Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].C([O:12][CH2:13][C:14](=[O:35])[C@@H:15]1[C@:32]2([CH3:33])[C@H:18]([C@H:19]3[C@H:29]([CH2:30][CH2:31]2)[C@:27]2([CH3:28])[C:22](=[CH:23][C:24](=[O:34])[CH2:25][CH2:26]2)[CH:21]=[CH:20]3)[CH2:17][CH2:16]1)(=O)C.[CH3:36][C:37]([SH:39])=[O:38]>C(Cl)Cl>[C:37]([S:39][C@@H:20]1[CH2:21][C:22]2[C@:27]([CH3:28])([CH2:26][CH2:25][C:24](=[O:34])[CH:23]=2)[C@@H:29]2[C@@H:19]1[C@H:18]1[C@:32]([CH3:33])([CH2:31][CH2:30]2)[C@@H:15]([C:14](=[O:35])[CH2:13][OH:12])[CH2:16][CH2:17]1)(=[O:38])[CH3:36]
Reactant: CC(=O)S
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)S[C@@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)CO)CC[C@H]3[C@H]12

Procedure:
The product of Example 3 was hydrolyzed by treating 0.5 g of the 21-acetoxy derivative in 8 ml methylene chloride with 10 ml methanol and 4 ml 0.2M aqueous potassium carbonate at room temperature under nitrogen for 30 minutes. The hydrolyzed product was extracted with methylene chloride, washed with water, dried and evaporated. A sample obtained by preparative high performance liquid chromatography showed M+ =404 daltons. An identical product was obtained by a different synthetic route involving alkaline hydrolysis of 21-acetoxy-4,6-pregnadiene-3,20-dione to the C-21-alcohol, followed by reaction with ethanethiolic acid.
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[CH2:12][CH:11]([CH:13]3[CH2:15][CH2:14]3)[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:1]([C:4]1[C:5]([C:35]2[CH:36]=[CH:37][C:38]([F:39])=[C:33]([Cl:32])[CH:34]=2)=[N:6][N:7]2[CH2:12][CH:11]([CH:13]3[CH2:15][CH2:14]3)[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C1CC1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC1C1CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
To a stirred suspension of Intermediate 348G (0.47 g, 1.087 mmol) in 1,4-dioxane (5 mL) was added K3PO4 (1.631 mL, 3.26 mmol), (3-chloro-4-fluorophenyl)boronic acid (0.246 g, 1.414 mmol) and the reaction mixture was purged with nitrogen for 10 min. PdCl2(dppf)-CH2Cl2 (0.053 g, 0.065 mmol) was then added and the reaction mixture was heated to 80° C. and stirred for 6 h. The reaction mixture was filtered through CELITE® and the filtrate was diluted with ethyl acetate (10 mL), and washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 2% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 348H as an off-white solid (0.4 g, 85%). MS(ES): m/z=435 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85-7.95 (m, 1H), 7.66-7.77 (m, 1H), 7.47 (t, J=9.07 Hz, 1H), 7.20-7.39 (m, 2H), 5.05 (d, J=17.37 Hz, 1H), 4.55 (d, J=17.37 Hz, 1H), 4.24 (br. s., 2H), 3.89 (br. s., 1H), 1.45 (s, 9H), 0.87-1.05 (m, 1H), 0.31-0.55 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][S:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)(=[O:19])=[O:18].Cl>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:24][C:23]3[CH:22]=[CH:21][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:27][CH:26]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: CS(=O)(=O)c1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (200 mg, 819 μmol) in MeOH (5 mL) was added a suspension of 4-methylsulfonylbenzaldehyde (158 mg, 860 μmol) in acetic acid (75 μl) and MeOH (2 mL). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (140 mg, 1.31 mmol, Aldrich) was added and the stirring was continued for 3 days. The reaction mixture was diluted with MeOH (6 mL) and poured into 0.1N HCl solution (10 ml). The resulting suspension was filtered and washed with water to give an off white solid as desired product (228 mg, 67% yield). MS +m/z: 412 (M+H)+
Reaction SMILES: [C:1]([C:9]1[O:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Pd]>[CH2:1]([CH:9]1[CH2:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[O:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1cc2ccccc2o1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(CC2Cc3ccccc3O2)cc1
Reaction time: 70 h
Yield: 92.3 %

