Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:1][C:2]1[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12

Procedure:
A 14.0 g amount of 4-amino-1,5-naphthalenedisulfonic acid is suspended in 100 ml of water and the solution is made basic with 5 N sodium hydroxide. The solution is warmed and absolute ethyl alcohol is added until a solid is precipitated. The solid is collected by filtration and is washed with 85% aqueous ethyl alcohol, ethyl alcohol and ether, then dried in vacuo to yield 12.0 g of 4-amino-1,5-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: I.[O:2]=[C:3]1[N:8]([CH2:9][C:10]#[CH:11])[N:7]=[N:6][C:5]2=[C:12]([C:15](=[NH:26])[NH:16][CH2:17][C:18](=O)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[CH:14][N:4]12.I>Cl>[C:19]1([C:18]2[N:26]=[C:15]([C:12]3[N:13]=[CH:14][N:4]4[C:3](=[O:2])[N:8]([CH2:9][C:10]#[CH:11])[N:7]=[N:6][C:5]=34)[NH:16][CH:17]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CCn1nnc2c(C(=N)NCC(=O)c3ccccc3)ncn2c1=O
Agent: Cl
Agent: I
Product: C#CCn1nnc2c(-c3nc(-c4ccccc4)c[nH]3)ncn2c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of crude 4-oxo-N-(2-oxo-2-phenylethyl)-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboximidamide hydroiodide (45 mg) in 3N HCl (4 mL) was heated at 80° C. overnight. After being cooled to room temperature, the mixture was left at 4° C. for 2 hours and the precipitate was filtered and washed successively with cold water, ethyl acetate and diethyl ether to give a mixture of the hydrochloride and hydroiodide salts of the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:5][C:6](=[O:34])[C@H:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:8][C:9](=[O:26])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[NH3:42]>CO>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([NH2:42])=[O:2])[CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)=[O:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:13])([CH3:17])([CH3:16])[CH3:18]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl-L-histidine methyl ester (2 g) is dissolved in a methanol solution saturated with ammonia, and the solution is stirred in a pressure bottle at room temperature for three days. The reaction mixture is concentrated under reduced pressure and the residue is crystallized with ether to give N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl-L-histidine amide (1.7 g) as white crystals. Yield: 87.2%
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19]C)=[CH:8][O:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1-c1coc2c(C)c(O)ccc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(O)ccc2c(=O)c(-c3ccccc3O)coc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
To a stirred solution of 7-hydroxy-3-(2-methoxyphenyl)-8-methyl-4H-chromen-4-one (5 gm, 17.7 mmol) in dry CH2Cl2 (50 ml) at −80° C. was added BBr3 (3.4 ml in DCM, 35.4 mmol). The reaction mixture was then stirred for 1 hour at −80° C. and 12 hours at room temperature. The reaction was then quenched with ice-cooled water. The reaction mixture was then extracted with CH2Cl2 and the organic layer was separated, washed with brine, dried over Na2SO4, and evaporated. The residue was purified by silica gel column chromatography using hexane-chloroform as the eluent to give 7-hydroxy-3-(2-hydroxy-phenyl)-8-methyl-chromen-4-one (3.5 gm, 72%) as white solid.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[K].[SH:18][CH2:19][CH2:20][OH:21].CN(C)C(=O)C.Cl>>[OH:21][CH2:20][CH2:19][S:18][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: OCCS
Agent: Cl
Agent: [K]
Solvent: CC(=O)N(C)C
Product: O=c1c2ccccc2sc2ccc(SCCO)cc12

Procedure:
5.6 g. (0.0225 mol) of 2-chlorothioxanthone and 2.6 g. (0.0225 mol) of the potassium salt of 2-mercaptoethanol are stirred for 18 hours in 20 mol of N,N-dimethylacetamide at 100° C. The reaction mixture is then poured into 2N hydrochloric acid and extracted with ethyl acetate. After conventional work-up and chromatographic purification, 3.5 g. of the analytically pure compound IIIaof melting point 94° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1]
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(CBr)c1Cl
Reaction time: 8 h
Yield: 47.2 %

