Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=O.B.C1COCC1.Cl>C1COCC1.O>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[CH2:9][CH2:10][N:5]([CH2:3][C@H:2]([NH2:1])[CH2:19][C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:6][CH2:7]1
Reactant: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccncc2)CC1
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Temperature: 25 °C

Procedure:
To a solution of (2R)-2-Amino-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-3-pyridin-4-yl-propan-1-one (6.18 g; 18 mmol, from Example 7) in THF (60 mL) was added, dropwise, BH3.THF (1.0M/THF) (73 mL; 73 mmol). The mixture was stirred at reflux for 2 hours, cooled to ambient temperature, cautiously treated with 6N HCl (45 mL), stirred at ambient temperature for 1 hours. The mixture was then diluted with water (100 mL), concentrated on a rotary evaporator to remove THF, and the aqueous residue washed with ether (30 mL). The aqueous layer was rendered basic (pH 9–10) with concentrated NH4OH, and the product extracted into dichloromethane (3×75 mL). The combined dichloromethane layers were washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo to yield the title compound as a free base (4.85 g.; 82%). The analytical sample was converted to the hydrochloride salt with ethereal HCl to yield an off-white crystalline solid, m.p. 177–178° C.; MS (+) ESI, [M+H]+ @ m/z 327; 1H NMR, 400 MHz, DMSO-d6. Analysis for C19H26N4O.HCl.0.3H2O.0.3 C2H6O Calculated: C, 61.61; H, 7.75; N, 14.66 Found: C, 61.45; H, 7.80; N, 14.49.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:30])=[CH:4][C:5]2[N:9]=[C:8]([C:10]([NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])=[O:11])[NH:7][C:6]=2[CH:28]=1.[H-].[Na+].I[CH2:38][CH3:39].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:30])=[CH:4][C:5]2[N:9]([CH2:38][CH3:39])[C:8]([C:10]([NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:15])([F:16])[F:17])=[O:11])=[N:7][C:6]=2[CH:28]=1.[Cl:1][C:2]1[C:3]([C:29]([NH:31][CH:32]2[CH2:34][CH2:33]2)=[O:30])=[CH:4][C:5]2[N:9]=[C:8]([C:10]([NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:15])([F:16])[F:17])=[O:11])[N:7]([CH2:38][CH3:39])[C:6]=2[CH:28]=1
Reactant: O=C(NC(c1cccc(C(F)(F)F)c1)C(F)(F)F)c1nc2cc(C(=O)NC3CC3)c(Cl)cc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)nc2cc(C(=O)NC3CC3)c(Cl)cc21
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)nc2cc(Cl)c(C(=O)NC3CC3)cc21
Yield: 18 %
Yield: 12 %

Procedure:
6-Chloro-N5-cyclopropyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazole-2,5-dicarboxamide (0.1 g, 0.22 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (2 ml). Sodium hydride (60%; 0.0082 g, 0.22 mmol) was added and the mixture was stirred while cooling with ice for 1 h. Subsequently, iodoethane (0.034 g, 0.22 mmol) was added dropwise. The reaction mixture was thawed while stirring within 16 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.012 g (12% of theory) of 5-chloro-N6-cyclopropyl-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazole-2,6-dicarboxamide and 0.018 g (18% of theory) of 6-chloro-N5-cyclopropyl-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-benzimidazole-2,5-dicarboxamide.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=N)N.[CH:13]1(C(Cl)=O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[C:17]2[C:7](=[CH:15][CH:14]=[CH:13][CH:18]=2)[NH:6][CH:5]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
A stock solution of 9.1 mg/mL α-interferon in 20 mM sodium phosphate buffer at pH 7.2 was prepared. A stock solution of perturbant was prepared by dissolving 800 mg of perturbant (L-arginine acylated with cyclohexanoyl chloride) in 2 mL of 20 mM Sodium Phosphate buffer (pH7).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][N:10]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[C:25]([C:32]([NH2:34])=[O:33])[N:24]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH2:12][CH2:11][N:10]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([C:32]([NH2:34])=[O:33])[N:24]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(c2ccc([N+](=O)[O-])c(C(N)=O)n2)CC[C@@H]1c1cc(F)c(F)cc1F
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccc(N)c(C(N)=O)n2)CC[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 0.5 h

Procedure:
To 993 mg (2.0 mmol) of the product of Step A in 40 mL of 3:1 methanol/tetrahydrofuran at 0° C. was added 166 mg (0.70 mmol) of nickel (II) chloride hexahydrate followed by 318 mg (8.4 mmol) of sodium borohydride in portions over 30 min. The reaction mixture was stirred for an additional 30 min and then quenched with 100 mL of a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous phase extracted with three 100-mL portions of 3:1 chloroform/isopropyl alcohol. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to yield a yellow solid which was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes gradient) to give the title compound as a yellow crystalline solid. LC/MS 465.6 (M+1).