Procedure:
To a solution of 22 g (0.1 mole) of 2-benzoylbenzo(b)furan in 250 ml acetic acid was added 3 g 10% Pd/C catalyst and the mixture hydrogenated at 3 atmospheres pressure, with shaking for 70 hours. The mixture was filtered and the filtrate concentrated in vacuo to obtain 19.4 g (92%) of the desired product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][CH:5]=1.Cl.[NH2:21][OH:22]>CO.O.C(OCC)(=O)C>[F:1][C:2]([F:19])([F:18])[CH:3]([NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:21][OH:22])=[CH:6][CH:5]=1
Reactant: NO
Reactant: CC(C)C(=O)NC(c1ccc(C=O)cc1)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)C(=O)NC(c1ccc(C=NO)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 118.5 %

Procedure:
In a solution of 0.16 g of N-[2,2,2-trifluoro-1-(4-formylphenyl)ethyl]isobutyramide in 4.0 mL of methanol and 1.0 mL of water, 0.075 g of hydroxylamine hydrochloride was added, and stirred at room temperature for 1.5 hour. After the completion of the reaction, the reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (10 mL×1), and the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 0.20 g of the aimed product as white crystal.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: O=c1cc(OCc2ccc(F)cn2)cc[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Yield: 90 %

Procedure:
4-(5-Fluoro-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 1c employing 4-(5-fluoro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:12][C:13](O)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14]
Reactant: COc1ccccc1CCOCC(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1CCOCCO
Temperature: 25 °C

Procedure:
The solution of 10.1 g of [2-(2-methoxyphenyl)ethoxy]acetic acid in 50 ml of tetrahydrofuran is added dropwise at 0-5° C. to the stirred mixture of 1.76 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. The reaction mixture is stirred at reflux over 5 hours and subsequently cooled to room temperature. 4 ml of water, 4 ml of 2N NaOH and once again 4 ml of water are successively added dropwise. The reaction mixture is poured onto 200 ml of 0.5 M HCl (cold) and extracted with ethyl acetate (2×200 ml). The organic phases are washed successively with water (200 ml) and brine (1×200 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.19 (1:1 EtOAc-heptane); Rt=3.32.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:13])=[O:12])=[O:9].[CH:59]1([CH:62]=O)[CH2:61][CH2:60]1.CO>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:56]=[CH:57][CH:58]=1)[O:5][C:6]1[CH:33]=[C:32]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH2:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][C:42]=3[C:49]3[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=3)[CH2:36][CH2:35]2)[CH:31]=[CH:30][C:7]=1[C:8]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:62][CH:59]3[CH2:61][CH2:60]3)[CH2:23][CH2:22]2)=[C:16]([N+:27]([O-:29])=[O:28])[CH:15]=1)(=[O:12])=[O:13])=[O:9]
Reactant: O=CC1CC1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCNCC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: CO
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NC5CCN(CC6CC6)CC5)c([N+](=O)[O-])c4)c(Oc4cccc(Cl)c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A suspension of EXAMPLE 187B (50 mg), cyclopropanecarbaldehyde (100 mg) and MP-CNBH3 resin (0.2 g, 2.43 mmol/g) in dichloromethane (4 mL)/methanol (3 mL) was shaken for 16 hours at room temperature. The product was filtered, washed with dichloromethane/methanol and concentrated. The crude product was purified by RP HPLC(C8, 30%-100% CH3CN/water/0.1% TFA) to yield the product. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ 8.35 (s, 1H), 8.10 (s, 1H), 7.67-7.75 (m, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 3H), 6.89 (d, 1H), 6.73 (dd, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 3.86 (s, 1H), 3.12 (s, 5H), 2.71-2.80 (m, 3H), 2.13-2.28 (m, 9H), 1.98 (s, 3H), 1.79 (s, 1H), 1.41 (t, 2H), 0.99-1.11 (m, 2H), 0.94 (s, 6H), 0.84 (d, 1H), 0.63 (d, 2H), 0.33 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[N:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]3[N:27]=[C:28]([NH2:30])[N:29]=[C:22]23)=[CH:17][C:16]=1[C:31]([F:34])([F:33])[F:32]>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]3[N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[O:6][C:2]([CH3:1])=[N:3][N:4]=5)[CH2:8][CH2:9]4)[N:29]=[C:22]23)=[CH:17][C:16]=1[C:31]([F:32])([F:33])[F:34]
Reactant: Cc1nnc(N2CCC(=O)CC2)o1
Reactant: Nc1nc2n(n1)CCCC2c1ccc(F)c(C(F)(F)F)c1
Product: Cc1nnc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(F)c(C(F)(F)F)c3)CC2)o1

