Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][N:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][N:20]=3)=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCNC3)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
Combine 6-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (4.0 g, 10.83 mmol), CH2Cl2 (100 mL), and TFA (25 mL). Stir at room temperature for 12 hours and add 1.0 M K2CO3 and CHCl3 to the reaction. Separate the organic layer, wash with brine, and dry over Na2SO4. Concentrate under reduced pressure and add mixture to 2, 10 g SCX columns, wash with MeOH, and elute with 1.0 N NH3 in MeOH. Concentrate to afford 2.91 g, 10.8 mmol (71% yield) of the title compound as a white foam: 1H NMR (500 MHz, DMSO-d6): 2.9-3.1 (2H, m), 3.2-3.5 (2H, m), 4.2-4.4 (2H, m), 6.9-7.2 (3H, m), 7.2-7.4 (1H, m), 7.4-7.6 (1H, m), 7.9-8.1 (1H, m), 8.2-8.4 (1H, m), 8.5-8.7 (1H, m), 8.2-9.4 (2H, m); MS m/z/269 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=3)[NH2:28])[CH2:19][CH2:18]2)[N:8]=1>N1C=CC=CC=1>[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:29]=[CH:30][CH:31]=3)[CH2:21][CH2:22]2)[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Solvent: c1ccncc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NS(C)(=O)=O)c4)CC3)cccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Methanesulfonyl chloride (8 μL; 1.2 eq) was added dropwise to a solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (0.03 g; 1 eq) in pyridine (0.5 mL). The reaction was stirred at r.t. overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (1 mL) and a saturated aqueous solution of sodium hydrogen carbonate (1 mL), extracted into dichloromethane (3×2 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography, eluting with a gradient from dichloromethane to dichloromethane/MeOH (98/2) affording the title compound in 44% yield (0.016 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][C@@H:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]4[C:42]([O:44]CC)=[O:43])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.[OH-].[Na+].Cl>O1CCOCC1>[CH3:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:33]([NH:35][C@@H:36]4[CH2:41][CH2:40][CH2:39][CH2:38][C@H:37]4[C:42]([OH:44])=[O:43])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@H]1NC(=O)C1(c2ccc(-c3ccc(CCN4CCC[C@H]4C)cc3)cc2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)N[C@@H]4CCCC[C@H]4C(=O)O)CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1R,2R)-ethyl 2-(1-(4′-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxamido)cyclohexanecarboxylate 2,2,2-trifluoroacetate (2.7 mg, 4.19 μmol) was added 5M sodium hydroxide (0.017 mL, 0.084 mmol). The reaction was stirred at room temperature overnight. The mixture was neutralized with 4M HCl in dioxane. The mixture was concentrated and triturated with acetonitrile to give the title compound. LCMS m/z=503.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].C(O)(=O)C.OO>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:15]=1)=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:8][N:16]=2
Reactant: Cc1ccc(N)c(C(=O)c2ccccc2)c1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2noc(-c3ccccc3)c2c1

Procedure:
A solution of 31.6 g (0.15 mole) of 5-methyl-2-aminobenzophenone, 350 ml of glacial acetic acid and 17 ml of 30% hydrogen peroxide was let stand at ambient temperature for 72 hr. The solution was poured into 2.5 liters of water. The mixture was let stand at ambient temperature for several days until the residue became crystalline. The solid was collected by filtration, dried, and chromatographed on 250 g silica gel to give 12.5 g (40%) of pale yellow solid, m.p. 64°-66° C. (after recrystallization from 2-propanol).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[Cl:17]>N1C=CC=CC=1>[Br:1][C:2]1[C:7]([NH:8][S:18]([C:13]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([CH3:10])[CH:12]=2)(=[O:19])=[O:20])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(Cl)cnc2Br)ccc1Cl
Reaction time: 18 h

