Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20](O)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][NH:48]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:20]([N:48]2[CH2:49][CH2:50][C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH2:47]2)=[O:21])=[N:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCn2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Reactant: c1ccc2c(c1)CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCn2nc(C(=O)N3CCc4ccccc4C3)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid (60 mg, 0.199 mmol) in DMF (2 mL) under an atmosphere of nitrogen was added HATU (152 mg, 0.398 mmol) and 1,2,3,4-tetrahydroisoquinoline (32 mg, 0.239 mmol). The reaction was stirred at room temperature for 1 hour. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product. 1H NMR (400 MHz, CDCl3) δ 7.69-7.58 (m, 1H), 7.53-7.48 (m, 1H), 7.33-7.30 (m, 1H), 7.22-7.10 (m, 4H), 7.08-7.06 (d, 1H), 6.94-6.92 (d, 1H), 5.24-5.22 (d, 2H), 4.81 (s, 1H), 4.60 (s, 1H), 4.39-4.35 (t, 2H), 3.90-3.87 (m, 1H), 3.78-3.75 (t, 2H), 3.64-3.61 (t, 1H), 3.18 (s, 3H), 2.93-2.90 (t, 1H), 2.82-2.79 (t, 1H); ES MS (M+1)=417.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[BH4-].[Na+]>C(O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6]
Reactant: COc1ccc(C=O)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of 3-chloro-4-methoxybenzaldehyde (156 g) in a mixture of ethanol (750 ml) and tetrahydrofuran (500 ml) was added sodium borohydride (25 g) under ice-cooling. After stirring at ambient temperature for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 1N-hydrochloric acid, water, aqueous sodium bicarbonate and brine, successively, and dried over magnesium sulfate. Evaporation of the solvent gave 3-chloro-4-methoxybenzyl alcohol (164 g) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+]([O-])=O.C(=O)([O-])[O-].[K+].[K+]>[Cu].C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1F
Yield: 71.9 %

Procedure:
2-Nitroaniline (14.9 g), 2-fluoronitrobenzene (29 g), potassium carbonate (14.9 g), copper powder (6.9 g) and xylene (100 ml) was mixed, the mixture was refluxed for 39 hours under argon atmosphere. The reaction mixture was allowed to cool, filtrated, and the filtrate was concentrated under reduced pressure. The residue was dissolved ethyl acetate, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby obtain 18.0 g of the titled compound as orange color crystals (Yield: 72%).
Reaction SMILES: ClC1C=CC(OC2C=CC(CN3CCC([C:18]4[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH:21]=[CH:22][CH:23]=4)CC3)=CC=2)=CC=1.[C:34]1([N:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([CH2:49][CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][CH:55](C4C=C(NC(=O)C(C)C)C=CC=4)[CH2:54][CH2:53]3)=[C:41]2[C:70]2C=CC=C[CH:71]=2)[CH:39]=CC=CC=1.C(N1C2C=CC(C=O)=CC=2C2C1=CC=CC=2)C.CC(C)C(NC1C=CC(C2CCNCC2)=CC=1)=O>>[CH2:34]([N:40]1[C:41]2[CH:70]=[CH:71][C:50]([CH2:51][N:52]3[CH2:53][CH2:54][CH:55]([C:23]4[CH:22]=[CH:21][C:20]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])=[CH:19][CH:18]=4)[CH2:56][CH2:57]3)=[CH:49][C:42]=2[C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH3:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Agent: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Agent: CCn1c2ccccc2c2cc(C=O)ccc21
Product: CCn1c2ccccc2c2cc(CN3CCC(c4ccc(NC(=O)C(C)C)cc4)CC3)ccc21