Reaction SMILES: [Br-:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][N+:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:27](=[O:28])[CH2:26][C:25]4[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:24]=4[CH:23]=[CH:22]3)[CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]>CO.[Pt](=O)=O>[BrH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:21]3[C:27](=[O:28])[CH2:26][C:25]4[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:24]=4[CH2:23][CH2:22]3)[CH2:15]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: [Br-]
Reactant: COc1ccc(CC[n+]2cccc(CN3C=Cc4cc(OC)c(OC)cc4CC3=O)c2)cc1OC
Agent: O=[Pt]=O
Solvent: CO
Product: Br
Product: COc1ccc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)cc1OC

Procedure:
3.7 g (0.0067 mol) of 3-[(N-(2-(3,4-dimethoxy-phenyl)ethyl)-pyridinium-3-yl)-methyl]7, 8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-bromide are hydrogenated in 70 ml of methanol in the presence of 0.7 g of platinum dioxide for 3 hours at ambient temperature and under 5 bar. The catalyst is removed by suction filtering, the methanol is distilled off in vacuo and the residue is dissolved in a little methanol and mixed with acetone. The precipitate is suction filtered and dried.
Reaction SMILES: C(N)CN.ClCC1SC=CN=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][NH:18][CH2:19][CH2:20][NH2:21].[C:22]([NH:24][C:25](=[N:28][CH3:29])SC)#[N:23]>>[C:22]([NH:24][C:25]([NH:28][CH3:29])=[N:21][CH2:20][CH2:19][NH:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][N:14]=1)#[N:23]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1nccs1
Agent: ClCc1nccs1
Solvent: NCCN
Product: CNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting ethylenediamine with 2-chloromethylthiazole by the procedure of Example 34, then reacting the resulting N-(2-thiazolylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3(a), gives N-cyano-N'-methyl-N"-[2-(2thiazolylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'- [2-(2-thiazolylmethylamino)ethyl]guanidine trihydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][Br:27])[C:12]=2[F:19])[CH:9]=1)[C:5]#[N:6]
Reactant: Cc1ccc(Cl)c(Oc2cc(Br)cc(C#N)c2)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Yield: 60.4 %

Procedure:
3-bromo-5-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (6.05 g, 17.76 mmol) and NBS (3.16 g, 17.76 mmol) were combined in carbon tetrachloride (100 mL) with a catalytic amount of AIBN (0.146 g, 0.888 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on silica gel (eluted with 0 to 10% Et2O in hexanes) to give 3-bromo-5-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile (4.5 g, 10.73 mmol, 60.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.95 (m, 1H), 7.52-7.61 (m, 4H), 4.75 (s, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:13][C:14]([F:41])([S:37]([OH:40])(=[O:39])=[O:38])[C:15]([F:36])([F:35])[C:16]([F:34])([F:33])[C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]>C(O)C>[F:41][C:14]([F:13])([S:37]([O-:40])(=[O:39])=[O:38])[C:15]([F:35])([F:36])[C:16]([F:34])([F:33])[C:17]([F:31])([F:32])[C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22].[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH3+:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)c1ccc(C(C)N)cc1
Solvent: CCO
Product: CC(C)c1ccc(C(C)[NH3+])cc1
Product: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
The perfluoro-octylsulphonate salt was prepared by mixing a solution of 1-(4-isopropylphenyl)ethylamine (16.1 g) in ethanol (20 ml) with a solution of perfluoro-octylsulphonic acid (50 ml). The solution was evaporated to dryness and the residue was recrystallised from chloroform as soft colourless plates of 1-(4-isopropylphenyl) ethyl ammonium perfluoro-octyl sulphonate, melting point 158° C.(d). (Found: C 34.3; H 2.5; N 2.2%. C19H18F17NO3S requires: C 34.40; H 2.73; N 2.11%).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12](NC)[NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:21][N:22](C(C)C)C(C)C.[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][C:37](Cl)=[O:38])=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:35]([O:36][C:37](=[O:38])[NH:22][CH2:21][C:12]1[NH:13][C:14]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:18])[CH3:19])[CH:15]=2)[C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNc1cc2ccc(O[Si](C)(C)C(C)(C)C)cc2[nH]1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CNC(=O)OCc3ccccc3)[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