Procedure:
Prepared in analogy to example 1h employing 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-one (see example 25b) and 8-(4-fluoro-3-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 1d-g). The title compound was obtained as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]([OH:17])=[O:16]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(F)c1
Reactant: O=C(O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)COCCc1cccc(F)c1
Temperature: 60 °C
Reaction time: 36 h
Yield: 63.2 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-ethanol (4.0 g, 28.5 mmol) in DMF (60 ml) was added a 60% dispersion of sodium hydride in oil (2.40 g, 60 mmol). The suspension was heated to 60° C. for 0.75 hours. Chloroacetic acid (4.72 g, 50 mmol) was added dropwise. After 36 hours at 60° C. the brown reaction mixture was brought to dryness under reduced pressure, dissolved in EtOAc and washed with 1M HCl, water and brine. The organic layers were dried over MgSO4, filtrated, the solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, EtOAc/heptane, 3/1) to yield [2-(3-fluoro-phenyl)-ethoxy]-acetic acid (2.02 g, 18 mmol; 36%) as colorless liquid. MS (m/e): 197.4 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:18](OC)=[O:19])[CH:11]=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])=[N:6][CH:7]=1.[BH4-].[Na+].[NH4+].[Cl-]>CO>[OH:19][CH2:18][C:10]1[CH:11]=[C:12]([CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:9]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cc(CO)cc(-c2ccc(C)cn2)c1
Reaction time: 3 h

Procedure:
To a stirred solution of dimethyl 5-(5-methylpyridin-2-yl)isophthalate (1.78 g, 5.93 mmol) in methanol (100 mL) was added sodium tetrahydroborate (2.0 g, 0.053 mol) at 0° C. After 3 h, the reaction was treated with sat. aq. NH4Cl and the volatiles were removed in vacuo. The residue was dissloved in water, basified to pH=9 by addition of NaHCO3, and then extracted with CH2Cl2 (70 mL×3). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Clc1ccc2c(Nc3ccc(N4CCOCC4)c(CN4CCCC4)c3)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (0.105 g, 0.26 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to pyrrolidine (0.65 mL, 7.75 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//90/10/1) to yield expected compound as a yellow solid (105 mg, 96% yield). LC-MS: m/z (ESI) 423.3 [M+H]+. mp=187-188° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH2:14])[CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:5]2.[CH2:23]([C:25]1[CH:30]=[C:29]([CH2:31]OS(C)(=O)=O)[CH:28]=[CH:27][N:26]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([C:25]1[CH:30]=[C:29]([CH2:31][NH:14][CH2:13][CH2:12][N:7]2[CH:6]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH:28]=[CH:27][N:26]=1)[CH3:24]
Reactant: CCc1cc(COS(C)(=O)=O)ccn1
Reactant: NCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
67 mg of 2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 180-b), 47 mg of 2-ethyl-4-[(methyl sulfonyl oxy)methyl]pyridine, and 30 mg of potassium carbonate were added to acetonitrile (2 ml), followed by stirring at 60° C. for 2 hours. After concentration, it was purified by PLC (chloroform:methanol=10:1) to obtain 26 mg (yield 28%) of a title compound as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[NH:17]([C:19]([NH:21][C:22]1[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=1)=[S:20])[NH2:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14](=[N:18][NH:17][C:19]([NH:21][C:22]3[S:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=3)=[S:20])[CH3:16])[C:12]=2[OH:13])=[CH:4][CH:3]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)cc2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1csc(-c2ccc(Cl)cc2)c1O