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[4-(4-CHLOROPHENOXY)BENZYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE (Example 108) N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 9-ethyl-9H-carbazole-3-carbaldehyde (22.3 mg, 0.100 mmol) and 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide (24.6 mg, 0.100 mmol) provided N-(4-{1-[(9-ethyl-9H-carbazol-3-yl)methyl]-4-piperidinyl}phenyl)-2-methylpropanamide. The product was obtained as a white crystalline solid (20 mg, 44%). 1H NMR (400 MHz, CDCl3) δ 8.21-7.09 (m, 12H), 4.38 (q, 2H, J=7.2 Hz), 3.81 (s, 2H), 3.25-3.03 (m, 2H), 2.60-2.38 (m, 2H), 2.31-2.09 (m, 2H), 1.98-1.69 (m, 4H), 1.44 (t, 3H, J=7.2 Hz), 1.23 (d, 6H, J=6.8 Hz); ESMS m/e: 454.3 (M+H)+.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1.[Mg].[CH3:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]2[CH2:30][CH2:31][N:32]=[C:20]12>O1CCCC1.O.C(OCC)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:22]2([OH:29])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]([CH3:18])[C:20]3=[N:32][CH2:31][CH2:30][N:21]23)=[CH:12][CH:11]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CN1C2=NCCN2C(=O)c2ccccc21
Agent: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1C2=NCCN2C(O)(c2ccc(Cl)cc2)c2ccccc21
Yield: 26.5 %

Procedure:
To a phenylmagnesium bromide solution prepared from 6.9 g of p-chlorophenyl bromide, 0.88 g of magnesium and 25 ml of dry diethyl ether was added dropwise a solution of 2.42 g of 10-methyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline-5-one in 30 ml of dry tetrahydrofuran with stirring and ice-cooling. The mixture was heated under reflux for 2 hours and then cooled. To the mixture were added dropwise 20 ml of water and stirring was continued for a while. The resulting mixture was extracted with hot chloroform and the insoluble material was filtered off and washed with hot chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was crystallized from ethanol and the crystals were further recrystallized from dimethylformamide to give 1.0 g of 5-(p-chlorophenyl)-5-hydroxy-10-methyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline as colorless needles, m.p. 207°-209° C. (decomp.).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:41])([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:42](OC)=[O:43].[F:46][C:47]([F:51])([F:50])[CH2:48][NH2:49]>>[OH:41][C:13]([C:9]1[CH:10]=[CH:11][C:12]2[C:3]3[CH2:2][N:49]([CH2:48][C:47]([F:51])([F:50])[F:46])[C:42](=[O:43])[C:4]=3[CH:5]=[CH:6][C:7]=2[CH:8]=1)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr
Reactant: NCC(F)(F)F
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(CC(F)(F)F)C3)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (0.66 g) and 2,2,2-trifluoroethylamine (2.0 ml), the title compound (0.34 g) was obtained as a colorless amorphous solid.
Reaction SMILES: [Na].Cl.[CH3:3][N:4]([CH2:6][CH2:7][Cl:8])[CH3:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:17]3[C:26]([C:12]=2[CH:11]=1)=[N:25][C:24]1[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[N:18]=3>COCCO>[ClH:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]([CH2:7][CH2:6][N:4]([CH3:3])[CH3:5])[C:17]3[C:26]([C:12]=2[CH:11]=1)=[N:25][C:24]1[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=1)[N:18]=3
Reactant: CN(C)CCCl
Reactant: Clc1ccc2[nH]c3nc4ccccc4nc3c2c1
Agent: Cl
Agent: [Na]
Solvent: COCCO
Product: CN(C)CCn1c2ccc(Cl)cc2c2nc3ccccc3nc21
Temperature: 100 °C

Procedure:
5.06 g sodium (0.22 mole) is dissolved in 300 ml 2-methoxyethanol, 15.9 g N,N-dimethylamino-2-chloroethane-HCl (0.11 mole) is added followed by 25.4 g 9-chloro-6H-indolo(2,3-b)quinoxaline (0.10 mole). The mixture is heated for 3 hours at 100° C., cooled and filtered. The filtrate is concentrated and poured into water. The raw base obtained is filtered off and washed with water and subjected to chromatography on silica gel with methanol as eluent. The purified base is dissolved after drying in acetone. The hydrochloride is precipitated by slowly dropwise adding concentrated hydrochloric acid with stirring. Yield 23.2 g, 66%, mp. 243°-246° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](O)=[O:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccccc1Cl
