Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22]
Reactant: CCI
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2cccc3c2CCC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 24.5 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (75 mg, 0.234 mmol) in acetonitrile (10 mL) was added potassium carbonate (96 mg, 0.702 mmol) and ethyl iodide (109 mg, 0.702 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 24%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:7]([CH:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C:6]1[C:7]([CH:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:16][CH2:17]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ncccc3NC(=O)C(F)(F)F)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1cccnc1C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N-[(1-{4-[3-(2,2,2-Trifluoro-acetylamino)-pyridin-2-yl]-cyclohexyl}-azetidin-3-ylcarbamoyl)-methyl]-3-trifluoromethyl-benzamide (0.042 g, 0.073 mmol, as prepared in Example 17: Step B) was dissolved in methanol (3 mL), treated with a solution of powdered potassium carbonate (1.103, 0.730 mmol) in water (3 mL), and stirred at ambient temperature for 5 d, then heated to 70° C. under reflux condenser for 18 h. After removing the methanol in vacuo, the reaction was diluted with water and extracted thrice with 3:1 EtOAc/2-PrOH. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a beige solid.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1.C(#N)C>C(OCC)(=O)C>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: CC(CC(C)(C)O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(CC(C)(C)O)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Yield: 21.2 %

Procedure:
In a 125 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide (25 mg, 0.046 mmol), cesium fluoride (70 mg, 0.46 mmol) and 18-crown-6 (12 mg, 0.046 mmol) were combined with acetonitrile to give an off-white suspension. The reaction was stirred at reflux for 72 h. A large excess of CsF and 18-crown-6 was added and the reaction was heated for an additional 24 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated. The crude material was suspended in water and collected by filtration then triturated with 1:2 dichloromethane/heptane to afford 4 mg (21%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide as a yellow solid. MS: [M+Na]+=433, 1H NMR (300 MHz, DMSO-d6) δ: 12.83 (br. s., 1H), 9.10 (s, 1H), 8.57 (dd, J=8.9, 5.5 Hz, 1H), 8.41 (d, J=2.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.71 (dd, J=9.8, 1.9 Hz, 1H), 7.20 (td, J=9.1, 2.3 Hz, 1H), 4.35 (s, 1H), 4.29-4.43 (m, 1H), 4.16 (s, 3H), 1.83 (dd, J=14.4, 7.9 Hz, 1H), 1.73 (dd, J=16.6, 4.9 Hz, 1H), 1.31 (d, J=6.4 Hz, 3H), 1.15 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=2[C:34]([F:37])([F:36])[F:35])=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[C:34]([F:35])([F:37])[F:36])=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F)NC1CNC1
Product: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F)NC1CN(C2CCC(O)(c3nccs3)CC2)C1

Procedure:
The title compound was prepared as white solids from reductive amination of 4-hydroxy-4-thiazol-2-yl-cyclohexanone, as prepared in Example 40 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-2,5-bis-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:6][CH:5]([OH:7])[CH2:4]1)#[N:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])(=O)=O>ClCCl>[Si:29]([O:7][CH:5]1[CH2:6][C:3]([C:1]#[N:2])([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:4]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#CC1(c2ccc(F)cc2)CC(O)C1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC(C#N)(c2ccc(F)cc2)C1
Temperature: 25 °C
Yield: 104 %

Procedure:
