Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:16](O)=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=O)(C)(C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:27]([NH2:29])[CH3:28]>>[NH:13]1[CH:12]=[C:11]([CH2:10][C@@H:9]([NH2:8])[CH2:16][NH:29][C@H:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH3:28])[N:15]=[CH:14]1
Reactant: COc1ccccc1[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]cn1)C(=O)O
Product: COc1ccccc1[C@H](C)NC[C@H](N)Cc1c[nH]cn1
Yield: 24.2 %

Procedure:
By using N-t-butoxycarbonyl-(D)-histidine (405 mg), and (1S)-1-(2-methoxyphenyl)ethanamine compound (200 mg) obtained by the method described in the publication (Japanese Patent Unexamined Publication No. 54/154724) as starting materials, the title compound (88 mg) was obtained in the same manner as that of Reference Example 71.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[N:13]([CH2:19][CH2:20][N:21]=3)[C:14](=[O:18])[C:15]=2[N:16]=O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:34](O)=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]3[N:13]([CH2:19][CH2:20][N:21]=3)[C:14](=[O:18])[C:15]=2[NH:16][CH:34]=[O:35])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CC(C)CN1C2=NCCN2C(=O)C(N=O)=C1NCc1ccc(Cl)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CC(C)CN1C2=NCCN2C(=O)C(NC=O)=C1NCc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of the nitroso compound of Procedure 87 (0.1 mol) in 200 ml. formic acid, sodium dithionite (0.25 mol) is added portionwise. After one hour, the reaction mixture is concentrated in vacuo, the residue dissolved in water and filtered. The filtrate is made basic with concentrated aqueous ammonia, and the product collected.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:6]=[CH:7][N:8]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].Cl>ClCCl>[CH3:1][N:2]([CH2:3][C:4]1[N:5]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH:6]=[CH:7][N:8]=1)[S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: CNCc1nccn1-c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1nccn1-c1ccc2c(c1)CCN2C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To tert-butyl 5-{2-[(methylamino)methyl]-1H-imidazol-1-yl}-1-indolinecarboxylate (0.20 g, 0.61 mmol; from Part H of Example 37) was added dichloromethane (6 mL) and triethylamine (0.25 mL, 0.67 mmol). Methanesulfonyl chloride (0.052, 0.67 mmol) was added in one portion, and the resulting yellow solution was stirred for 2 h. The reaction was then poured into aqueous 1N hydrogen chloride (10 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and saturated aqueous sodium chloride (10 mL), dried over sodium sulfate, and concentrated to give tert-butyl 5-(2-{[methyl(methylsulfonyl)amino]methyl}-1H-imidazol-1-yl)-1-indolinecarboxylate (250 mg, 100%) as a brown oil). LC/MS (ESI+): 407.3 (M+H)+.
Reaction SMILES: O.Cl.[C:3]([C:7]1[CH:8]=[C:9]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][CH2:24]OC3C=CC(CNCC)=CC=3)[N:22]=2)[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].C(C1C=C(C2OC=C(CCOC3C=CC(CNCC)=CC=3)N=2)C=C(C(C)(C)C)C=1O)(C)(C)C.Cl.[CH:70]([C:72]1[CH:73]=[C:74]([CH:77]=[CH:78][C:79]=1[OH:80])[CH:75]=[O:76])=[O:71].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:14]([C:11]1[CH:10]=[C:9]([C:18]2[O:19][CH:20]=[C:21]([CH2:23][CH2:24][O:80][C:79]3[CH:78]=[CH:77][C:74]([CH:75]=[O:76])=[CH:73][C:72]=3[CH:70]=[O:71])[N:22]=2)[CH:8]=[C:7]([C:3]([CH3:4])([CH3:5])[CH3:6])[C:12]=1[OH:13])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: CCNCc1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2nc(CCOc3ccc(C=O)cc3C=O)co2)cc(C(C)(C)C)c1O
Yield: 48.9 %

