Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].C(=O)([O-])[O-].[NH4+:33].[NH4+:34]>C(O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20](=[NH:34])[NH2:21])=[CH:18][CH:19]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[NH:33])[NH2:3]
Reactant: N#Cc1ccc(NC(=O)N(c2cccc(C#N)c2)C2CCCCCC2)cc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1ccc(NC(=O)N(c2cccc(C(=N)N)c2)C2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N′-(4-cyanophenyl)cycloheptylurea (0.065 g, 0.21 mmol) in anhydrous ethanol (5 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered and allowed to warm to ambient temperature and stir overnight. The reaction was concentrated in vacuo to give a white amorphous solid. This was dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.118 g, 1.23 mmol) was added. The reaction was stirred under a nitrogen atmosphere at ambient temperature overnight. The reaction mixture was concentrated in vacuo to give a white solid. The product was purfied by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 minutes. The major fraction was concentrated to give N-(3-amidinophenyl)-N′-(4-amidinophenyl)cycloheptylurea as a white solid (mp204-206° C.); LRMS (M+H)+ m/z 351, (M+2H)+2 m/z 176.2; HRMS calc. 351.1933, found 351.1936; 1H NMR (DMSO-d6): 9.4(bs, 2H), 9.2(broad s, 2H), 9.18 (broad s, 2H), 7.95 (broad s, 2H), 7.8-7.5(m, 6H), 7.47 (d, 2H), 3.9(bd, 4H), 1.83(m, 4H).
Reaction SMILES: [C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[C:8]([CH2:26][CH3:27])=[CH:9][C:10]2[CH:11]3[CH:19]([CH2:20][CH2:21][C:22]=2[CH:23]=1)[CH:18]1[C:14]([CH3:25])([C:15](=O)[CH2:16][CH2:17]1)[CH2:13][CH2:12]3)([CH3:4])([CH3:3])[CH3:2].C(OP([CH2:38][C:39]#[N:40])(=O)OCC)C>>[C:1]([Si:5]([CH3:29])([CH3:28])[O:6][C:7]1[C:8]([CH2:26][CH3:27])=[CH:9][C:10]2[CH:11]3[CH:19]([CH2:20][CH2:21][C:22]=2[CH:23]=1)[CH:18]1[C:14]([CH3:25])([C:15](=[CH:38][C:39]#[N:40])[CH2:16][CH2:17]1)[CH2:13][CH2:12]3)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CCC1C2CCC2(C)C(=O)CCC12
Product: CCc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CCC1C2CCC2(C)C(=CC#N)CCC12
Yield: 56.5 %

Procedure:
The reaction was carried out as described in procedure C using silyl ether 12 (1 g, 2.6 mmol) and diethyl(cyanomethyl)phosphonate (691 mg, 631 μl, 3.9 mmol). Flash column chromatography (SiO2 hexane:ethyl acetate 20:1) afforded the two isomers 24 as a colourless oil (641 mg, 1.47 mmol, 57%). m/z (FAB) 435.3 (M+, 100%); HRMS (FAB+) calcd for C28H41ONSi 435.2957, found 435.2961.