Product: O=C(Cc1ccccc1Cl)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-chlorophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (d, J=8.4 Hz, 1H), 8.02-8.05 (m, 1H), 7.97-8.01 (m, 1H), 7.89-7.93 (m, 1H), 7.46-7.54 (m, 2H), 7.31-7.36 (m, 2H), 3.82-3.83 (m, 6H), 3.09-3.12 (m, 4H); MS (ESI−) M/Z 397 (M−H)−.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:11]2[C:15]([CH2:16][OH:17])=[C:14](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:13][N:12]=2)[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][N:28]=1.[Cl-].[NH4+]>C1COCC1.O>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([O:17][CH2:16][C:15]2[C:11]([C:6]3[CH:7]=[CH:8][C:9]([F:10])=[C:4]([F:3])[CH:5]=3)=[N:12][O:13][C:14]=2/[CH:18]=[CH:19]/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:28][CH:29]=1
Reactant: OCc1c(-c2ccc(F)c(F)c2)noc1/C=C/c1ccccc1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a suspension of sodium hydride (1.23 mg, 28.1 mmol) in 45 mL THF was added a solution of [3-(3,4-difluoro-phenyl)-5-([E]-styryl)-isoxazol-4-yl]-methanol (8.0 g, 25.5 mmol) in THF (84 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. A solution of methyl 6-chloronicotinate (4.92 g, 28.1 mmol) in THF (84 mL) was added. The reaction was stirred at room temperature for 3 h and water (150 mL) and saturated aqueous ammonium chloride solution (100 mL) were added. Extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:4 to 2:3) afforded the title compound (9.24 g, 81%) as a yellow solid. MS: m/e=507.1 [M+CH3COO]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([C:26]([N:37]2[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]2)=[O:28])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid and 1-methanesulfonyl-piperazine hydrochloride. Off-white powder. MS (m/z): 534.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18](Cl)[C:3]=1[C:4](/[C:6](=[CH:9]/[NH:10][CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])/[C:7]#[N:8])=[O:5].[H-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]#[N:8])=[CH:9][N:10]2[CH:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(CCC)N/C=C(\C#N)C(=O)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCC(CCC)n1cc(C#N)c(=O)c2c(Cl)cccc21
Temperature: 100 °C
Yield: 39.2 %

Procedure:
(E)-2-(2,6-dichlorobenzoyl)-3-(1-propylbutylamino)acrylonitrile (0.020 g, 0.059 mmol) was dissolved in dioxane (2 mL). Sodium hydride (0.007 g, 0.18 mmol, 60% wt. dispersion in mineral oil) was added in one portion. Reaction was heated overnight at 100° C. Solution was cooled and quenched with MeOH and concentrated. Flash chromatography gave the desired product (0.007 g, 40%)
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:11](=[O:13])[CH2:10][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][C:7]=2[NH:6][CH:5]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C)C=O>[CH3:20][S:21]([N:6]1[C:7]2[CH2:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:11](=[O:13])[C:12]=2[C:4]([CH3:3])=[CH:5]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a suspension of 60% sodium hydride (0.085 g, washed with hexane thrice) in dimethylformamide (10 ml) was added 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.4 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of methanesulfonylchloride (0.22 g) in dimethylformamide (2 ml), and the mixture was stirred at the same temperature for 18 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give colorless crystals of 1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.50 g).