Procedure:
From 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (25.3 mg, 0.10 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (21.8 mg, 0.10 mmol), the desired product was obtained in the same manner as in Synthetic Example 50 as a pale yellow solid (37.1 mg, yield 82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:41][C@H:42]([CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[C:43]([N:45]([CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[O:55][CH2:56][CH2:57][OH:58])[CH3:46])=[O:44].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:41][C@@H:42]([C:43](=[O:44])[N:45]([CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:55][CH2:56][CH2:57][OH:58])[CH3:46])[CH2:59][C:60]2[CH:69]=[CH:68][C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:61]=2)[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@H](N)Cc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (113 mg, 0.45 mmol) and 7-aza-1-hydroxybenzotriazole (61 mg, 0.45 mmol) were dissolved in N,N-dimethylformamide (1 ml) and dichloromethane (1 ml). The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-2-amino-N-{2-[2-(2-hydroxyethoxy)phenyl]ethyl}-N-methyl-3-(2-naphthyl)propionamide (175 mg, 0.45 mmol) and ethyldiisopropylamine (0.08 ml, 0.45 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with a 10% aqueous solution of sodium hydrogen sulfate (50 ml). The aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using ethyl acetate/heptane 3:1 as eluent, to give 211 mg of ((3-((1R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethylcarbamoyl)phenyl)methyl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][CH2:50][CH2:51][CH3:52]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[NH:49][CH2:50][CH2:51][CH3:52])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: CCCNc1cc(C(=O)OC)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCCNc1cc(C(=O)OC)ccc1NC(=O)CCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
In chloroform (10 ml), 5-t-butoxycarbonylamino valeric acid (574 mg), WSCI hydrochloride (690 mg), and HOBt (487 mg) were dissolved. Then, the solution was stirred at room temperature for 30 minutes. The solution was added with the compound (503 mg) obtained in Example 3-1 and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After having been washed with a saturated aqueous sodium hydrogen carbonate solution, a saturated aqueous ammonium chloride solution, and a saturated saline solution, the resultant was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (540 mg) as a colorless viscous substance.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:26])(=[O:25])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:3]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:25])(=[O:26])[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=1)=[CH2:2]
Reactant: O=C(Oc1ccc(S(=O)(=O)Nc2ccccc2)cc1)c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=Cc1ccc(C(=O)Oc2ccc(S(=O)(=O)Nc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.7 %

Procedure:
A mixture of 18.5 g (0.0402 mol) of 4-(N-phenylsulfamoyl)phenyl 4-(2-bromoethyl)benzoate, 5.55 g (0.0402 mol) of potassium carbonate and 250 ml of acetone was stirred at room temperature for approximately 48 hours. The mixture was filtered and concentrated to an oily solid. Recrystallization from ethanol:water gave 11.7 g (76.6% of theory) of 4-(N-phenylsulfamoyl)phenyl 4-vinylbenzoate; mp=59°-60° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:9]1[CH3:19]>ClCCl>[CH3:7][N:8]1[C:9]([CH3:19])=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:12]1[C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: Cc1cc(-c2ccccc2)cn1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)c(C(=O)C(=O)Cl)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Oxalyl chloride (19.5 mL, 0.21 mol) was added slowly to a 0° C. solution of 1,2-dimethyl-4-phenyl-pyrrole (30.5 g, 0.178 mol) in dry dichloromethane (150 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was removed in vacuo to afford 2-(1,5-dimethyl-3-phenyl-pyrrol-2-yl)-2-oxo-acetyl chloride (46 g, 99%) as a brown oil.