3-cyano-3-(4-fluorophenyl)cyclobutan-1-ol (112, 19.8 g, 103.6 mmol) was dissolved in dichloromethane (200 mL) under argon, then 2,6-lutidine (27.78 g, 30.1 mL, 259 mmol) was added and the solution cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulphonate (32.9 g, 28.6 mL, 124.3 mmol) was added dropwise and the stirred reaction mixture was then allowed to warm up to room temperature overnight. The reaction mixture was washed successively with water, hydrochloric acid (0.1M), saturated sodium bicarbonate solution and brine before being dried over sodium sulphate. Filtration and evaporation gave 32.9 g of a yellow oil which was used in the next step without further purification. Rt=1.30 min (Method 18). Detected mass: 306.3 (M+H+).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])(=O)=O)=CC=1.[F:20][C:21]([F:31])([F:30])[CH2:22][CH2:23][S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:31][C:21]([F:20])([F:30])[CH2:22][CH2:23][S:24]([CH:27]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]#[CH:11])[C:28]#[N:29])(=[O:25])=[O:26]
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Reactant: C#CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCCCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of 1.0 g of 7-octynyl p-toluenesulfonate and 0.7 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of dimethyl sulfoxide was added 0.5 g of potassium carbonate at room temperature. The reaction mixture was stirred at room temperature for 2 hours, at 60° C. for 2 hours, and then at 90° C. for 6 hours. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.28 g of 2-(3,3,3-trifluoropropylsulfonyl)-9-decynenitrile (hereinafter referred to as the present compound (25)).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1OB(O)O.C1(C)C=CC=CC=1>C(O)C.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>[F:16][C:17]1[CH:22]=[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][CH3:31])[CH2:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[F:8]
Reactant: CCC[C@H]1CC[C@H](c2ccc(OB(O)O)c(F)c2)CC1
Reactant: Fc1cc(F)cc(Br)c1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](c2ccc(-c3c(F)cccc3F)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3,5-Difluorobromobenzene (30 g), tetrakis(triphenylphosphine)palladium (0) (1.8 g), ethanol (150 mL), and a 2 mol/L aqueous potassium carbonate solution (155 mL) were mixed with each other and heated to 50° C. A solution prepared by dissolving 2-fluoro-4-(trans-4-propylcyclohexyl)phenylboric acid (49.3 g) in ethanol (300 mL) was added thereto, and stirring was performed at 50° C. for five hours. After the temperature was decreased to room temperature by natural cooling, toluene (300 mL) was added thereto and the mixture was separated. The resulting organic layer was washed with a saturated saline solution (200 mL) twice. Anhydrous sodium sulfate was added to perform drying, and the organic solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography and recrystallized using ethanol to obtain 4-[2-fluoro-4-(trans-4-propylcyclohexyl)phenyl]-3,5-difluorobenzene (39.1 g). (2-2) The subsequent processes were performed by the same method as in Example 1 to obtain [3,5-difluoro-4-(2-fluoro-4-(trans-4-propylcyclohexyl)phenyl)phenyl]-(5,6,7-trifluoro-2-naphthyloxy)difluoromethane (20.5 g).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH2:13](Cl)Cl.CO.[Si](C=[N+]=[N-])(C)(C)C>C(O)(=O)C>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: ClCCl
Reactant: C#CCC1CCC(C(=O)O)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: C#CCC1CCC(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 88 (240 mg, 1.45 mmol) in 7:3 CH2Cl2:MeOH (10 mL) was added TMS Diazomethane (2.0 M in hexanes) (0.9 mL, 1.8 mmol) in 0.2 ml aliquots until the color remained yellow. The reaction was allowed to stir for an additional 0.25 hours at room temperature. After stirring, glacial acetic acid was added dropwise until the solution became colorless. The reaction was concentrated in vacuo to an oil which was purified by flash chromatography on silica gel using ether:petroleum ether (1:9) to yield 89 (210 mg, 80%) as a clear oil. 1H NMR (CDCl3) δ 3.60 (s, 3H), 2.25–2.13 (m, 1H), 2.08–1.94 (m, 3H), 1.95–1.90 (m, 2H), 1.49–1.31 (m, 3H), 1.10–0.93 (m, 2H); 13C NMR (CDCl3) δ 176.7, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3; APCI m/z (rel intensity) 181 (MH+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][N:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1)(=[O:37])=[O:36]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)=[O:29])[C:7]([N:47]1[CH2:48][CH2:49][CH:44]([N:41]2[CH2:40][CH2:39][N:38]([S:35]([CH3:34])(=[O:36])=[O:37])[CH2:43][CH2:42]2)[CH2:45][CH2:46]1)=[O:8]