[6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-yl]-methylamine (0.70 g, 1.01 mmol) is dissolved in DCM (10 ml), cooled to 0° C. DIEA (0.35 ml, 2.02 mmol) and Cbz-Cl (0.17 g, 1.01 mmol) are added. The mixture is stirred for 1 hour at room temperature. The reaction mixture is concentrated and the residue is purified by column chromatography (10% ethyl acetate in hexanes) to provide [6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-ylmethyl]-carbamic acid benzyl ester.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c7) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:31]([CH3:32])=[N:30][NH:29][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:5]=2[NH:29][N:30]=[C:31]3[CH3:32])=[O:28])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: Cc1n[nH]c2c1cc(Cl)c1nc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)oc(=O)c12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1n[nH]c2c(C(=O)NC3(C4CC4)CC3)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)cc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a solution of 150 mg (0.25 mmol) of the above 5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 3 mL of N,N-dimethylformamide is added 100 mg (0.75 mmol) of bicyclopropyl-1-ylamine hydrochloride and 104 μL (0.75 mmol) of triethylamine. The reaction is stirred at 50° C. for 24 hours and then concentrated in vacuo. The residue is taken-up with acetone and after filtration the filtrate is evaporated. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:2) affords 70 mg (48%) of a solid; LC/MS:578/580 (M+H)+, m.p.: 228-229° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:66][O:67][C:68](=[O:71])[CH2:69][NH2:70].C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:70][CH2:69][C:68]([O:67][CH3:66])=[O:71])=[O:36])=[CH:38][CH:39]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)CCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 233 (28.7 mg, 0.05 mmoles) in anhydrous dimethylformamide (0.5 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (14 mg, 0.07 mmoles) and 1-hydroxybenzotriazole hydrate (10 mg, 0.07 mmoles) at room temperature for 15 minutes. A mixture of glycine methyl ester hydrochloride (12.6 mg, 0.1 mmole) and N,N-diisopropylethylamine (0.014 ml, 0.1 mmole) in anhydrous dimethylformamide (0.235 ml) was added to the reaction and shaken at room temperature overnight. The reacton mixture was acidified with 1N aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered and filtrate concentrated in vacuo. The residue purified by HPLC to provide the titled compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:23]([CH3:25])[CH3:24])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Li+].O.CO>O1CCCC1>[CH2:16]([O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:23]([CH3:25])[CH3:24])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)O)cc2cc(OCc3ccccc3)ccc21
Yield: 95.5 %

Procedure:
5-Benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid ethyl ester (47.5 g, 1.0 eq.) and lithium hydroxide (6.56 g, 1.1 eq.) in a mixture of tetrahydofuran (360 mL), water (180 mL) and methanol (120 mL) was refluxed for 2 h then the reaction mixture was concentrated in vacuo. The residue was stirred vigorously in aqueous hydrochloric acid (2N, final pH: 2). The white precipitate was filtered, washed with water then dried in vacuo to yield 41.6 g (96%) of the desired product as white oil. MS (m/e): 308.5 (M−H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([O:30][P:31]([O:35][CH3:36])([O:33]C)=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[O:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][C@@H:45]([NH:54][C:55]2[CH:60]=[CH:59][C:58]([S:61]([NH2:64])(=[O:63])=[O:62])=[CH:57][C:56]=2[S:65]([C:68]([F:71])([F:70])[F:69])(=[O:67])=[O:66])[CH2:46][S:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:39][CH2:38]1>ClCCCl>[ClH:1].[P:31]([OH:33])([O:35][CH3:36])([O:30][C@@H:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:22]=[CH:23][C:24]([C:25](=[O:26])[NH:64][S:61]([C:58]3[CH:59]=[CH:60][C:55]([NH:54][C@H:45]([CH2:44][CH2:43][N:40]4[CH2:41][CH2:42][O:37][CH2:38][CH2:39]4)[CH2:46][S:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[C:56]([S:65]([C:68]([F:70])([F:71])[F:69])(=[O:67])=[O:66])[CH:57]=3)(=[O:62])=[O:63])=[CH:28][CH:29]=2)[CH2:19][CH2:20]1)=[O:32]