Reaction SMILES: [OH-].[Na+].C(OC([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([N:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)=[CH:23][CH:24]=3)[N:19]([C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.O>CO>[OH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([N:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]4)=[CH:23][CH:24]=3)[N:19]([C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)[CH:18]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(-c2cn(-c3ccncc3)c3cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(-c4ccc(O)cc4)cn(-c4ccncc4)c3c2)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
2 N sodium hydroxide aqueous solution (18 μL, 0.035 mmol) was added to a mixture solution of tert-butyl 4-(3-(4-(tert-butoxycarbonyloxy)phenyl)-1-(pyridin-4-yl)-1H-indol-6-yl)piperazine-1-carboxylate (10 mg, 0.018 mmol) in methanol (0.5 mL) at room temperature. After stirring at room temperature for 3.5 hours, followed by addition of water, the mixture was extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The target compound was obtained as white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][N:3]4[C:4]5[C:9](=[CH:8][N:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]4=[O:1])[CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2cnccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cnccc32)CC1
Reaction time: 0.08 h
Yield: 68.8 %

Procedure:
To a solution of 0.38 g of (2-oxo-1,6-naphthyridin-1(2H)-yl)acetaldehyde in 14 mL of dichloromethane, 0.35 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.12 mL of acetic acid were added, the mixture was stirred for 5 minutes, and then, 0.32 g of sodium triacetoxyborohydride was added to the reaction mixture and the mixture was stirred for 4 hours 20 minutes. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and chloroform were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.36 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,6-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a colorless oily substance.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:41])[C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1>[Pd]>[NH2:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:41])[C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:33][CH:34]=2)=[CH:22][CH:23]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Product: COC(=O)[C@@H](N)Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1
Yield: 98.3 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using methyl (S)-2-benzyloxycarbonylamino-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (1.53 g) and palladium on carbon (5%, 150 mg) and the reaction mixture was treated to give methyl (S)-2-amino-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (1.14 g). Propyl bromide (0.24 ml) and potassium carbonate (387 mg) were added to a solution of the amine derivative (1.12 g) obtained above in N,N-dimethylformamide (10 ml). The mixture was stirred at 70° C. for 16 hours. The reaction mixture was partitioned between ethyl acetate and water and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using dichloromethane/methanol=19/1 to give the title compound (196 mg) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)OCC(C)C.[NH2:27][C:28]1[CH:32]=[C:31]([Br:33])[S:30][C:29]=1[C:34]([NH2:36])=[O:35].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[Br:33][C:31]1[S:30][C:29]([C:34](=[O:35])[NH2:36])=[C:28]([NH:27][C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[CH:32]=1
Reactant: CS(=O)(=O)c1ccc(N2CCC[C@H]2C(=O)O)cc1
Reactant: NC(=O)c1sc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(N2CCC[C@H]2C(=O)Nc2cc(Br)sc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(methylsulfonyl)phenyl]proline (512 mg) and triethylamine (0.314 mL) in tetrahydrofuran (10 mL) was added 2-methylpropyl chlorocarbonate (0.259 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Thereafter, to the reaction system was added 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, and the mixture was stirred at 60° C. for 19 hr. Ethyl acetate (20 mL) and aqueous sodium hydrogen carbonate (10 mL) were added to the reaction mixture, and the separated organic layer was washed with brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the object fraction was concentrated under reduced pressure to give N-(5-bromo-2-carbamoylthiophen-3-yl)-1-[4-(methylsulfonyl)phenyl]prolinamide as a pale-yellow amorphous solid. To a solution of N-(5-bromo-2-carbamoylthiophen-3-yl)-1-[4-(methylsulfonyl)phenyl]prolinamide produced above in ethanol (5 mL) was added 2M aqueous sodium hydroxide solution (2.83 mL), and the mixture was stirred at 70° C. for 10 hr. The reaction mixture was neutralized with 6M hydrochloric acid (0.6 mL) under ice-cooling, and water (2 mL) was added dropwise at room temperature. The precipitated solid was collected by filtration to give the title compound (208 mg) as a pale-yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:32]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[N:35]=4)=[O:31])=[CH:22][CH:23]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Reactant: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)n3)cc2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a solution of butyl 4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (118.0 mg, 0.36 mmol) in DMF (3.5 mL) was added phenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate (153.5 mg, 0.54 mmol), followed by triethylamine (0.10 mL, 0.73 mmol). The solution was stirred at rt overnight and then purified directly by HPLC using a gradient of 50-80% MeCN in water to yield 107.7 mg (58%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.88 (s, 1 H), 9.73 (s, 1 H), 8.08 (s, 1 H), 8.04 to 7.97 (m, 2 H), 7.58 (d, J=8.6 Hz, 2 H), 7.51 to 7.49 (m, 1 H), 7.44 (d, J=8.5 Hz, 2 H), 7.22 (s, 1 H), 4.26 (t, J=6.6 Hz, 2 H), 1.71-1.64 (m, 2 H), 1.47-1.38 (m, 2 H), 0.93 (t, J=7.3, 3 H); MS [M+H]+=514.2; LCMS RT=3.49 min.