Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[N+](=[CH2:13])=[N-]>CO>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:13])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: Nc1cccnc1C(=O)O
Solvent: CO
Product: COC(=O)c1ncccc1N
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
3-Aminopicolinic acid (115) (0.585 g, 4.24 mmol) was dissolved in MeOH (absolute, 45 mL). The solution was stirred while an ethereal solution of diazomethane was added until a yellow color persisted (~30 mL). The solution was stirred an additional 30 min, and the solvent rota-evaporated. The resulting residue was dried under reduced pressure at room temperature to yield 0.635 g (98.5%) of crude 116 as a yellow residue. The crude residue was chromatographed on a column of silica (12 g, Mallinckrodt, grade 62, mesh 60-200, used as received) using CHCl3 -MeOH [19:1, (180 mL), 7:3 (100 mL), 1:1 (100 mL), 100% MeOH (150 mL)]. After collecting appropriate fractions, rota-evaporating off the solvent and drying under reduced pressure at 25° C., 0.333 g (51.7%) of 116 was obtained as a yellow solid; mp 139°-146° C.; Rf =0.54 [CHCl3 -MeOH (9:1)]. IR (KBr) 3455, 3295, 3160, 1689, 1617, 1408, 1335, 1244, 1115. 1H NMR (CDCl3) δ3.98 (t, J=7.2, 3, CH3O--), 5.73 (d, J=1.8, 2, NH2), 7.05 (dd, J1 =1.2, J2 =8.4, 1, H-4), 7.22 (dd, J1 =4.2, J2 =8.4, 1, H-5), 8.07 (dd, J1 =1.2, J2 =4.2, 1, H-6).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[C:11]([NH:13]C(=O)C(F)(F)F)[CH:10]=[CH:9][C:8]=1[S:20](Cl)(=[O:22])=[O:21].[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:32][O:31][B:30]([OH:33])[C:29]=2[CH:34]=1.N1C=CC=CC=1>C(#N)C>[NH2:13][C:11]1[CH:10]=[CH:9][C:8]([S:20]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[CH2:32][O:31][B:30]([OH:33])[C:29]=3[CH:34]=2)(=[O:21])=[O:22])=[C:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:12]=1
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c(Cc2ncco2)c1)C(F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Cc2ncco2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(oxazol-2-ylmethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (450 mg, 1.2 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (212 mg, 1.42 mmol) in 10 mL of ACN was added pyridine (228 uL, 2.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow residue (540 mg, yield 92%). A small portion of the crude mixture was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:25])([F:24])[F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:34](=[N:36][OH:37])[NH2:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:38](N1C=CN=C1)(N1C=CN=C1)=[O:39].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[C:22]([F:24])([F:23])[F:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:34]3[NH:35][C:38](=[O:39])[O:37][N:36]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3C(F)(F)F)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (169 mg, 0.315 mmol) and 1,1′-carbonyldiimidazole (56.2 mg, 0.35 mmol) dissolved in acetonitrile (3.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.188 mL, 1.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C26H27ClF3N7O2 [M+H]+ 562. found 562. 1H NMR (500 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.95 (s, 1H), 8.80 (s, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 5.40-5.31 (m, 1H), 3.95-3.85 (m, 1H), 3.80-3.72 (m, 2H), 3.59-3.51 (m, 1H), 2.44-2.33 (m, 1H), 2.11-1.95 (m, 2H), 1.95-1.83 (m, 1H), 1.42-1.32 (broad, 2H), 1.11-0.98 (broad, 2H), 0.89 (d, J=12.1, 1H), 0.67 (d, J=6.3, 3H), 0.65-0.53 (m, 2H), 0.53-0.34 (m, 3H).
Reaction SMILES: Br[CH2:2][O:3][CH3:4].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1.[H-].[Na+]>O>[CH3:4][O:3][CH2:2][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: COCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromomethyl-methylether (0.87 ml) was added dropwise to a stirred suspension of p-hydroxyacetophenone (1 g) and sodium hydride (0.44 g) at 0° C. under nitrogen. The mixture was stirred for 1 h at room temperature. Then water was added and the mixture was extracted with ethylacetate. The organic layer was dried over magnesium sulphate and concentrated in vacuo to leave p-methoxymethoxyacetophenone (1.4 g) as yellow solid which was processed without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH2:6])[CH2:3][CH2:2]1.C([O:9][C:10]([C:12]1[C:17]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=2[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=1[CH3:30])=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:1]1([CH2:4][O:5][NH:6][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[F:26])=[C:16]([CH3:27])[C:15](=[O:28])[N:14]([CH3:29])[C:13]=2[CH3:30])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1C
Reactant: NOCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C(=O)NOCC3CC3)c(C)n(C)c(=O)c2C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
O-cyclopropylmethyl-hydroxylamine (0.046 g, 0.527 mmol) was added to a solution of 4-(2-fluoro-4-methylphenylamino)-1,2,5-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (0.070 g, 0.211 mmol) in THF (2 mL). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (1.05 mL, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 1 hour, the reaction was quenched by addition of a saturated aqueous solution of NaHCO3 and partitioned between EtOAc and brine. The aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by flash column chromatography (30:1 methylene chloride/MeOH) gave 0.032 g (40%) desired product as a yellow solid; MS ESI (+) m/z 374 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 6.91 (d,1H), 6.83 (d, 1H), 6.63 (t, 1H), 3.59 (s, 3H), 3.47 (d, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.86 (s, 3H) 0.99 (m, 1H) 0.48 (m, 2H) 0.18 (m, 2H). 19F (376 MHz, CD3OD)-132.1 (s, 1F).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:33].[C:34]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:33])=[C:2]([NH:1][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCC1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3CCCC3)cc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172) and cyclopentanone by General Procedure T.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[C:10]([C:13]1[O:14][C:15](=O)[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][C:19]([Br:29])=[CH:18][CH:17]=2)(=[O:12])[CH3:11]>>[C:10]([C:13]1[N:6]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)[C:15](=[O:14])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:20][C:19]([Br:29])=[CH:18][CH:17]=2)(=[O:12])[CH3:11]
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: NCc1cccc(F)c1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1cccc(F)c1