Reaction SMILES: [CH2:1]([O:5][C:6]12[CH2:13][CH2:12][C:9]([CH2:14][CH2:15][CH3:16])([CH2:10][CH2:11]1)[C:8](=O)[CH2:7]2)[CH2:2][CH2:3][CH3:4].[OH-].[K+].C(O)COCCO.O.NN>>[CH2:1]([O:5][C:6]12[CH2:11][CH2:10][C:9]([CH2:14][CH2:15][CH3:16])([CH2:8][CH2:7]1)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC12CCC(CCC)(CC1)C(=O)C2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CCCCOC12CCC(CCC)(CC1)CC2
Temperature: 180 °C
Reaction time: 2 h

Procedure:
A mixture of 4-n-butoxy-1-n-propylbicyclo(2,2,2)octane-2-one (2.08 g, 0.009 mol) hydrazine hydrate (8.4 ml, 98-100%) and potassium hydroxide (2.80 g, 0.050 mol) in diethylene glycol (40 mol) was stirred and heated under reflux for 4 h (180° C., oil bath temperature). The reaction mixture was cooled and hydrazine hydrate (4 ml) and potassium hydroxide (1.00 g) were added and the apparatus was arranged for distillation. The temperature was raised slowly to 240° C. in 2 h, and the reaction mixture was kept at this temperature for 2 h. The reaction mixture was cooled and the residue and the distillate were separately diluted with water, washed with ether (3×50 ml). All the ether washings were combined and washed with water (2×50 ml) dilute hydrochloric acid (2×50 ml) and water (2×50 ml). The ether solution was dried (MgSO4) and ether was removed to give a residue which was chromatographed on a neutral alumina column (1.5×30 cm) using light petroleum (bp 40°-60° C.) as eluent. Four fractions were collected (20 ml each) the solvent was removed to leave a residue which was distilled in a short-path distillation apparatus under reduced pressure to give the required compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:34]=[C:33]4[C:13]([CH2:14][CH2:15][C:16]5[N:20]=[C:19]([CH:21]6[CH2:25][CH2:24][CH2:23][N:22]6[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1>ClCCl.C(OCC)(=O)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]2[CH2:8][O:9][C:10]3[CH:34]=[C:33]4[C:13]([CH:14]=[CH:15][C:16]5[N:20]=[C:19]([CH:21]6[CH2:25][CH2:24][CH2:23][N:22]6[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[NH:18][C:17]=54)=[CH:12][C:11]=3[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2c([nH]1)-c1cc3c(cc1CC2)-c1ccc(Cl)cc1CO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(Cl)ccc1-4
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.6 %

Procedure:
To a solution of tert-butyl 2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.9 g, 3.96 mmol) in dichloromethane (35 mL) was added manganese(IV) oxide (17 g, 198 mmol). The reaction mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield tert-butyl 2-(9-chloro-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.52 g, 81%). LCMS-ESI+: calculated for C27H26ClN3O3: 475.9; observed [M+1]+: 476.45.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([N:26]=[C:27]=[S:28])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Na+].[NH2:30][C:31]1[CH:40]=[C:39]2[C:34]([C:35]([OH:55])=[CH:36][C:37]([S:41]([NH:44][C:45]3[CH:46]=[C:47]([S:51]([O-:54])(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=3)(=[O:43])=[O:42])=[CH:38]2)=[CH:33][CH:32]=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:17]=[C:18]3[C:23]([CH:22]=[CH:21][C:20]([NH:26][C:27]([NH:30][C:31]4[CH:40]=[C:39]5[C:34]([C:35]([OH:55])=[CH:36][C:37]([S:41]([NH:44][C:45]6[CH:46]=[C:47]([S:51]([OH:54])(=[O:53])=[O:52])[CH:48]=[CH:49][CH:50]=6)(=[O:42])=[O:43])=[CH:38]5)=[CH:33][CH:32]=4)=[S:28])=[CH:19]3)=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)Nc3cccc(S(=O)(=O)[O-])c3)cc2c1