Procedure:
In a flask, 4.75 g (15 mmole) of the compound of Example 1 C, 2.36 g (15.75 mmole) of 3-formyl-4-hydroxybenzaldehyde, and 3.93 g (15 mmole) of triphenylphosphine were dissolved in 45 ml tetrahydrofuran with stirring, under nitrogen. The solution was chilled to −10° and a solution of 2.36 ml (15 mmole) diethyl azodicarboxylate in 15 ml. Tetrahydrofuran was added over 10 minutes, with stirring. The reaction exothermed to +1° C. The bath was removed and the reaction stirred under nitrogen for 18 hours. The reaction was then stripped, dissolved in a minimum amount of methylene chloride and placed in the freezer. The diethoxycarbonylhydrazine was then filtered off and the filtrate was chromatographed, Prep 500, two columns, eluting with 0 to 20% ethyl acetate/toluene gradient over 30 minutes. The appropriate fractions were bulked and stripped to give 3.3 g (49%) product which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([O:23][CH3:24])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:12]=1>>[CH3:31][C:29]1[NH:28][N:27]=[C:26]([NH:25][C:13]2[N:12]=[C:11]([O:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:20]3[C:15]([CH:14]=2)=[C:16]([O:23][CH3:24])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[CH:30]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Reactant: N#Cc1ccc(O)cc1
Product: COc1ccc2c(Oc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 10 was used, starting from 4-hydroxy-benzonitrile and (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-5,6-dimethoxy-isoquinolin-1-yloxy]-benzonitrile. LC-MS m/e 402(MH+).
Reaction SMILES: C([C:4]1[CH:5]=[C:6]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)(=O)C.C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:6]2[N:7]3[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:5]=2)=[O:22])=[CH:19][CH:18]=1)#[N:21]
Reactant: CC(=O)c1cc(C(=O)c2ccc(C#N)cc2)n2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: OCCO
Product: N#Cc1ccc(C(=O)c2ccc3ccccn23)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A solution of 1-acetyl-3-(4-cyanobenzoyl)indolizine (12) (1.56 grams, 5.69 mmol), ethylene glycol (1 mL), and p-toluenesulfonic acid (2.16 grams, 11.38 mmol) in benzene (150 mL) was refluxed for 3 hours. The reaction mixture was cooled to room temperature, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). The combined layers were concentrated in vacuo. Purification by flash column chromatography (Rf 0.3, ethyl acetate in hexane) afforded 3-(4-cyanobenzoyl)indolizine (13) as a light yellow solid (1.12 grams, 80%). 1H NMR (CDCl3) δ 6.56 (d, J=4.8, 1H), 7.04 (t, J=6.9, 1H), 7.28 (m, 2H), 7.61 (d, J=9.0, 1H), 7.78 (m, 2H), 7.89 (m, 2H), 9.98 (d, J=7.2, 1H). ESMS calcd (C16H10N2O2): 246.1. found: 247.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].F[B-](F)(F)F.[CH3:18][O+](C)C>>[CH3:18][O:12][C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:1]=1
Reactant: O=C1CCCc2ccccc2N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=Nc2ccccc2CCC1

Procedure:
A sample of the title compound of EXAMPLE 165 (3.2 g, 20.0 mmol) was reacted with trimethyloxonium tetrafluoroborate (4.4 g, 30.0 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 2.5 g (73%) of the title material.
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C@H:16]2[C@H:20]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[F:28])[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]2)=[O:15])[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:41])[CH3:42])[NH:17][C@H:16]2[C:14]([NH:13][C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:44])=[O:5])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(=O)O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 3-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (20 mg, 0.031 mmol) was treated with 30% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 12 mg.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC2C=CC(C(OCC)=O)=CC=2Cl)C(C=O)=CN=1)CCC.[C:47]1([CH2:53][CH2:54][C:55]([O:57]C(C)(C)C)=[O:56])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[C:7](/[CH:10]=[C:54](\[CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)/[C:55]([OH:57])=[O:56])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CCc1ccccc1
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Agent: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1ccc(C(=O)OC)cc1

Procedure:
The title compound was prepared using 2-n-butyl-1-[(4-carbomethoxyphenyl)methyl]imidazole-5-aldehyde, prepared by the method described for the preparation of 2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde in Example 44, and t-butyl 3-phenylpropanoate by the procedure of Example 27, except, instead of basic hydrolysis, trifluoroacetic acid hydrolysis of the t-butyl ester is employed.
Reaction SMILES: O[N:2]1[CH2:7][CH2:6][CH2:5][C:4]2[S:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]1=2.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][N:2]1[CH2:7][CH2:6][CH2:5][C:4]2[S:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]1=2
Reactant: CCOC(=O)c1csc2c1N(O)CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1csc2c1N(Cl)CCC2

