Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1([CH2:28][C:29]2[N:34]=[C:33]3[CH2:35][O:36][C:37](=O)[C:32]3=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:37]1[C:32]2[C:33](=[N:34][C:29]([CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:30][CH:31]=2)[CH2:35][O:36]1
Reactant: O=C1OCc2nc(CN3CCOCC3)ccc21
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CN3CCOCC3)ccc21
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (113 mg, 0.75 mmol.) in THF (1 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (2 mL of a 1M solution in THF, 2 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is removed and a solution of 2-morpholin-4-ylmethyl-7H-furo[3,4-b]pyridin-5-one (120 mg, 0.5 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and then poured into a 10% aqueous HCl solution. The resulting solution is stirred for 48 h at room temperature. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH, EtOAc, Et2O (3×5 mL). The residual solid is purified by chromatography (silica gel, 5% MeOH in EtOAc). The product containing fractions are concentrated to give the title compound as a yellow solid (65 mg, 35%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[SH:13].[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([N+:24]([O-:26])=[O:25])=[C:21](Br)[CH:22]=1)=[O:17]>CN(C=O)C>[CH3:14][O:15][C:16]([C:18]1[S:19][C:20]([N+:24]([O-:26])=[O:25])=[C:21]([S:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[CH:22]=1)=[O:17]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reactant: Sc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Sc2ccc3ccccc3c2)c([N+](=O)[O-])s1

Procedure:
To a suspension of NaH (30 mg, 1.24 mmol) in DMF was slowly added dropwise naphthalene-2-thiol (199 mg, 1.24 mmol, Aldrich Chemical Company) in DMF at rt. This clear solution was then added dropwise to a solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 300 mg, 1.27 mmol) in DMF at rt. Aqueous workup resulted in isolation of 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step b was followed using 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (194 mg, 0.56 mmol) and m-CPBA (354.4 mg, 1.2 mmol) resulting in 4-(naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 27: step a was followed using 4-(naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (32 mg, 0.085 mmol) sodium thiomethoxide (7.55 mg, 0.94 mmol) resulting in 5-methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step f was followed using 5-methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester (29 mg, 0.77 mmol) and dimethyl aluminum amide (0.39 mL, 0.39 mmol) resulting in the title compound 5-methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxamidine triflouroacetate (19 mg, 70%). 1H-NMR (CD3OD): δ: 8.67 (m, 1H), 8.37 (s, 1H), 8.05–8.15 (m, 2H), 7.95–8.01 (d, J=7.21 Hz, 1H), 7.90–7.95 (d of d, J=6.7, 2.0 Hz), 7.65–7.75 (m, 2H), 2.70 (s, 3H).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32])([O-:27])=[O:26].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([NH:32][CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1CCN(c2ccc(Nc3ncc4ccc(NCc5cccc([N+](=O)[O-])c5)n4n3)cc2)CC1
Temperature: 120 °C

Procedure:
Into a 8-dram vial, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (66.6 mg, 0.000172 mol), 3-nitrobenzylamine (31.42 mg, 0.0002065 mol) Palladium Acetate (4.00 mg, 0.0000178 mol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (30.0 mg, 0.0518 mmol), and Cesium Carbonate (240.0 mg, 0.7366 mmol) were added. The mixture was purged with nitrogen for 15 minutes. 1,4-Dioxane (2.00 mL) was added. The reaction vessel was sealed and heated at 120° C. for 2 hours. The reaction mixture was partitioned with DCM. The solid was filtered through celite and washed with DCM. The filtrate was evaporated to give a semi-solid. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN (0 to 20% ACN). The collected fractions were lyophilized to give N(2)-[4-(4-Methyl-piperazin-1-yl)-phenyl]-N(7)-(3-nitro-benzyl)-pyrrolo[2,1-f][1,2,4]triazine-2,7-diamine a solid (32 mg, 32%). The solid was triturated with Et2O to give a yellow solid. LCMS (E/I+) 459.14 (M+H). NMR 1H (DMSO-d6)-9.75 (bs, 1H), 9.31 (s, 1H), 8.36 9 s, 1H), 8.27 (s, 1H), 8.14 (d, 1H, J=8.20 Hz), 7.86 (d, 1H, J=7.60 Hz), 7.59-7.73 (m, 3H), 7.49 (bs, 1H), 7.09 (bs, 1H), 6.98 (d, 2H, J=8.20 Hz), 6.55 (bs, 1H), 4.76 (s, 2H), 3.75 (d, 2H, J=12.89 Hz), 3.54 (d, 2H, J=11.72 Hz), 3.16 (q, 2H, J=18.79 Hz), 2.79-2.99 (m, 5H).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[C:25]1([C@H:31]([NH2:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@H:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@H](Cc1ccccc1)c1ccccc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)N[C@H](Cc4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 82 %