Procedure:
To a stirred solution of 2-bromo-5-chloro-pyridin-3-ylamine (4.12 g, 20 mmol) in anhydrous pyridine (100 mL) was added 3-methyl-4-chlorobenzenesulfonyl chloride (6.35 g, 26 mmol) and the progress of the reaction was followed by LCMS. The reaction mixture was stirred overnight (18 h), then concentrated to remove as much of the pyridine as possible. The residue was dissolved in THF and was stirred 18h with aqueous sodium hydroxide (20 mL) in THF to cleave the bis-sulfonamide. The reaction mixture was subsequently neutralized with aqueous HCl and extracted with EtOAc; the organic phase was washed with water (2×100 mL), brine, and then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using EtOAc-hexane to provide N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-methyl-benzenesulfonamide as a white crystalline solid. MS m/z 397.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (6.43 g, 35.9 mmol) and Et3N (5.50 ml, 39.5 mmol) in THF (70 ml) was added phenyl isocyanate (3.90 ml, 35.9 mmol), and the reaction mixture was stirred at room temperature for 4 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-(N′-phenylureido)phenylacetate (9.64 g, 90%) as a white crystalline powder. mp 153-155° C.; 1H-NMR (CDCl3) δ1.26 (t, J=7.1 Hz, 3 H), 3.52 (s, 2 H), 4.15 (q, J=7.1 Hz, 2 H), 6.98-7.04 (m, 1 H), 7.07-7.11 (m, 4 H), 7.18-7.25 (m, 5 H), 7.42 (s, 1 H); MS (FAB) m/z 299 (M++1); Anal. Calcd. for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.22; H, 6.10; N, 9.36.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[NH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]([CH3:32])([CH3:31])[C:28](=[O:30])[NH:29][C:24]=2[CH:23]=1>CS(C)=O.C(OC(=O)C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:34]=[CH:33][C:25]3[O:26][C:27]([CH3:31])([CH3:32])[C:28](=[O:30])[NH:29][C:24]=3[CH:23]=2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: CC1(C)Oc2ccc(N)cc2NC1=O
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(C)Oc2ccc(Nc3nc(Cl)nc4[nH]ccc34)cc2NC1=O
Temperature: 100 °C
Yield: 48.5 %

Procedure:
To a solution of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.056 g, 0.30 mmol) in dimethylsulfoxide (1 mL) was added DIPEA (0.12 mL, 0.60 mmol) and 6-amino-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.085 g, 0.44 mmol). After heating at 100° C. for 15 h, the mixture was diluted with ethylacetate and sequentially washed with saturated NaHCO3 and brine. The organic extracts were dried over Na2SO4 and concentrated to give 6-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (0.05 g).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][CH:12]=1)=O.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:4]([C:2]#[N:1])=[C:5]([CH:22]=1)[O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2C(N)=O)c1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
The above amide (490 mg) and triethylamine (0.37 ml) in dichloromethane (10 ml) was treated dropwise with trichloroacetyl chloride (0.16 ml) in dichloromethane (10 ml) with stirring at 0-5° C. After 0.5 h, more trichloroacetyl chloride (0.8 ml) was added and stirring continued for 0.25 h. The reaction mixture was washed with aqueous sodium bicarbonate solution, dilute hydrochloric acid, water, then brine, and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography (silica gel, dichloromethane as eluent) to give 1,1-dimethylethyl {[3-(5-chloro-2-cyanophenoxy)phenyl]methyl}carbamate (240 mg) as a colourless solid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:17][C@@H:16]2[C@@H:11]([C@@H:12]([Cl:30])[CH2:13][CH2:14][C:15]2([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:30].[Cl:30][C@@H:12]1[C@@H:11]2[C@@H:16]([CH2:17][NH:9][CH2:10]2)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2Cl
Agent: Cl
Solvent: C1COCCO1
Product: Cl[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 192.9 %

Procedure:
10 cm3 of a 6.3N solution of hydrochloric acid in dioxane are added to a solution of 1.03 g of (3aR,7S,7aR)-2-tert-butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindole in 5 cm3 of dioxane. The reaction mixture is stirred at room temperature for 2 hours and then concentrated to dryness under reduced pressure (2.7 kPa). 0.84 g of (3aR,7S,7aR)-7-chloro-4,4-diphenyl-perhydroisoindole hydrochloride is obtained in the form of a solid which is used in the crude state in the next test.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O>[CH3:31][C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[CH3:2])=[CH:11][CH:12]=2)=[CH:21][CH:22]=1)([CH3:30])[C:27]([OH:29])=[O:28]
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C(C)(C)C(=O)O)cc2)cc1
Temperature: 150 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50.9 mg, 0.189 mmol), 2-(4-chlorophenyl)-2-methylpropanoic acid (50 mg, 0.252 mmol), Na2CO3 (107 mg, 1.007 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (1.782 mg, 2.52 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was heated under microwave irradiation at 150° C. for 10 min. To the resulting mixture was added 2 M HCl (8 mL) and extracted with 5% EtOAc/hexane (10 mL). To the aqueous phase was added ACN (2 mL) to dissolve the solid precipitates. The mixture was purified by HPLC. LCMS m/z=352.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.12 (d, J=13.6 Hz, 0.4H), 1.35 (d, J=6.4 Hz, 2.6H), 1.48 (s, 6H), 1.57-1.72 (m, 1H), 1.89-2.00 (m, 2H), 2.09-2.21 (m, 1H), 2.93-3.11 (m, 4H), 3.22-3.35 (m, 1H), 3.37-3.48 (m, 1H), 3.62-3.75 (m, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.52 (d, J=7.9 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:7]1[CH2:6][CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]1=[O:1]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CCOC(=O)C1CCCC(=CN(C)C)C1=O