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N=C=S)cc3c2)ccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(NC(=S)Nc4ccc5c(O)cc(S(=O)(=O)Nc6cccc(S(=O)(=O)O)c6)cc5c4)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 170 mg (0.39 mmol) of compound 135 dissolved in 5 mL of DMF was added a solution of 100 mg (0.25 mmol) of compound 18 in 5 mL of DMF. The reaction was allowed to stir at ambient temperature. After 4 days, the DMF was removed by rotary evaporation and kept under high vacuum to remove traces of DMF. Then, the resulting residue was treated with dichloromethane (50 mL) and sonicated to form a suspension. The solid, insoluble product was collected by vacuum filtration. This solid was dissolved in methanol and then the methanol was removed by rotary evaporation. The resulting solid was again treated with dichloromethane, sonicated, and collected by vacuum filtration. This provided 172 mg of an orange solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16](O)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH2:31][C:29](=[O:30])[O:28]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:26][C:27]1([CH3:35])[O:34][C:32](=[O:33])[CH:31]([C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:29](=[O:30])[O:28]1
Reactant: CCCCCCCC(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (11 mmol) was added to a stirred solution of octanoic acid (10 mmol) and 4-dimethylaminopyridine (12 mmol) in dry dichloromethane (40 ml). The mixture was stirred at room temperature for 1 hour and Meldrum's acid (10 mmol) was added. The stirring was continued at room temperature overnight. The solvent was removed in vacuum and the residue redissolved in ethyl acetate and filtered. The filtrate was washed with 2 M HCl solution and dried over MgSO4. The solvent was rotary evaporated to obtain the title product as an oil in 95% yield and was used without purification in the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19](OCC)=[O:20])=[CH:15]2)(=[O:8])=[O:7].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(O)C>[OH:20][CH2:19][C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc2cc(CO)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a mixture of ethyl 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.76 g) and tetrahydrofuran (15 mL) was added lithium aluminum hydride (0.15 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added ethanol (5 mL), and saturated aqueous ammonium chloride solution (0.5 mL) was added. The resulting inorganic salt was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.55 g, yield 82%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point>173° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH3:49])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH3:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of hexaethylene glycol monobenzyl ether from above (22.3 g) in anhydrous THF (100 ml) was added to a suspension of 50% NaH (3.5 g) in anhydrous THF (100 ml). The suspension was stirred at ambient temperature for 30 min and then a solution of triethylene glycol methyl tosyl ether from above (22.0 g) in THF (100 ml) was added dropwise. The mixture was refluxed under nitrogen overnight, cooled to ambient temperature, quenched with water (500 ml), and extracted with diethyl ether (3×300 ml). The ether extracts were combined, dried (sodium sulfate), and concentrated in vacuo to give nonaethylene glycol benzyl methyl ether as an oil (27 g, 88%), 1H-NMR (CDCl3) δ: 7.31 (m, 5, 5 phenyl CH), 4.54 (s, 2, benzyl CH2), 3.62-3.52 (m, 36, 18 CH2O), 3.35(s, 3, CH3).
Reaction SMILES: [CH:1]1([S:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[F:15][C:16]([F:21])([F:20])[C:17]([NH2:19])=[O:18].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[O-2].[Mg+2]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH:1]1([S:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)(=[N:19][C:17](=[O:18])[C:16]([F:21])([F:20])[F:15])=[O:5])[CH2:3][CH2:2]1
Reactant: NC(=O)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: O=C(N=S(=O)(c1ccc([N+](=O)[O-])cc1)C1CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
1.58 g (3.58 mmol) of rhodium(II) acetate dimer was added, under argon, to a suspension of 15.1 g (71.53 mmol) (RS)-1-cyclopropane sulfinyl-4-nitrobenzene, 17.8 g (157.37 mmol) trifluoroacetamide, 38.0 g (118.02 mmol) iodobenzene diacetate and 12.7 g (314.73 mmol) magnesium oxide in 801 ml DCM and stirred overnight at room temperature. The mixture was filtered through Celite with suction and concentrated by evaporation. The residue that remained was purified chromatographically (hexane/ethyl acetate 2:1). 18.0 g (55.97 mmol; yield: 78%) of the product was obtained.