Procedure:
A solution of 2.25 g of ethyl 4-hydroxy-6,7-dihydrothieno[3,2-b]pyridine-3-carboxylate (see example 20) in 10 ml of phosphorous oxychloride is refluxed for 1 hour. After cooling excess reagent is distilled off under reduced pressure, the residue dissolved in 40 ml of dichloromethane and washed with 20 ml of 2N NaOH solution and 20 ml of water. After drying over magnesium sulfate, the filtrate is slurried with 500 mg of charcoal, filtered and evaporated to dryness. The residue is recrystallized from ether/pentane to yield ethyl 4-chloro-6,7-dihydrothieno[3,2-b]pyridine-3-carboxylate, mp 69°-70°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC1CCC(N)CC1
Product: CC1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 4-methylcyclohexylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.83-0.85 (m, 3 H), 1.17-1.75 (m, 9 H), 3.27 (s, 4 H), 3.34 (s, 1 H), 3.77 (s, 4 H), 6.29 (bs, 1 H), 6.98-7.06 (m, 2 H), 7.27 (d, J=8.4 Hz, 1 H), 7.39-7.42 (m, 1 H), 7.48 (s, 1 H), 7.58-7.60 (m, 3 H), 7.84 (m, 1 H), 7.98-8.00 (m, 1 H), 8.21 (m, 1H), 10.45 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1>[CH3:14][N:13]([CH2:12][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[C:21]([OH:23])=[O:22])[CH3:15]
Reactant: CN(C)Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[3-bromo-5-(trifluoromethyl)phenyl]-N,N-dimethylmethanamine (2 g, 7.1 mmol) in THF (40 mL) at −78° C. was dropwise added a solution of n-butyllithium (2.50 M in hexane, 3.12 mL, 7.81 mmol). The resulting mixture was stirred at −78° C. for 20 min. Excess crushed solid CO2 was added and the mixture was stirred at −78° C. for another 15 min. The reaction was quenched by the addition of water (0.156 mL), and allowed to warm to room temperature. The solvents were evaporated and the solid was dried overnight under vacuum to give 3-[(dimethylamino)methyl]-5-(trifluoromethyl)benzoic acid.Li salt as a white solid contaminated with valeric acid. The crude acid was dissolved in aqueous hydrochloric acid (1M in water, 5 eq) and water (20 vols). Dissolution was not complete. The solids were removed by suction filtration, washed with methylene chloride and set aside. The resulting aqueous solution was transferred to a separatory funnel and washed with methylene chloride (3×). The washed aqueous phase was transferred to a round bottom flask. The filtered solids were added to the aqueous phase. The mixture was concentrated to dryness under reduced pressure. On heating in the water bath, the mixture turned homogeneous. On concentration, the solution afforded a gummy solid, which was azeotropically dried in toluene it was a free-flowing solid. The resulting powder was suspended in ether and filtered. The filter cake was briefly dried under suction. The product was transferred to a round bottom flask and dried under high vacuum at 40° C. overnight. LC-MS: (AA) ES+248; 1H NMR (400 MHz, CD3OD) δ ppm 8.46 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 4.51 (s, 2H), 2.89 (s, 6H).
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:24]2[C:32]3[C:31]([O:33][CH3:34])=[N:30][CH:29]=[N:28][C:27]=3[N:26]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:25]=2)O)=[C:18]([F:44])[N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.O>ClCCCl>[C:38]1([S:35]([N:26]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([O:33][CH3:34])[C:32]=3[C:24]([CH2:22][C:19]3[CH:20]=[CH:21][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[Cl:15])=[N:17][C:18]=3[F:44])=[CH:25]2)(=[O:37])=[O:36])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: COc1ncnc2c1c(C(O)c1ccc(N(Cc3ccccc3Cl)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: COc1ncnc2c1c(Cc1ccc(NCc3ccccc3Cl)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
To {5-[(7-Benzenesulfonyl-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-hydroxy-methyl]-6-fluoro-pyridin-2-yl}-(2-chloro-benzyl)-carbamic acid tert-butyl ester (44, 0.400 g, 0.612 mmol) in 15.0 mL of 1,2-dichloroethane, triethylsilane (2.0 mL, 12 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol) were added. The reaction was heated at 80° C. for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (45, 0.30 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:34]=1)(O)=[O:2]>S(Cl)(Cl)=O>[CH3:32][N:31]([CH3:33])[C@H:28]1[CH2:27][CH2:26][C@H:25]([C:23]([NH:22][C:9]2[C:8]3[CH:34]=[C:4]([CH2:1][OH:2])[CH:5]=[CH:6][C:7]=3[O:11][C:10]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:13])=[O:24])[CH2:30][CH2:29]1
Reactant: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)O)cc23)CC1
Solvent: O=S(Cl)Cl
Product: CN(C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(CO)cc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Trans-5-carboxy-3-[4-(dimethylamino)cyclohexyl-carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (243 mg) obtained in Example 78 is suspended in thionyl chloride (2.5 ml), and the mixture is stirred at room temperature for 10 minutes, then stirred at 50° C. for 10 minutes. The mixture is cooled to room temperature and stirred for one hour. The reaction solution is concentrated to dryness under reduced pressure. The resulting residue is suspended in tetrahydrofuran/chloroform (2:1, 15 ml), and thereto is added sodium borohydride (150 mg), and the mixture is stirred at room temperature overnight. To the reaction solution is poured 1N hydrochloric acid under ice-cooling, and the mixture is stirred for 0.5 hour. A saturated aqueous sodium hydrogen carbonate solution is further poured thereto, and the mixture is extracted with chloroform. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform, then chloroform/methanol=200/1) to give trans-3-[4-(dimethylamino) cyclohexylcarbonylamino]-5-hydroxymethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (46 mg). This product is dissolved in chloroform (1 ml), and thereto is added 2N hydrogen chloride in methanol (0.1 ml), and the reaction solution is concentrated under reduced pressure. The resulting residue is suspended in ethyl acetate-methanol, and the precipitates are collected by filtration, and dried to give the title compound (45 mg).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][C@@H:11]([CH3:21])[CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH:7]=[C:6]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:5]=1.[NH2:34][C:35]1[S:39][N:38]=[C:37]([CH3:40])[N:36]=1>>[OH:13][CH2:12][CH:11]([CH3:21])[O:10][C:8]1[CH:7]=[C:6]([O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=2)[CH:5]=[C:4]([CH:9]=1)[C:3]([NH:34][C:35]1[S:39][N:38]=[C:37]([CH3:40])[N:36]=1)=[O:2]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Reactant: Cc1nsc(N)n1
Product: Cc1nsc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)CO)c2)n1

