Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24].[CH3:25][N:26](C=O)C>C(OCC)(=O)C.[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[O:20][C:7]1([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:24])#[N:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C#N)ccc1O2
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (143 g, 0.36 mol), Zn(CN)2 (84.7 g, 0.72 mol), Pd(PPh3)4 (20 g, 17 mmol) and dry DMF (1 liter) was stirred under an argon atmosphere at 90° C. for 6 hours. The resulting mixture was, after cooled, diluted with ethyl acetate (1 liter), and washed with aqueous 12% ammonia, water, and saturated brine in order. The organic layer was dried over sodium sulfate, and concentrated, and the residue was treated with methanol, and the resulting insoluble solid was taken out through filtration, and dried under a reduced pressure to obtain tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate as a colorless solid.
Reaction SMILES: [C:1]([CH2:11][CH2:12][C:13]([O:15][CH:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([N:26]([CH3:38])[C:27](=[O:37])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:17])=[O:14])([O:3]CC1C=CC=CC=1)=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH2:11][CH2:12][C:13]([O:15][CH:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([N:26]([CH3:38])[C:27](=[O:37])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:17])=[O:14])([OH:3])=[O:2]
Reactant: [H][H]
Reactant: CC(OC(=O)CCC(=O)OCc1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(OC(=O)CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
20-(3-(Carbobenzyloxy)propionyloxy)-4-methyl-5a-4-azapregnan-3-one (0.05 g, 0.095 mM) was reduced with hydrogen in ethyl acetate in the presence of 5% palladium on carbon, to obtain the title compound. MS M+1 calculated for C25H39NO5, mw=433.64; observed m/e 434.
Reaction SMILES: [C:1]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[C:1]([C:5]1[C:14]([O:15][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CC(C)(C)c1nc2ncccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cccnc4nc3C(C)(C)C)c2cc1OC
Temperature: 140 °C
Reaction time: 5.5 h
Yield: 9.1 %

Procedure:
2-Tert-butyl-[1,8]naphthyridin-3-ol (40 mg), 4-chloro-6,7-dimethoxyquinoline (132 mg), and 4-dimethylaminopyridine (72 mg) were suspended in o-dichlorobenzene (3 ml), and the suspension was stirred at 140° C. for 5.5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (7 mg, yield 9%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([NH:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[OH:24].Cl.[CH:26]1([C:29](=N)OCC)[CH2:28][CH2:27]1>C(Cl)Cl>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[NH:11][C:9]1[NH:8][C:7]2[C:2]3[N:1]=[C:29]([CH:26]4[CH2:28][CH2:27]4)[O:24][C:3]=3[C:4]([C:20]([O:22][CH3:23])=[O:21])=[CH:5][C:6]=2[N:10]=1
Reactant: CCOC(=N)C1CC1
Reactant: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c(N)c1O
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc2nc(Nc3c(F)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 35.6 %

Procedure:
Under N2 atmosphere to a cold solution of methyl 7-amino-2-[(2-chloro-6-fluorophenyl)amino]-6-hydroxy-1H-benzimidazole-5-carboxylate (0.400 g, 1.05 mmol) in DCM (25 mL), was added HCl salt of ethyl cyclopropanecarboximidate (Intermediate-57, 0.234 g, 1.57 mmol) at 0° C. The reaction mass was stirred at 0-5° C. for 1 h and at RT for 24 h. The obtained crude was purified by column chromatography on neutral alumina eluting with 1.0-2.0% MeOH:DCM to afford 0.150 g of the desired product. (DMSO-d6): δ 1.23 (m, 4H), 2.26 (m, 1H), 3.88 (s, 3H), 6.75 (s, 1H), 7.39 (m, 1H), 7.51 (m, 2H), 7.70 (s, 1H), 9.37 (s, 1H), 11.59 (s, 1H); MS [M+H]+: 401.21.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[I:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1>>[F:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([N:24]3[CH:25]=[C:21]([I:20])[N:22]=[CH:23]3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: Ic1c[nH]cn1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1F
Product: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1F

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidine (example A.46) (1.50 g, 5.1 mmol) and commercially available 4-iodo-imidazole (1.48 g, 7.63 mmol) according to the general procedure IVa. Obtained as a light red solid (2.23 g, 97%). MS (ISP) 452.9 [(M+H)+]; mp 206° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[O:16][C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14][C:13]2([CH3:25])[CH3:24].O>ClCCl>[C:5]([C:18]1[CH:19]=[C:10]([Br:9])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:14][C:13]2([CH3:24])[CH3:25])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCC1(CC)CC(C)(C)c2cc(Br)ccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCC1(CC)CC(C)(C)c2cc(Br)cc(C(C)=O)c2O1
Reaction time: 0.08 h
Yield: 84.4 %