Procedure:
2-chloro-1-methyl-3-nitrobenzene (1 g, 5.8 mmol) was dissolved in CCl4 (10 mL), then N-bromosuccinimide (2.28 g, 12.8 mmol) and benzoyl peroxide (846 mg, 3.5 mmol) were added. The mixture was stirred overnight at reflux. The solid was removed by filtration, and the filtrate was washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in DCM and purified on silica gel using 30% hexane/AcOEt to afford 1-(bromomethyl)-2-chloro-3-nitrobenzene (686 mg, 47% yield); 1H NMR (400 MHz, CDCl3): δ 4.64 (s, 2H), 7.42 (t, J=7.9 Hz, 1H), 7.67 (dd, J=1.6 Hz, J=7.9 Hz, 1H), 7.75 (dd, J=1.6 Hz, J=7.9 Hz, 1H).
Reaction SMILES: Cl[C:2]1(Cl)[C:9](=[O:10])[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([O:18][CH3:19])[CH2:16][CH3:17]>[Zn].[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[CH3:19][O:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:8][C:9](=[O:10])[CH2:2]2
Reactant: CCC(CCCCC1CCC2C1CC(=O)C2(Cl)Cl)OC
Agent: [Cl-]
Agent: [Zn+2]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC(CCCCC1CCC2CC(=O)CC12)OC

Procedure:
6,6-dichloro-2-(5-methoxyhept-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichlorohexahydro-4-(5-methoxyheptyl)-2(lH)-pentalenone} or the isomer (45.9 g) are added to a single-neck 100 ml, round-bottom flask equipped with a condenser. The solution is stirred by a magnetic stirrer and powdered zinc metal (92 g) and glacial acetic acid (312 ml) are added and the solution heated under reflux for one hour, during which time white ZnCl2 precipitates out of solution. The solution is filtered, washed with sodium hydrogen carbonate and extracted three times with ether. The ether extracts are combined and dried over anhydrous sodium sulfate. The resulting yellow oil is chromatographed with silica gel and eluted with 3:1 hexane:ether. The fractions are combined, yielding 2-(5-methoxyhept-1-yl)-bicyclo[3.3.0]octan7-one {hexahydro-4-(5-methoxyheptyl)-2(1H)-pentalenone} as a clear, colorless oil. B.
Reaction SMILES: C(OC1C(OC(=O)C)C(OC(=O)C)C(COC(=O)C)OC1[C:24]1[C:32]2[C:28](=[N:29][C:30](=[O:33])[N:31]=2)[CH:27]=[CH:26][C:25]=1[C:34]([O-])=O)(=O)C.[OH-:37].[Na+]>C(O)C>[OH:37][C:26]1[C:25]([CH3:34])=[CH:24][C:32]2=[N:31][C:30](=[O:33])[N:29]=[C:28]2[CH:27]=1
Reactant: [OH-]
Reactant: CC(=O)OCC1OC(c2c(C(=O)[O-])ccc3c2=NC(=O)N=3)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(cc1O)=NC(=O)N=2
Yield: 92 %

Procedure:
A solution of (16) (0.30 g, 1.32 mmol) in 10% sodium hydroxide (5 ml) and ethanol (5 ml) was heated under reflux for 1.5 h. When cooled to room temperature the ethanol was removed in vacuo and the mixture was filtered to give (18) as a white solid (0.20 g, 92%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>>[CH2:1]([NH:8][CH2:12][CH2:11][CH2:10][C:9]1[NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C1CCCN1Cc1ccccc1
Product: c1ccc(CNCCCc2nc3ccccc3[nH]2)cc1

Procedure:
By the procedure of Example 2 N-benzylpyrrolidone was reacted with o-phenylenediamine to yield 2-(3-benzylaminopropyl)benzimidazole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[C:17]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])(=[O:21])[C:18]([CH3:20])=O.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]([CH:4]([NH:5][C@H:18]([C:17]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH3:20])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:16]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CC(=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)C(Cc1c[nH]c2ccccc12)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In a manner similar to Example 16 tryptophan methyl ester is condensed with pyruvoyl-L-proline in the presence of sodium cyanoborohydride to yield N-[1-methoxycarbonyl-2-(3-indolyl)-ethyl]-alanyl-L-proline.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:35]=[CH:36][C:37]=3[O:38][CH:39]([CH3:41])[CH3:40])[CH2:14][CH2:15][N:16]([CH2:18][C:19]3([NH:27]C(=O)OC(C)(C)C)[CH2:24][O:23]C(C)(C)[O:21][CH2:20]3)[CH3:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:27][C:19]([CH2:18][N:16]([CH2:15][CH2:14][C:13]1[CH:35]=[CH:36][C:37]([O:38][CH:39]([CH3:41])[CH3:40])=[C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:12]=1)[CH3:17])([CH2:24][OH:23])[CH2:20][OH:21]
Reactant: CC(C)Oc1ccc(CCN(C)CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CC(C)Oc1ccc(CCN(C)CC(N)(CO)CO)cc1C12CC3CC(CC(C3)C1)C2
Yield: 49 %