Reaction SMILES: C([N:8]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[C:27]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:29]=[CH:30][C:22]=2[CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:36]([O:35][C:33]([CH2:32][O:31][C:27]1[C:23]2[CH2:24][CH2:25][CH2:26][CH:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:21][C:22]=2[CH:30]=[CH:29][CH:28]=1)=[O:34])[CH3:37]
Reactant: [H][H]
Reactant: CCOC(=O)COc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)COc1cccc2c1CCCC(NC[C@H](O)COc1ccccc1)C2
Yield: 80.8 %

Procedure:
A mixture of (2S)-1-[N-benzyl-(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (0.55 g) and 10% Pd/C (50% wet, 150 mg) in methanol (6 ml) was stirred at room temperature in the presence of hydrogen at an atmospheric pressure for 4 hours and filtered. The filtrate was evaporated in vacuo and the residue was chromatographed (chloroform-ethanol) over silica gel (8 g) to afford (2S)-1-[(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (365 mg) as a pale yellow solid. The solid (109 mg) was treated with 4N hydrogen chloride in ethyl acetate and powdered from ether to afford (2S)-1-[(1-ethoxycarbonylmethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol hydrochloride (96 mg) as a colorless amorphous powder.
Reaction SMILES: [Na].CN(C)[C:4]1[CH2:8][CH2:7][CH2:6][N+:5]=1[CH3:9].COS([O-])(=O)=O.C(OC(=O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)C.O>C(O)C.C(OCC)C>[CH3:29][O:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9]
Reactant: CCOC(=O)Cc1cccc(OC)c1
Reactant: CN(C)C1=[N+](C)CCC1
Agent: COS(=O)(=O)[O-]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COc1cccc(CC2CCCN2C)c1

Procedure:
Add a solution of 8.1 g of sodium in 160 ml of ethanol dropwise at 90°, with stirring, in a stream of nitrogen to 83.4 g of 2-dimethylamino-1-methyl-1-pyrrolinium-methylsulfate and 48.3 g of 3-methoxyphenylacetic acid ethyl ester. Stir the resulting reaction mixture for a further 30 minutes at 90° and then distribute the reaction mixture between 300 ml of water and 300 ml of diethyl ether. Concentrate the ether phase and boil the residue with conc. hydrochloric acid until carbon dioxide ceases to evolve. After cooling, alkalize the boiled residue with 6 N sodium hydroxide solution before extracting it with diethyl ether. Dry the ether extract over sodium sulfate; concentrate it, and reduce the concentrate in methanol with platinum/hydrogen. Separate the catalyst by filtration, concentrate the filtrate and distil to obtain a yield of 23.0 g (45% of theory) of title compound (b.p. 88° at 0.005 mm of Hg).
Reaction SMILES: [NH2:1]C1C2N(C([C@H]3CC[C@H](C(N)=O)CC3)=NC=2C2C=CC=C(OCC3C=CC=CC=3)C=2)C=CN=1.C[O:35][C:36]([CH:38]1[CH2:43][CH2:42][CH:41]([C:44]2[N:48]3[CH:49]=[CH:50][N:51]=[C:52]([NH2:53])[C:47]3=[C:46]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][C:62]4[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:63]=4[F:69])[CH:55]=3)[N:45]=2)[CH2:40][CH2:39]1)=O>>[NH2:53][C:52]1[C:47]2[N:48]([C:44]([CH:41]3[CH2:42][CH2:43][CH:38]([C:36]([NH2:1])=[O:35])[CH2:39][CH2:40]3)=[N:45][C:46]=2[C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][C:62]3[C:67]([F:68])=[CH:66][CH:65]=[CH:64][C:63]=3[F:69])[CH:55]=2)[CH:49]=[CH:50][N:51]=1
Reactant: COC(=O)C1CCC(c2nc(-c3cccc(OCc4c(F)cccc4F)c3)c3c(N)nccn23)CC1
Reactant: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](C(N)=O)CC1
Product: NC(=O)C1CCC(c2nc(-c3cccc(OCc4c(F)cccc4F)c3)c3c(N)nccn23)CC1

Procedure:
The procedures for trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid amide were applied to 4-{8-Amino-1-[3-(2,6-difluoro-benzyloxy)-phenyl]-imidazo[1,5-a]pyrazin-3-yl}-cyclohexanecarboxylic acid methyl ester to afford the title compound; MS (ES+): m/z 478.02 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.O=S(Cl)[Cl:14]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