Reactant: COP(=O)(OC)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Solvent: ClCCCl
Product: COP(=O)(O)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c(S(=O)(=O)C(F)(F)F)c3)cc2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of (R)-4-(4-((4′-chlorobiphenyl-2-yl)(dimethoxyphosphoryloxy)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 122, 57.4 mg, 0.11 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 69, 60 mg, 0.11 mmol), EDC (41.6 mg, 0.22 mmol), TEA (0.03 ml, 0.22 mmol), and DCE (2 ml) were stirred at r.t. for 4 days. The volatiles were removed under reduced pressure and the concentrate was purified by reverse phase HPLC according to the following conditions:
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:14]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(CNCc1cccc2ccccc12)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a solution of 1-naphthaldehyde (2.2 ml, 16.0 mmol) in tetrahydrofuran (6 ml) was added 2,2-diethoxyethanamine (2.9 ml, 20.0 mmol) and the mixture was stirred at room temperature 0.5 hr. And then sodium triacetoxyborohydride (10.6 g, 50 mmol) was added and the mixture was stirred for additional 4 hr. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with saturated aqueous sodium bicarbonate (200 ml), water (200 ml) and brine (200 ml). The organic layer was dried over magnesium sulfate (5 g) and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=100:0 to 70:30) to obtain the title compound (3.0 g, 46%).
Reaction SMILES: C(N(CC)CC)C.C(O[CH:13]=[CH:14][C:15](=O)[C:16]([O:18][CH3:19])=[O:17])CCC.Cl.[NH2:22][C:23]([NH2:25])=[NH:24]>C(#N)CC>[NH2:25][C:23]1[N:24]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:13][N:22]=1
Reactant: CCCCOC=CC(=O)C(=O)OC
Reactant: N=C(N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCC#N
Product: COC(=O)c1ccnc(N)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
Triethylamine (29 mL, 210 mmol) was added to a suspension of methyl 4-butoxy-2-oxo-3-butenate (37 g, 200 mmol, JP-A-2003-89690) and guanidine hydrochloride (23 g, 240 mmol) in propionitrile (50 mL), and the mixture was stirred for 4 hours at 100° C. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 18 g as the mixture of the title Reference Compound and the butyl ester form of the title Reference compound as a gray-white solid (Yield: 60%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15]N(C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].[NH2:24][C@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27].Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][NH:24][C@H:25]([CH2:29][OH:30])[CH:26]([CH3:28])[CH3:27])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8]
Reactant: CC(C)[C@H](N)CO
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)c(OC)cc1OC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN[C@H](CO)C(C)C)C(=O)c1cc(Br)c(OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-dimethylaminoacrylate obtained in Step 4 of Example 1 in toluene was added L-valinol (20.6 g). After stirring at room temperature for 1 hr, the completion of the reaction was confirmed by HPLC. 1 mol/L Hydrochloric acid (200 mL) was added to the reaction mixture, and after stirring, the toluene layer was separated. The toluene layer was further washed successively with 1 mol/L hydrochloric acid (200 mL), water (200 mL), 5% aqueous sodium hydrogencarbonate solution (200 mL) and water (200 mL). After washing, toluene was evaporated under reduced pressure, toluene (200 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. THF (200 mL) was further added to the concentrated residue, and the mixture was concentrated again under reduced pressure. THF (160 mL) was added to the obtained concentrated residue to give ethyl 2-(5-bromo-2,4-dimethoxybenzoyl)-3-((S)-1-hydroxymethyl-2-methylpropylamino)acrylate as a tetrahydrofuran solution. The solution was directly used in the next step.