Procedure:
A stirred, cooled (ice bath) suspension of aluminum chloride (1.1 g, 8.38 mmol) in anhydrous dichloromethane (20 mL) was treated with acetyl chloride (0.6 mL, 8.38 mmol). After 5 minutes, a solution of 6-bromo-2,2-diethyl-4,4-dimethyl chroman (Intermediate 25, 1.66 g, 5.59 mmol) in dichloromethane was added. The reaction mixture was stirred for 1 h. The reaction mixture was then poured into water and extracted with diethyl ether (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as an oil (1.6 g, 84%).
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>C(Cl)Cl>[C:1]([NH:9][C:10](=[O:11])[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of benzoylisocyanate (4.8 g, 32.6 mmol) in CH2Cl2 (180 mL) at 0° C. was added 4-amino-1-N-boc-piperidine (6.0 g, 30 mmol). The reaction mixture was stirred at room temperature for 4 h and concentrated. The residue was treated with Et2O (100 mL). The precipitate was filtered and washed with Et2O to yield 5.70 g (55%) of the title compound as a white solid. LC/MS: m/z (ES+) 337 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:45])[CH2:14][CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[C:16](=[O:19])[CH2:17][F:18])(C)(C)C>C(Cl)Cl>[F:18][CH2:17][C:16](=[O:19])[CH:15]([NH:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([N:31]1[C:44]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[S:38][C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])=[O:22])[CH2:14][C:13]([OH:45])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a stirred ice cold solution of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid tert-butyl ester (130 mg, 0.24 mmol) in anhydrous DCM (5 mL). The mixture was stirred at 0° C. for 0.5 h then at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The gum was lyophilized twice from HPLC grade water to afford the title compound as a white powder (77 mg, 66%): IR (solid) 1670, 1716, 1782 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.96-0.99 (1H, m), 1.23-1.26 (2H, m), 1.42-1.44 (1H, m), 1.60 (1H, m), 1.91-1.98 (1H, m), 2.51-2.89 (2H, m), 3.11-3.22 (1H, m), 3.57-3.60 (1H, m), 4.30-4.72 and 5.05-5.29 (4H, 2 m), 7.11-7.17 (2H, m), 7.24-7.30 (2H, m), 7.34-7.38 (2H, m), 7.57-7.63 (2H, m), 8.07-8.61 (1H, m); 13C NMR (100 MHz, DMSO) δ (DMSO+TFA) 18.8/18.9 (CH2), 22.2/22.3 (CH2), 25.8/26.1 (CH2), 31.5/33.2 (CH2) 43.2 (CH2), 50.6/51.1 (CH), 54.4/54.5 (CH), 82.8/82.9 (2d, J 178.6/178.1, CH2F), 119.9/120.0 (CH), 120.4/120.5 (CH), 124.0/124.1 m (CH), 125.9/126.0 (C), 126.4/126.5 (CH), 139.6/139.7 (C), 156.0/156.4 (CO), 170.3 (CO), 170.7/170.8 (CO), 202.2/202.3 (2d, J 14.6/15.1, CO).; 19F (376 MHz, DMSO) δ chemical shift (multiplicity, relative intensity) −226.7 (t, 3), −226.9 (t, 3), −230.4 (t, 1), −231.2 (t, 1), −232.7 (t, 10), −233.0 (t, 10).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:13])[NH:9][CH2:10][CH2:11][OH:12])([CH3:6])([CH3:5])[CH3:4].Cl[CH2:15][C:16]([CH2:18]Cl)=[CH2:17]>CN1CCCC1=O.O>[C:3]([O:7][C:8]([N:9]1[CH2:18][C:16](=[CH2:15])[CH2:17][O:12][CH2:11][CH2:10]1)=[O:13])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C=C(CCl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=C1COCCN(C(=O)OC(C)(C)C)C1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (992.6 mg, 60% in mineral oil, 24.8 mmol) was added portionwise to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (2 g, 12.4 mmol) in 1-methyl-2-pyrrolidinone (20 ml) at −2° C., in order to maintain the temperature below 5° C. The mixture was then stirred for 30 minutes, cooled to −5° C., and a solution of 3-chloro-2-chloromethyl-1-propene (1.44 ml, 12.4 mmol) in 1-methyl-2-pyrrolidinone (10 ml) added dropwise in order to maintain the temperature below 3° C. Once addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for a further 18 hours. The reaction mixture was diluted with water and extracted with ether (2×50 ml). The combined organic extracts were dried over magnesium sulphate and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using ethyl acetate:pentane (10:90) to give the title compound as a clear oil, 713 mg.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH2:11][C:12]3[N:13]=[C:14]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)[S:15][C:16]=3[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[NH:29][C:28](=[O:30])[O:27][N:26]=4)=[C:21]([O:31][CH3:32])[CH:20]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[OH:1][C:5]1([OH:4])[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[N:13]=[C:14]([C:33]3[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=3)[S:15][C:16]=2[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[C:21]([O:31][CH3:32])[CH:20]=2)[CH2:9][CH2:10]1
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC3(CC2)OCCO3)ccc1-c1noc(=O)[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(O)(O)CC2)ccc1-c1noc(=O)[nH]1
Temperature: 50 °C
Yield: 62.7 %