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methanesulphonyl-4-piperidin-4-yl-piperazine.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[N:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]>CN(C=O)C>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:3]1[N:4]=[CH:5][N:1]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[C:22]#[N:23])[N:2]=1
Reactant: c1ccc(-c2nc[nH]n2)nc1
Reactant: N#Cc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2cnc(-c3ccccn3)n2)c1
Temperature: 145 °C

Procedure:
2-(1H-1,2,4-Triazol-3-yl)pyridine (0.24 g, 1.6 mmol), potassium carbonate (0.45 g, 3.2 mmol) and 3-fluorobenzonitrile (0.20 g, 1.6 mmol) were stirred in DMF (20 mL) at ambient temperature. The resulting reaction mixture was heated at 145° C. for 16 h, after which time it was quenched with H2O (30 mL) and diluted with EtOAc (200 mL). The EtOAc solution was washed with H2O (3×100 mL), then brine (100 mL) and dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with hexane:EtOAc (40:60) to afford 3-(3-pyridin-2-yl-1H-1,2,4-triazol-1-yl)benzonitrile as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:32](=[O:33])[CH2:31][N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Reactant: CN1CCN(CC(=O)O)CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)CN4CCN(C)CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 173) (150 mg, 0.59 mmol) and commercially available (4-methyl-piperazin-1-yl)-acetic acid (77 mg, 0.68 mmol) in accordance with the general method 14 described in example 119 and was obtained as an off-white solid (210 mg, 96%); MS: m/e=448.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)NC3CCCCC3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (350 mg) and cyclohexyl isocyanate (0.32 ml) in dry THF (15 ml) containing triethylamine (0.62 ml) was stirred at room temp for 48 h. The mixture was then evaporated and the residue partitioned between water and DCM. The dried extracts were evaporated giving the crude title compound as a white solid (616 mg, >100%, contaminated with dicyclohexyl-urea)
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3C=CC=CC=3)=[C:31]([NH:43][S:44]([CH2:47]CC3C=CC=CC=3)(=[O:46])=[O:45])[CH:30]=2)[OH:28])=[CH:17][CH:16]=1)C1C=CC=CC=1.C[OH:57]>C(O)(=O)C.[OH-].[OH-].[Pd+2].ClCCl>[C:36]([OH:57])(=[O:35])[CH3:37].[C:36]([OH:57])(=[O:35])[CH3:37].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:30]=2)[OH:28])=[CH:17][CH:16]=1
Reactant: CO
Reactant: O=C(NCCCCc1ccc(CCCCNC[C@H](O)c2ccc(OCc3ccccc3)c(NS(=O)(=O)CCc3ccccc3)c2)cc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCCCc2ccc(CCCCN)cc2)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
A mixture of {4-[4-(4-{2-[3-(benzylmethanesulfonylamino)-4-benzyloxyphenyl]-2-(R)-hydroxyethylamino}butyl)phenyl]butyl}carbamic acid benzyl ester (36) (0.41 g, 0.54 mmol), palladium dihydroxide (0.12 g, 10% Pd(OH)2 on carbon, 50% wet), ten drops of acetic acid, methanol (9 mL), and dichloromethane (6 mL) was stirred at rt for 16 h under atmospheric hydrogen pressure. The catalyst was removed by filtration through a Celite pad and the filtrate was concentrated by rotary evaporation and further dried under high vacuum to give the desired amine diacetic acid salt 39 as a white solid (0.30 g, 96%): m/z (ESI) 450 [C23H35N3O4S+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.F[C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.O>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:16]1[CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of potassium t-butoxide (12.3 g) in DMSO (100 mL) was added at once 3-chlorophenol (12.86 g). The resulting solution was stirred for 5 minutes at room temperature, then 3-fluoronitrobenzene (12.70 