Procedure:
In the same manner as in Example 411, the title compound was synthesized from 3-fluorobenzylamine and 3-acetyl-6-bromo-4-phenylisochromen-1-one.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH:10]1C[O:11]1.Cl[CH2:14]Cl>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:14])[CH:10]=[O:11]
Reactant: Cc1cccc(CC2CO2)c1C
Reactant: ClCCl
Product: Cc1cccc(C(C)C=O)c1C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), prepared according to example 4 (0.84 g, 5.18 mmol), was dissolved in dry dichloromethane (50 mL) and powdered Cu(BF4)2 hydrate (318 mg) was added at room temperature. After 2 h at room temperature, the mixture was washed with water, dried over Na2SO4 and concentrated under reduced pressure to yield 0.84 g (100%) of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:20][S:21](O)(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:18][CH:19]=1
Reactant: O=S(=O)(O)Cl
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccccc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
6,8-Dichloro-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline (intermediate 4, example 2) was introduced in portions into chlorosulfonic acid (6.6 ml). The mixture was subsequently stirred at 40° C. for one hour. The reaction mixture was then cooled to room temperature and an ice/water mixture was added. The precipitate which separated out during this was filtered off with suction and taken up in ethyl acetate which, after washing with saturated brine was dried over magnesium sulfate. Subsequent concentration afforded 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-benzenesulfonyl chloride as a solid crude product, a portion of which (150 mg) was directly introduced in portions into dimethylamine solution (5 ml, approx. 40% in water) cooled to 10° C. The resulting suspension was subsequently stirred at this temperature for 1.5 h. Then ice-water was added and, after extraction three times with ethyl acetate, the combined ethyl acetate phases were washed with saturated brine and dried over magnesium sulfate. The residue was taken up with water and, after addition of 2 N HCl, freeze dried. The crude product obtained in this way was then purified by preparative HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].I[CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH3:11]
Reactant: Oc1ccccc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccccc1Br
Yield: 95.2 %

Procedure:
Into a 500-mL round-bottom flask was placed CH3COCH3 (200 mL), 2-bromophenol (10.38 g, 60.00 mmol, 1.00 equiv), iodoethane (28.08 g, 180.04 mmol, 3.00 equiv) and potassium carbonate (33.12 g, 239.64 mmol, 3.99 equiv). The resulting solution was heated to reflux overnight in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). Purification afforded 11.48 g (95%) of 1-bromo-2-ethoxybenzene as a colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH2:17][O:18][Si](C(C)(C)C)(C)C)([CH3:16])[C:11](=[O:15])[CH2:12][C:13]#[N:14])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:8][CH2:9][C:10]([CH2:17][OH:18])([CH3:16])[C:11](=[O:15])[CH2:12][C:13]#[N:14]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)(CO[Si](C)(C)C(C)(C)C)C(=O)CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(CO)(CO)C(=O)CC#N