Procedure:
When the product of Step G was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 49% yield. 1H-NMR (CDCl3) 1.34 (d, 6H, J=6.00 Hz); 1.73 (s, 6H); 2.03 (s, 3H); 2.08 (s, 6H); 2.4 (s, 3H); 2.51 (s, 2H); 2.66 (s, 4H); 3.42 (d, 2H, J=10.87 Hz); 3.47 (d, 2H, J=10.88 Hz); 4.56-4.61 (m, 1H); 6.72 (d, 1H, J=8.34 Hz); 6.98 (dd, 1H, J=2.12, 8.24 Hz); 6.97 (d, 1H, J=2.12 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([OH:35])[C:33]#[CH:34].C(N(C(C)C)CC)(C)C>[Cl-].[Na+].O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:34]#[C:33][CH2:32][OH:35]
Reactant: C#CCO
Reactant: FC(F)(F)c1ccc(Cl)c(I)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: OCC#Cc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-chloro-3-iodobenzotrifluoride (10.0 g), copper(I) iodide (124 mg), triphenylphosphine (428 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (675 mg), propargyl alcohol (2.12 ml), diisopropylethylamine (22.6 ml) and tetrahydrofuran (180 ml) was stirred at room temperature for 15 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (7.63 g) as a brown oil.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[CH2:14][OH:15]>O>[NH2:8][C:6]1[N:7]=[CH:2][C:3]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH2:14][OH:15])=[CH:4][CH:5]=1
Reactant: Nc1cccc(F)n1
Reactant: OCC1CCCN1
Solvent: O
Product: Nc1ccc(N2CCCC2CO)cn1
Temperature: 205 °C
Yield: 91.1 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and pyrrolidin-2-ylmethanol (0.678 g, 6.7 mmol) in water (0.3 mL) was heated to 205° C. for 0.5 h in a sealed tube in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:3) to afford (1-(6-aminopyridin-3-yl)pyrrolidin-2-yl)methanol (0.785 g, 91%) as a yellow oil. LC-MS: [M+1]+=194, tR=0.968 min.
Reaction SMILES: IC.[C:3]([C@H:10]([CH:14]([NH2:22])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)C(O)=O)([O:5][C:6](C)(C)C)=[O:4].[C:23](=[O:26])([O-])[O-:24].[K+].[K+]>CN(C=O)C>[C:15]([O:24][C:23]([NH:22][C@@H:14]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH2:10][C:3]([O:5][CH3:6])=[O:4])=[O:26])([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)[C@@H](C(=O)O)C(N)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 199.1 %

Procedure:
Iodomethane (0.987 mL, 15.85 mmol) was added in one portion to boc-(R)-3-amino-3-(4-chloro-phenyl)-propionic acid (950 mg, 3.17 mmol) and potassium carbonate (876 mg, 6.34 mmol) in DMF (15 mL). The resulting suspension was stirred at 80° C. for 24 hours. The reaction mixture was concentrated and diluted with EtOAc (25 mL) with water (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (R)-methyl 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoate (990 mg, 100%) as a orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.C1COCC1.O.NN>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([C@H:21]2[CH2:25][CH2:24][CH2:23][N:22]2[CH3:26])[NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1CCC[C@@H]1[C@H](c1ccc(Cl)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1[C@@H](N)c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 48.7 %