A solution of 4-bromo-2-fluorobenzoic acid (10.8 g, 50.0 mmol) in SOCl2 (50 mL) was stirred at 70° Celsius for 1 hour. After cooling to rt, the resulting mixture was concentrated to give 4-bromo-2-fluorobenzoyl chloride as colorless oil, which was used directly in the next step without purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][C@@H:10]([CH3:24])[C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.C(Cl)(Cl)(Cl)Cl.[O-2].[Ca+2].[I:32]I>CO.[Cl-].[Ca+2].[Cl-].C1COCC1>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][C@@H:10]([CH3:24])[C@@H:11]2[C:12](=[O:14])[CH2:13][I:32])[CH2:3]1
Reactant: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: II
Agent: [Ca+2]
Agent: [Cl-]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CI

Procedure:
A mixture of 3α-hydroxy-16α-methyl-5α-pregnan-20-one (21 g) methanol (80 ml), carbon tetrachloride (40 ml), THF (120 ml), calcium oxide (25 g) and calcium chloride in methanol (10%, 3 ml) is stirred at 25°-30°. A solution of iodine (20 g) in calcium chloride (10%, 70 ml) is added to the steroid mixture over 1 hr. The mixture is stirred an additional 2 hr at 30°, filtered through a pad of filter aid, and the filtrate concentrated under reduced pressure to an oil. The oil is dissolved in methylene chloride and flash chromatographed over silica gel (100 g) eluting with methylene chloride/ethyl acetate (4/1). The appropriate fractions are pooled, concentrated and the residue triturated with ether to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][C@H:4]([OH:6])[C:3]1([CH3:8])[CH3:7].Cl[C:10]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:6][C@H:4]1[CH2:5][C@@H:2]([NH:1][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([S:18][CH3:19])[N:11]=2)[C:3]1([CH3:8])[CH3:7]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)[C@H](N)C[C@@H]1O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
A mixture of (1S,3R)-3-amino-2,2-dimethylcyclobutanol (550 mg crude), 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (887 mg, 4.78 mmol) and DIEA (1.12 g, 8.7 mmol) in isopropanol (20 mL) was stirred at 85° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0.6% MeOH in DCM) to afford the title compound (760 mg, 2.88 mmol, 66.3% yield). MS (ESI) m/z 265.1 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH2:23]I)[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]([CH:11]1[C:17](=[C:18]2[CH2:22][CH:21]([CH2:23][N:27]=[N+:28]=[N-:29])[O:20][C:19]2=[O:25])[O:16][C@H:15]2[N:12]1[C:13](=[O:26])[CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OC(CI)CC1=C1O[C@@H]2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: [N-]=[N+]=NCC1CC(=C2O[C@@H]3CC(=O)N3C2C(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the compound of Example 41 (500 mg), 50 ml of tetrahydrofuran and tetrabutylammonium azide (364 mg) is stirred at room temperature for 30 minutes. The mixture is partitioned between ethyl acetate and brine. The organic phase is separated, washed with brine, dried (MgSO4) and stripped of the solvents. The residue is subjected to chromatography over an SiO2 column using toluene/t-butyl methyl ether (12/1). The title compound is obtained as an oil, having characterization data as indicated below.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C=O)C>O>[OH:12][C@@:11]([CH3:14])([CH2:13][N:16]([CH3:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][N:3]1[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]1[Cl:1]
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CNCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 60 °C
Reaction time: 9 h
Yield: 91.4 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (500 mg, 2.3 mmol), N-methylbenzylamine (334 mg, 2.76 mmol) and DMF (2.5 ml) was stirred at 60° C. for 9 hours. The reaction mixture was allowed to return to room temperature and added water followed by extraction with ethyl acetate twice. The organic phases were combined, washed with water three times, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford (S)-1-[2-hydroxy-3-(N-methyl-N-benzylamino)-2-methylpropyl]-2-chloro-4-nitroimidazole (712 mg, yield 91%) as a yellow oil.