Procedure:
To a suspension of 10 mg of 3-{4-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-1,2,4-oxadiazol-5-one in 2 mL of dioxane was added 0.5 mL of a 6N aqueous solution of hydrochloric acid. The resulting mixture was heated to 50° C. for 2 h and then poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized in acetonitrile to give 6 mg of 3-{4-[4-(4,4-dihydroxy-piperidin-1-ylmethyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-1,2,4-oxadiazol-5-one as yellowish solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]([O:20][CH3:21])[C:11]=1[CH2:22][CH:23]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:26]([NH:25][CH2:23][CH2:22][C:11]1[C:12]([O:20][CH3:21])=[N:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCNC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A mixture of the compound from Step H above (1.55 g, 4.26 mmol), aminodiphenylmethane (1.11 mL, 6.40 mmol), and powdered 4 Å molecular sieves (2.80 g) in dichloromethane (20 mL) was stirred for 30 min. Then sodium triacetoxyborohydride (132 mg, 0.625 mmol) was added. The resultant mixture was stirred overnight, diluted with dichloromethane, filtered, and the filtrate was washed with saturated aqueous sodium carbonate solution. The layers were separated, and the aqueous solution was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel; dichloromethane as eluant) to yield the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.48 (s, 1H), 7.18-7.38 (m, 10H), 4.84 (s, 1H), 4.78 (s, 2H), 3.81 (s, 3H), 2.77 (m, 4H), 1.62 (br s, 1H), 0.97 (s, 9H), 0.12 (s, 6H). LC/MS: 531 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:16]([O:18][CH3:19])=[O:17].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:2]([Cl:1])[CH:3]=1)[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8]2)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc2cc(N)ccc2n1Cc1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cc2cc(NC(C)=O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Yield: 32 %

Procedure:
Methyl N-(3,4-dichlorobenzyl)-5-aminoindole-2-carboxylate (0.28 g) was dissolved in acetic anhydride and heated to 90° C. for 1 hour. Upon cooling, the title compound crystallised as white needles, was filtered off, washed with diethyl ether and dried in vacuo to yield the desired end product (0.1 g, 32%); NMR δ (CD3SOCD3) 2.03 (s, 3H), 3.80 (s, 3H), 5.80 (s, 2H), 6.88 (in, 1H), 7.36 (in, 3H), 7.52 (d, 2H), 8.08 (s, 1H), 9.88 (s, 1H); M/z (−) 391 (M+), 389.
Reaction SMILES: [CH2:1]([CH2:7][C:8]([NH2:10])=[S:9])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:11]([NH:10][C:8](=[S:9])[CH2:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=S)CCc1ccco1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(NC(=S)CCc1ccco1)c1ccccc1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
12.11 g (0.07 mol) of 2-furfurylthioacetamide was dissolved in 30 ml of pyridine. To the above solution, 9.94 g (0.07 mol) of benzoylchloride was added, and the mixture was stirred at 60° C. for 15 hours. The solvent was distilled away from the reaction mixture, and a residue thus obtained was added to ethyl acetate and washed successively with water twice, 1N hydrochloric acid, water three times, and brine. A resultant organic extract layer was dried, and the solvent was distilled away therefrom.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([O:16]CC)=O.[CH3:19][O:20][C:21]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:22]=1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N#N.CCO>CCCCCCC>[CH3:19][O:20][C:21]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:22]=1[CH2:23][N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:16]
Reactant: CCOC(=O)c1c(O)c2ccccc2n(C)c1=O
Reactant: COc1ccc(CNc2ccccc2)c(OC)c1
Agent: N#N
Solvent: CCCCCCC
Solvent: CCO
Product: COc1ccc(CN(C(=O)c2c(O)c3ccccc3n(C)c2=O)c2ccccc2)c(OC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate (9.25 g, 37.4 mmol) and N-(2,4-dimethoxybenzyl)-aniline (9.10 g, 37.4 mmol) in heptane (200 mL) was stirred at 110° C. under a flow of N2 for 6 h letting the EtOH evaporate from the reaction mixture. The product started to precipitate and some extra heptane was added. The reaction mixture was then stirred at 100° C. overnight, still under a gentle flow of N2. The product (12.21 g, 73%) crystallized from the reaction mixture and was collected by filtration while still warm (ca 50° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([N:25]1[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[CH:26]1)[CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=2)[CH:15]=[CH:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[CH:14][N:13]2[CH2:12][CH2:11][C@@H:10]([N:25]2[CH:29]=[C:28]([C:30]([NH2:32])=[O:31])[N:27]=[CH:26]2)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc([N+](=O)[O-])cc21)n1cnc(C(N)=O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 94.7 %

