° C. under N2. After 15 h, the reaction mixture was concentrated under high vacuum, the residue dissolved in 5% methanol-methylene chloride and then filtered through a celite-silica plug. The filtrate was concentrated and purified by silica chromatography (EtOAc/hexane) to afford the product as a pale yellow oil. MS m/z: 428 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][OH:12])[CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)cc(CO)c1
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cc(Br)cc(CO)c1
Reaction time: 16 h

Procedure:
To 3-bromo-5-(hydroxymethyl)benzoic acid (7.0 g, 30 mmol) in 20% methanol/benzene (100 mL) is added trimethylsilyldiazomethane (2M in hexanes), and the reaction is stirred 16 h. The reaction is concentrated under reduced pressure to afford the title compound. ESI MS m/z 244.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[N+:29]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35])([O-:31])=[O:30]>>[N+:29]([C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:7])=[CH:22][CH:23]=1)=[O:35])([O-:31])=[O:30]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Product: O=C(Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1)c1ccccc1[N+](=O)[O-]
Yield: 62.4 %

Procedure:
4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (31.7 mg, 0.083 mmol) and 2-nitrobenzoic acid (38 mg, 0.10 mmol) were reacted as described in example 34 to give 26.7 mg of 4-[[(2-nitrophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine, HR—FAB—MS: obs. mass 516.2113. Calcd. mass 516.2134 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH2:8][CH:9]=O)[CH3:2].[C:22]1([C@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH2:8][CH:9]=[N:30][C@@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:29])[CH3:2]
Reactant: CCOC(=O)CN(CCC=O)C(=O)OCc1ccccc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN(CCC=N[C@H](C)c1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
2[(Benzyloxycarbonyl)-(3-oxo-propyl)-amino]-acetic acid ethyl ester (0.32 g; 1.09 mmol)) is dissolved in dichloromethane (10 ml). Molecular sieves (2 g; 3 Angström) are added. The reaction mixture is cooled to 0° C. and (R)-(+)-1-phenylethylamine (0.132 g; 1.09 mmol) is added and the mixture is stirred at 0° C. for 4 hours. The solids are filtered off and the solvent is removed under reduced pressure. 0.35 g of a light yellow oil (yield 93%) is obtained. The obtained imine is directly used in the next step.
Reaction SMILES: [BH4-].[Na+].[CH:3]1[C:8]([CH2:9][C@@H:10]([NH2:14])[C:11](O)=[O:12])=[CH:7][CH:6]=[C:5]([F:15])[CH:4]=1.II.CO>C1COCC1>[F:15][C:5]1[CH:4]=[CH:3][C:8]([CH2:9][C@@H:10]([NH2:14])[CH2:11][OH:12])=[CH:7][CH:6]=1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](CO)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To the solution of sodium borohydride (0.48 g, 13.1 mmol) in THF (10 mL) was added D-4-fluorophenylalanine (1.0 g, 5.5 mmol). After cooling to 0° C., the solution of iodine (1.4 g, 5.5 mmol) in THF (10 mL) was added dropwisely. The mixture was stirred at reflux for 18 h. after cooling to the room temperature, methanol (7 mL) was added to stop the reaction. After removal of solvent, 20% potassium hydroxide (50 mL) was added. The mixture was stirred for 4 h and extracted with methylene chloride (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-10% methanol in methylene chloride in 30 min afforded (R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamine (0.73 g, 79%).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][CH2:10]C2C=C3C(=O)NC(=O)C3=CC=2)=[CH:3][CH:2]=1.O.[NH2:29]N>C(O)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][CH2:9][CH2:10][NH2:29])=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2cc(CCC=Cc3ccc(-c4ccccc4)cc3)ccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NCCC=Cc1ccc(-c2ccccc2)cc1

Procedure:
A mixture of 280 ml of ethanol, 7.9 g of the product of Stage A and 1.3 ml of hydrazine hydrate was refluxed and then allowed to return to ambient temperature. The precipitate was filtered off and washed with ethanol. After concentration, the product was poured into a 2N hydrochloric acid solution and extraction was carried out with ethyl acetate. The organic phase was washed with water, dried, filtered and concentrated under reduced pressure to obtain 2.89 g of the desired product melting at approximately 188°-194° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([CH2:21][O:22][C:23]2[C:28]([CH3:29])=[CH:27][C:26]([Br:30])=[CH:25][C:24]=2[CH3:31])[CH2:16]1)=O)(C)(C)C>ClCCl>[Br:30][C:26]1[CH:27]=[C:28]([CH3:29])[C:23]([O:22][CH2:21][C@H:17]2[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]2)=[C:24]([CH3:31])[CH:25]=1
Reactant: Cc1cc(Br)cc(C)c1OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1OC[C@H]1CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (80 mL) was added dropwise during 20 minutes to a solution of (S)-N-(tert-butoxycarbonyl)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine (37.0 g, 92.9 mmol) in dichloromethane (250 mL) at a temperature of 5° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The solvent was then evaporated and the residue partitioned between 25% aqueous sodium hydroxide (200 mL) and ether (500 mL). The organic layer was removed and the aqueous phase extracted with additional ether (2×300 mL). The combined ether layers were washed with brine (100 mL), stirred over magnesium sulfate for 2 hours, and filtered to give a solution of (S)-3-(4-bromo-2,6-dimethylphenoxymethyl)piperidine.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[C:36]([CH3:37])=[N:35][N:34]=[N:33]1)[C:26](O)=[O:27]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[C:36]([CH3:37])=[N:35][N:34]=[N:33]3)=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1F
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.58 min; Mass spectrum (ESI+): m/z=508 [M+H]+.