Procedure:
To a solution of 244 (0.40 g, 1.03 mmol) and MeOH:THF (1:1, 10 mL) was added hydrazine monohydrate (0.514 g, 10.3 mmol) and the reaction was stirred at 50° C. for 18 h. The reaction mixture was poured into water and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (500:50) to afford 0.130 g (48.8%) of (S)-(3,4-dichlorophenyl)((R)-1-methylpyrrolidin-2-yl)methanamine (246).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br>ClCCl.Cl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4cscn4)ccc3c2n1CC(C)(C)O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(OCc4cscn4)ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-[4-amino-2-ethoxymethyl-7-(thiazol-4-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (400 mg, 0.94 mmol, which can be prepared as described in International Application No. PCT/US04/28021 Example 137) in dichloromethane (50 mL) was cooled to 0° C. in an ice bath. A solution to of boron tribromide in dichloromethane (3.76 mL of 1.0 M) was added slowly. The reaction mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was diluted with hydrochloric acid (20 mL of 6 N) and stirred for 30 minutes. The layers were separated. The organic layer was washed with 6 N hydrochloric acid (3×20 mL) and then discarded. The aqueous layer was made basic by the addition of solid potassium carbonate. A precipitate was isolated by filtration, dissolved in hot chloroform, and then purified by prep HPLC (HORIZON HPFC system eluting with 0-10% CMA in chloroform over 192 mL and then with 10-40% CMA in chloroform over 1400 mL) to provide a solid. This material was crystallized from acetonitrile to provide 181 mg of 1-[4-amino-2-hydroxymethyl-7-(thiazol-4-ylmethoxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 260-262° C. Anal. calcd for C19H21N5O3S: % C, 56.81; % H, 5.41; % N, 17.26. Found: % C, 56.82; % H, 5.54; % N, 17.23.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][CH2:11][C@H:12]([N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1)[CH3:13]>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([C@H:12]([CH3:13])[CH2:11][NH:10][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: Cc1nc(C(=O)O)c[nH]1
Reactant: C[C@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)NC[C@@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1

Procedure:
(R)—N-{2-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propyl}-2-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 247 starting from 2-methyl-1H-imidazole-4-carboxylic acid and (R)-4-[1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl]-2-chlorobenzonitrile. The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH (98:2) as an eluent. The resulting product was triturated in DCM at RT to afford the title compound. 1H NMR (400 MHz, CDCl3): 1.61 (3H, d), 2.39 (3H, s), 3.74-3.81 (1H, m), 3.85-3.91 (1H, m), 4.63 (1H, m), 6.59 (1H, d), 7.45 (1H, d), 7.49 (1H, d), 7.62 (1H, t), 7.66 (1H, d), 7.84 (1H, dd), 8.00 (1H, d), 10.04 (1H, broad s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:31]=[C:32]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:33]=1)[C:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46].Cl>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52][N:34]([C:32]2[CH:31]=[C:11]([CH:10]=[C:9]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:52][C:51]3[CH:54]=[CH:55][C:48]([CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:49][CH:50]=3)[CH:33]=2)[C:12]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]=2)=[O:13])[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[CH:50][CH:49]=1)[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)Cc1ccc(CCl)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cc(NC(=O)OC(C)(C)C)cc(NC(=O)OC(C)(C)C)c2)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)cc(N(Cc3ccc(CC(C)C)cc3)C(=O)OC(C)(C)C)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 170.1 %

Procedure:
A solution of ethyl 4-[3-[3,5-bis(tertbutoxycarbonylamino)benzoyl]indol-1-yl]butyrate (300 mg) in N,N-dimethylformamide (5 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 54 mg) in N,N-dimethylformamide (5 ml ) at 0° C. The mixture was stirred at 0° C. for 30 minutes, and a solution of 4-isobutylbenzyl chloride (38.8 mg) in N,N-dimethylformamide (5 ml) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, and poured into a mixture of 0.1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, aqueous solution of sodium bicarbonate and brine in successively. After dryness over magnesium sulfate and evaporation of the solvent, the residue was chromatographed on silica gel (25 g) eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl 4-[3-[3,5-bis[N-(4-isobutylbenzyl )-N-tert-butoxycarbonylamino] benzoyl]indol-1-yl]butyrate (155 mg) as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O.C(OCC)(=O)C>[C:3]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: BrC1CCCCC1
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(c2ccc(OC3CCCCC3)cc2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (1.18 g) in dimethylformamide (25 ml) was added 1-acetyl-4-(4-hydroxyphenyl)piperazine (5 g) and bromocyclohexane (5.59 ml) and stirred for 1 hour at 100° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetyl-4-(4-cyclohexyloxyphenyl)piperazine (0.92 g).