Procedure:
Ethyl 2-oxo-cyclohexanecarboxylate (38 mg, 0.22 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (49 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 226.1 [(M+H)+].
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH2:14][C:15]([C:17]1[CH:21]=[C:20]([CH2:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])[N:19]([CH2:34][CH2:35][CH3:36])[N:18]=1)=O.C(N(CC)CC)C>ClCCl>[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH3:24])[N:19]([CH2:34][CH2:35][CH3:36])[N:18]=1)#[N:14]
Reactant: CCCn1nc(C(N)=O)cc1CC(C)(C)NC(=O)OC(C)(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc(C#N)cc1CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
A solution of trifluoroacetic anhydride (3.93 mL, 27.8 mmol) in dichloromethane (51 mL) was added slowly to a 0° C. solution of tert-butyl 2-[3-(aminocarbonyl)-1-propyl-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate (8.21 g, 25.3 mmol) and triethylamine (10.6 mL, 75.9 mmol) in dichloromethane (51 mL). After the addition was complete, the cooling bath was removed and the solution was stirred for 90 minutes. The solution was transferred to a separatory funnel and washed with 2 M aqueous sodium carbonate (200 mL). The aqueous layer was extracted twice with chloroform. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an off white solid that was recrystallized from 10% ethyl acetate in hexanes, isolated by filtration, and dried to yield 6.77 g of tert-butyl 2-(3-cyano-1-propyl-1H-pyrazol-5-yl)-1,1-dimethylethylcarbamate as a white crystals, mp 115-116° C. MS (ESI) m/z 307 (M+H)+; Anal. Calcd for C16H26N4O2: C, 62.72; H, 8.55; N, 18.28. Found: C, 62.61; H, 8.46; N, 18.52.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[F:13][C:14]([Si](C)(C)C)([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(Cl)Cl.O>[OH:12][C:8]1([C:14]([F:16])([F:15])[F:13])[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC2(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 73.3 %