Procedure:
To a stirred solution of 5-(tert-butyldimethylsilyloxy)-4-((tert-butyldimethylsilyloxy)methyl)-4-methyl-3-oxopentanenitrile (1 equivalent) in anhydrous THF at 0° C. is added tetrabutylammonium fluoride (1-5 equivalents) and stirring is continued at rt until the reaction is substantially complete as determined by LCMS or TLC. Water is added followed by extraction with EtOAc. The extracts are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 5-hydroxy-4-(hydroxymethyl)-4-methyl-3-oxopentanenitrile.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.C(#N)C.[OH-].[Li+]>O1CCCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:9]2[C:10]([CH3:17])=[N:11][C:12]3[C:7]([C:8]=2[CH3:26])=[C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])[CH:15]=[C:14]([CH3:16])[CH:13]=3)=[CH:24][CH:23]=1
Reactant: COC(=O)COc1cc(C)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(OCC(=O)O)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1

Procedure:
A solution of [3-(4-chlorobenzyl)-2,4,7-trimethylquinolin-5-yloxy]acetic acid methyl ester (0.045 g), acetonitrile (2.0 mL), tetrahydrofuran (1.0 mL) and 4.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 2 hours. The organic solvents were removed under reduced pressure and the pH of the residue adjusted to 5-6 by the addition of saturated aqueous sodium dihydrogenphosphate solution. The resulting mixture was extracted with chloroform and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and trituration of the residue with diethyl ether and then methanol gave title compound, 0.025 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 26.5 mg (0.06 mmol) ethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) in 3.0 ml EtOH and 4.0 ml of THF was added 240.1 mg NaOH (6.00 mmol, 3.0 ml of a 2M aqueous solution). After stirring at room temperature for 72 hours, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 10.4 (1H, s), 7.91-7.81 (5H, m), 7.54 (1H, d, J=8.1 Hz), 7.45 (1H, d, J=1.7 Hz), 7.23 (4H, s), 6.04 (1H, t, J=4.7 Hz), 2.35 (5H, s), 1.33 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([S:32]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=3)[CH:5]=[CH:4][C:3]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])(=[O:33])=[O:34])[CH:31]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: Nc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(Br)cc1S(=O)(=O)Nc1cc(-c2ccncc2)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of N-(2-amino-4-pyridin-4-ylphenyl)-4-chlorobenzene sulfonamide (0.1 mmol) in pyridine (0.5 mL), 5-bromo-2-methoxy-benzenesulfonyl chloride (0.12 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then was diluted with ethyl acetate (10 mL). The contents were washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum. The residue obtained was purified by column chromatography eluting with hexanes/ethyl acetate (1:1) followed by ethyl acetate to give 49 mg of 5-bromo-N-[2-(4-chlorobenzenesulfonylamino) -5-pyridin-4-ylphenyl]-2-methoxybenzenesulfonamide. LC: Tr 0.94 min, MS: 610.8 (M+1)+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([NH:17][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CN
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCC(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and isobutylamine as starting materials to give the aimed compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=4)[CH:27]=[CH:28][CH:29]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C#N)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M181) (265 mg, 0.492 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (122 mg, 59%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([CH3:30])[CH:20]=1
Reactant: CN
Reactant: COc1ccccc1-c1cc(C)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(C)cc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.041 g, 32%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2-methoxyphenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.17 g, 0.40 mmol) and methylamine (0.124 g, 4.0 mmol). mp 165-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3c(Cl)nccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1nccc2c(NC3CCNCC3)cccc12

Procedure:
Deprotection was performed (room temperature, 2 hours) by using Intermediate 84 (81.9 mg) and a mixed solution of trifluoroacetic acid and methylene chloride (1:1, 2 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (64 mg) as yellow powdery crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[NH2:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1>>[NH2:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:3]([F:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1
Reactant: Cc1cc(C(=O)O)nc(N)n1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(F)c1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(F)c2)nc(N)n1
Yield: 70 %

Procedure:
The title compound is prepared in 70% yield (170 mg, clear colorless oil) from (−)-1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (179 mg, 0.65 mmol, Amine-12, single enantiomer) and 2-amino-6-methylpyrimidine-4-carboxylic acid (100 mg, 0.65 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=O)[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[S:24])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:13]#[N:14]
Reactant: N#Cc1c(Br)ccc2c1CCC(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1c(Br)ccc2c1CCC(=S)N2
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-2-oxo-1,2,3,4-tetrahydroquinoline-5-carbonitrile (145-2; 1.3 g, 0.0052 mol) in toluene (20 mL) was added Lawesson's reagent (2.1 g, 0.0052 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, DMSO-d6) δ 7.612-7.561 (m, 1H), 6.980-6.959 (t, J=8.4 Hz, 1H), 3.779-3.769 (d, J=4 Hz, 4H).