Procedure:
The compound of Production Example 89 was obtained as a colorless amorphous substance using 200 mg (0.40 mmol) of the obtained 5-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-3-(4-methanesulfonyl-phenoxy)-benzoic acid methyl ester and 5-amino-3-methyl-[1,2,4]thiadiazole, by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([O:31]C)=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]([CH3:28])([CH3:27])[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=[O:30])[CH:23]=3)[NH:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(NC(=O)c3ccccc3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(NC(=O)c2ccccc2)c1
Yield: 88.7 %

Procedure:
To a solution of methyl 2-(3-benzamido-5-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (61 mg, 0.14 mmol) in methanol (4 mL) was added a 1 M solution of sodium hydroxide (1.63 mL, 1.63 mmol). The mixture was stirred and heated to reflux for 3 h. The mixture was concentrated, dissolved in water and acidified to pH=5-6. The precipitated solid was collected by filtration, dissolved in tetrahydrofuran, and dried over anhydrous magnesium sulfate. After evaporation of the organic solvent, the residue was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to afford 54 mg of 2-(3-benzamido-5-chloro phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 91%; MS (ESI+APCI) M+1=417.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5]([OH:7])=O.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[NH:32][CH:29]([CH3:31])[CH3:30])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CC(C)N
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Product: CC(C)NC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and isopropylamine were reacted by a procedure similar to that to prepare 137 in Example 47 to give 231. MS: (ESI+) 455.1
Reaction SMILES: [O-][CH2:2]C.[Na+].[NH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:7]=1[C:22](=[O:24])[CH3:23].C(OCC)=O.Cl>COCCOC.O>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]2[C:7]([C:22]([OH:24])=[CH:23][CH:2]=[N:5]2)=[CH:8][C:9]=1[O:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC=O
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Sodium ethoxide (74.8 g, 1.1 mol) was added to a solution of 1-(2-amino-4-benzyloxy-5-methoxyphenyl)ethanone (29.3 g, 108 mmol) in DME (700 mL) and stirred for 30 min. Ethyl formate (44 mL, 540 mmol) was added and the mixture was stirred overnight (in case of incomplete reaction, additional sodium ethoxide can be added and the reaction monitored by LC/MS). After the reaction was complete, the mixture was diluted with water (40 mL) and acidified to neutral pH with 1M HCl. The solid was filtered, washed with water and dried to afford 7-benzyloxy-6-methoxyquinolin-4-ol (22 g, 72%). 1H NMR (400 MHz, CDCl3): δ 10.7 (br s, 1H), 7.70 (s, 1H), 7.49-7.46 (t, 1H), 7.43-7.41 (br d, 2H), 7.37-7.33 (t, 2H), 7.30-7.28 (d, 1H), 6.84 (s, 1H), 6.21-6.19 (d, 1H), 5.21 (s, 2H), 3.96 (s, 3H). LC/MS (M+H=282).