g) was added all at once. The resulting dark mixture was heated at 120° C. for 12 hours, cooled to room temperature then poured into water (700 mL). The resulting mixture was extracted with ether (2×200 mL). The organic fraction was washed with 2N NaOH (100 mL), then with water (100 mL). After drying (MgSO4), the solvent was evaporated and the resulting dark oil was distilled to give 3-(3-chlorophenoxy)nitrobenzene as a yellow oil, b.p. 135-140° C. at 0.05 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29](O)=[O:30])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][CH:57]([OH:65])[CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C>[OH:65][CH:57]([CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)[CH2:56][NH:55][C:29]([C:28]1[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=2)=[O:30]
Reactant: NCC(O)CN1CCOCC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCC(O)CN2CCOCC2)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 2-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (33 mg, 1.2 eq.), EDAC.HCl (47 mg, 1.2 eq.) and 1-amino-3-morpholin-4-yl-propan-2-ol (34 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.071 mL, 2.5 eq.). After stirring at rt for 2 weeks, the reaction was concentrated, diluted with DCM. Solid sodium bicarbonate was added to the mixture followed by stirring for 15 mins. The orange suspension was then loaded on to a silica gel to give the titled compound as an orange solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].O.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:27]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a mixture of sodium hydride (content, 60%; 36 mg) and anhydrous dimethylformamide (5 ml), a solution of the compound (224 mg) obtained in Example 318 in anhydrous dimethylformamide (3 ml) and ethyl iodide (0.072 ml) were successively added dropwise at 0° C. in a nitrogen atmosphere and stirred at room temperature for 24 h. Water was added to the reaction mixture, which was distilled under reduced pressure; thereafter, ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane ethyl acetate=1:1) to give 213 mg of the titled compound (yield, 87%).
Reaction SMILES: C(O[N:6]([CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=4[F:43])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:15]=1)=[O:12])[C:7](C)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:52]>Cl>[ClH:52].[ClH:52].[CH3:7][NH:6][CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH:21]2[CH2:22][CH2:23][N:24]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=4[F:43])=[CH:32][CH:33]=3)[CH2:25][CH2:26]2)[CH:15]=1)=[O:12]
Reactant: ClCCl
Reactant: CC(=O)N(CC(=O)Nc1ccc(C)c(C2CCN(Cc3ccc(Oc4cc(F)c(F)cc4F)cc3)CC2)c1)OC(C)(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CNCC(=O)Nc1ccc(C)c(C2CCN(Cc3ccc(Oc4cc(F)c(F)cc4F)cc3)CC2)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
2-[(tert-butoxy)-N-methylcarbonylamino]-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy) phenyl]methyl}(4-piperidyl))phenyl]acetamide was dissolved in CH2Cl2 (15 mL) and trifluoroacetic acid (5 mL) was added dropwise to the stirred solution. Stirring was continued for 30 minutes then the reaction mixture was concentrated in vacuo to give a gum. This was partitioned between CH2Cl2 (2×30 mL) and saturated aqueous NaHCO3 (30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the free base. This was dissolved in methanolic hydrogen chloride (1.6 M, 5 mL), and concentrated in vacuo to yield 2-(methylamino)-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]acetamide dihydrochloride (292 mg, 88% yield) as a white solid. LCMS (method A): 7.35 min, 498.3 (M+H)+; 1H NMR (D6-DMSO) δ 11.20 (br s, 1H), 10.68 (s, 1H), 9.03 (m, 2H), 7.84 (td, J=10.7, 7.7 Hz, 1H), 7.67 (m, 2H), 7.59 (dt, J=11.0, 8.0 Hz, 1H), 7.40 (m, 2H), 7.13 (d, J=8.5 Hz, 1H), 7.09 (m, 2H), 4.27 (d, J=5.1 Hz, 2H), 3.90 (t, J=5.7 Hz, 2H), 3.39 (d, J=11.8 Hz, 2H), 3.06 (m, 2H), 2.95 (m, 1H), 2.61 (t, J=5.4 Hz, 3H), 2.26 (s, 3H), 2.04 (m, 2H,), 1.86 (d, J=13.4 Hz, 2H).