Procedure:
To a mechanically stirred mixture of 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-nitroindol-1-yl)-2-butyl]imidazole-4-carboxamide (450 mg, 0.98 mmol) and ammonium chloride (45 mg) in ethanol (10 ml) and water (5 ml) was added portionwise iron powder (450 mg) at 90° C. The resulting mixture was stirred for 40 minutes at 90° C. After cooling, the insoluble material was filtered through Celite and washed with ethanol and ethyl acetate. The filtrate and the washing were combined and concentrated in vacuo. The resulting residue was extracted with ethyl acetate and washed with brine. The organic layer was dried (sodium sulfate) and concentrated in vacuo to give 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (397 mg, 94.7%). This material was used for the next reaction without further purification.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:24]([OH:26])=O)[CH2:20][CH:21]([CH3:23])[CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:35]>C(#N)C>[C:1]([NH:18][C@H:19]([C:24]([F:35])=[O:26])[CH2:20][CH:21]([CH3:23])[CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
FMOC-L-Leucine (5 g, 14.14 mmol) (Bachem) was dissolved in acetonitrile (70 mL). Pyridine (1.14 mL, 14.14 mmol) (Aldrich) and cyanuric fluoride (1.91 g, 14.14 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (300 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford FMOC-L-leucyl fluoride as a white powder. (Yield 4.57 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12]O)=[CH:3]1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:15][CH2:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(CCO)c2ccccc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Cn1cc(CCBr)c2ccccc21
Temperature: 0 °C
Yield: 73 %

Procedure:
To a solution of 1-methyl-3-(2-hydroxyethyl)indole (4.00 g,0.023 mol) in 50 mL of acetonitrile at -20° C. under Ar was added a solution of CBr4 (10.16 g, 0.031 mol) in 25 mL of acetonitrile, followed by a solution of triphenylphosphine (8.00 g, 0.031 mol) in 125 mL of acetonitrile. The mixture was stirred and allowed to warm to 0° C. over 2 h. The resulting mixture was evaporated and the residue was chromatographed (SiO2 /hexane, then ethyl acetate-hexane=1:4) to give the product (4.00 g, 74%) as a brown oil: IR (neat) 2940, 1617, 1552 cm-1 ; 1Hnmr (200 MHz, CDCl3) δ 7.58 (d, J=7.6 Hz, 1H), 7.33-7.09 (m, 3H), 6.95 (s, 1H), 3.77 (s, 3H), 3.62 (t, J=7.9 Hz, 2 H), 3.32 (t, J=7.7 Hz, 2H).
Reaction SMILES: Cl.Cl.[OH:3][CH:4]([CH3:16])[CH2:5][C:6]1[N:7]=[N:8][C:9]([NH:14][NH2:15])=[CH:10][C:11]=1[NH:12][CH3:13].[C:17](OC(=O)C)(=[O:19])C.C(=O)(O)[O-].[Na+]>C(O)=O>[OH:3][CH:4]([CH3:16])[CH2:5][C:6]1[N:7]=[N:8][C:9]([NH:14][NH:15][CH:17]=[O:19])=[CH:10][C:11]=1[NH:12][CH3:13]
Reactant: CNc1cc(NN)nnc1CC(C)O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CNc1cc(NNC=O)nnc1CC(C)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Thirteen and one half grams of 3-(2'-hydroxypropyl)methylamino-6-hydrazinopyridazine dihydrochloride are dissolved in 25 ml of formic acid, and there are subsequently added thereto at 0° C 6 ml of acetic anhydride and after 30 minutes 8.4 g sodium bicarbonate. The mixture is stirred at 0° C for 30 minutes and left at room temperature overnight. The solvent is removed and the residue consisting of 3-(2'-hydroxypropyl)methylamino-6-(2'-formylhydrazino)pyridazine is recrystallized from acetone/ethanol (8:2). It melts at 130°-132° C.