Procedure:
To a stirred solution of 5-methoxy-1-indanone (1.00 g, 6.17 mmol) and trifluoromethyltrimethylsilane (1.32 g, 9.26 mmol) in dry THF (15 ml) was added 1.0M THF solution of tetrabutylammonium fluoride (0.05 ml) with ice-cooling. The reaction mixture was stirred at room temperature for 21 h. To a mixture was 1N HCl (20 ml). and stirred at room temperature for 25 h. The reaction mixture was diluted with CH2Cl2-water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined solution was washed with water and brine, dried (MgSO4) and concentrated in vacuo to give crude product as a dark yellow oil. The crude product was purified by column chromatography on silica gel with hexane-ethyl acetate(5:1-3:1) to give Compound 62 (1.05 g, 73%) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:11]([CH3:15])[C:12]([OH:14])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[S:22]1[CH:26]=[N:25][N:24]=[C:23]1[NH2:27]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:11]([C:15]3[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=3)[C:12]([NH:27][C:23]3[S:22][CH:26]=[N:25][N:24]=3)=[O:14])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C(=O)O)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: Nc1nncs1
Product: O=C(Nc1nncs1)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
Example 152 was prepared from 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid (10 and 30 mg, 0.03 and 0.88 mmol) and 1,3,4-thiadiazol-2-amine using General Coupling Method A to give 4 mg (% yield) and 6 mg of the respective diastereomers. MS found: (M+H)+=426. NMR(CDCl3) δ 8.8 (s, 1H); 7.97-8.01 (d, 1H); 7.60 (s, 1H) 7.0-7.59 (m, 12H); 4.85 (d, 1H); 4.56 (d, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14](=[O:26])[NH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:17][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:29][C:30]([NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:31]>CN(C=O)C>[CH2:3]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14](=[O:26])[N:15]([CH2:29][C:30](=[O:31])[NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:17][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(-c2ccccc2Cl)[nH]c1=O)OCc1ccccc1
Reactant: O=C(CI)NCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccccc2Cl)ccc(NC(=O)OCc2ccccc2)c1=O)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a suspension of NaH (60% in mineral oil, 287 mg, 7.17 mmol, 1.2 eq.) in anhydrous DMF (12 mL) is added [6-(2-chloro-phenyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-carbamic acid benzyl ester (15A) (Bernstein, P. R. et. al., J. Med. Chem., vol. 37, p 3313-3326 (1994)) (2.121 g, 5.98 mmol). After being stirred for 30 minutes, the orange solution is cooled to 0° C. and 2-iodo-N-phenethyl-acetamide (1.902 g, 6.58 mmol, 1.1 eq.) is added. The mixture is stirred at room temperature for 3 hours and is quenched with 1 N HCl (8 mL), extracted with ethyl acetate (3×). The organic layer is washed in sequence with 1 N HCl, saturated Na2S2O3, water and brine; is dried over anhydrous Na2SO4 and concentrated. The residue is purified via silica gel chromatography (2-10% ethyl acetate in dichloromethane) to provide compound 15B as a yellow solid (605 mg, 20%):
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C@@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11][C@H:10]1[CH2:24]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:31]([CH2:24][C@H:10]1[C@H:9]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:30])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:11]1)=[N+:32]=[N-:33]
Reactant: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN=[N+]=[N-]
Temperature: 60 °C
Yield: 94.5 %

Procedure:
A mixture of crude methanesulfonic acid trans-4-(benzyl-methyl-amino)-1-[2-(4-fluorophenyl)-ethyl]-piperidin-3-ylmethyl ester (139 mg, 294 μmol) and sodium azide (58 mg, 882 μmol) in N,N-dimethylformamide (2 mL) was heated at 60° C. for 20 hours, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed three times with water, dried over sodium sulfate, and concentrated under vacuum to provide a gum (106 mg, 95%) which was used without purification. 1H NMR (300 MHz, CDCl3) δ7.33 (m, 5H), 7.16 (m, 2H), 6.99 (t, J=9 Hz, 2H), 3.70 (m, 2H), 3.52 (d, J=13 Hz, 1H), 3.41 (m, 1H), 3.20 (m, 2H), 2.83 (m, 2H), 2.61 (m, 2H), 2.42 (m, 1H), 2.3-1.8 (m, 4H), 2.19 (s, 3H), 1.75 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].F[C:10]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][O:6][C:10]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CN(C)CCO
Reactant: N#Cc1ccc(C(F)(F)F)cc1F
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCOc1cc(C(F)(F)F)ccc1C#N
Temperature: 60 °C

Procedure:
To N,N-dimethylaminoethanol (15 mL) cooled at 0° C. was added NaH 60% (1.15 g, 4 mol eq) and then 2-fluoro-4-trifluoromethyl-benzonitrile (1 mL, 7.18 mmol). The mixture was heated at 60° C. for 4 h then the solvent was removed at reduced pressure and water was added to the residue. The aqueous phase was extracted with EtOAc (3×30 mL), the organic phases were dried over sodium sulfate and evaporated to dryness to give 26b as pale yellow oil (2.1 g, quantitative yield). 1HNMR (DMSO, 200 MHz) δ 1.21 (s, 3H), 1.31 (s, 3H), 2.21 (t, 2H, J=8), 2.48 (t, 2H, J=8), 6.54 (dd, 1H, J=2), 6.82 (m, 2H).
Reaction SMILES: [CH:1]([CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35])=O.Cl.[NH2:37][OH:38].C([O-])(=O)C.[Na+]>CO.O>[OH:38][N:37]=[CH:1][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:24][C:25]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[O:26])([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:15])[C:5]1=[O:35]
Reactant: NO
Reactant: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=NO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
In 1 ml of methanol was dissolved 0.050 g of (+)-1-formylmethyl-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one, and a solution of 0.021 g of hydroxylamine hydrochloride and 0.021 g of sodium acetate in 1 ml of water was added thereto. The resulting mixture was stirred at room temperature for 1 hour and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=1/1) to give 0.045 g of the title compound.