Procedure:
The title compound was prepared in a yield of 82% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and (R)-1,2-diphenylethylamine.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([N:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1)=[O:18])=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[O:26]=[S:22]1(=[O:25])[CH2:21][CH2:20][N:19]([C:17]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[C:9]([OH:10])=[O:8])=[O:18])[CH2:24][CH2:23]1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCCN1C(=O)N1CCS(=O)(=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H]1CCCCN1C(=O)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-1-(1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl)-piperidine-2-carboxylic acid benzyl ester (1.53 g; 4.021 mmol) in ethyl acetate (100 mL) is added 10% palladium on carbon (500 mg) and the reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight. After this time, the mixture is filtered through Celite®. The Celite® is washed with 50% ethyl acetate in ethanol then ethanol and the combined filtrates are concentrated in vacuo to afford the title compound as a white solid, m/z 291 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:5]2[CH:6]=[N:7][C:8]([CH3:10])=[CH:9][C:4]=2[N:3]=1.[C:18]([O:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C@@H:29]([CH2:34]I)[CH2:28]2)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:18]([O:22][C:23](=[O:36])[NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C@@H:29]([CH2:34][N:15]1[CH2:16][CH2:17][CH:12]([N:11]3[C:5]4[CH:6]=[N:7][C:8]([CH3:10])=[CH:9][C:4]=4[N:3]=[C:2]3[CH3:1])[CH2:13][CH2:14]1)[CH2:28]2)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cc2nc(C)n(C3CCNCC3)c2cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C[C@H](CI)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cc2nc(C)n(C3CCN(C[C@@H]4Cc5ccc(NC(=O)OC(C)(C)C)cc5C4)CC3)c2cn1
Temperature: 85 °C
Reaction time: 4 h
Yield: 53.8 %

Procedure:
A solution of 2,6-dimethyl-3-piperidin-4-yl-3H-imidazo[4,5-c]pyridine (20 mg, 0.086 mmol) in acetonitrile (0.80 mL) was treated with (R)-(2-iodomethyl-indan-5-yl)-carbamic acid tert-butyl ester (50 mg, 0.13 mmol) and cesium carbonate (85 mg, 0.26 mmol). The mixture was stirred at 85° C. for 4 hrs. The mixture was filtered and the solvent was evaporated. Flash chromatography (10/1 CH2Cl2/CH3OH) afforded (R)-{2-[4-(2,6-dimethyl-imidazo[4,5-c]pyridin-3-yl)-piperidin-1-ylmethyl]-indan-5-yl}-carbamic acid tert-butyl ester (22 mg, 54%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH:5]1[CH2:10][CH2:9][O:8][CH:7]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:13]2=[O:32])[CH2:6]1.[Na]>ClC(Cl)C>[CH3:1][CH:2]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:24][O:23][C:22]4[CH:25]=[C:26]5[C:30](=[CH:31][C:21]3=4)[CH2:29][CH2:28][O:27]5)[C:13]2=[O:32])[CH2:6]1)[CH3:4]
Reactant: O=C1N(CC2CNCCO2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CC(C)=O
Agent: [Na]
Solvent: CC(Cl)Cl
Product: CC(C)N1CCOC(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
To a solution of acetone (0.04 mL, 0.53 mmol) in dichloroethane (5 mL) was added 1′-(morpholin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.04 g, 0.11 mmol) and sodium triacetoxyhydroborate (0.11 g, 0.53 mmol), then the mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography with ethyl acetate/methanol/ammonium hydroxide (15/1/0.1) to afford 1′-{[4-(1-methylethyl)morpholin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.02 g, 54%) as a colorless foam; 1H NMR (300 MHz, CDCl3) δ7.38-7.25 (m, 1H), 7.18-7.04 (m, 3H), 6.50 (s, 0.5H), 6.44 (s, 0.5H), 6.41 (s, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53 (t, J=8.7 Hz, 2H), 4.00-3.55 (m, 5H), 2.97 (t, J=8.7 Hz, 2H), 2.85-2.55 (m, 3H), 2.37-2.03 (m, 2H), 1.05-0.98 (m, 6H); MS (ES+) m/z 421.0 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[C:29]2[CH3:37])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[C:29]2[CH3:37])[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)O)cnn3c1NCc1ccccc1)CC2
Product: CC1=Cc2ccccc2C12CCN(C(=O)c1cnc3c(C(=O)NS(C)(=O)=O)cnn3c1NCc1ccccc1)CC2
Yield: 61 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(2-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.078 g, 0.158 mmol) obtained in step 2 and methanesulfonamide (0.075 g, 0.791 mmol), the title compound (0.055 g, 61%) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.P([O-])(O)(O)=O.[K+]>[CH2:20]([O:13][N:10]1[C:11]2[C:6](=[CH:5][C:4]([C:16]([F:19])([F:17])[F:18])=[C:3]([C:1]#[N:2])[CH:12]=2)[NH:7][C:8](=[O:15])[C:9]1=[O:14])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Product: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2OCc1ccccc1
Reaction time: 2 h
Yield: 74.3 %

Procedure:
To a solution of 10.0 g (~36.9 mmol) of 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione in a mixture of 700 ml of ethanol and 175 ml of 1M potassium dihydrogen phosphate buffer pH 7.4 was added 14 g (~81 mmol) of benzylbromide. Stirring was continued for 2 h at 25° C. The precipitate was filtered off and washed with ice-cold ethanol to give the title compound (9.9 g; 75%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: N#Cc1ccccn1
Reactant: Nc1ccc(F)cc1
Product: N=C(Nc1ccc(F)cc1)c1ccccn1

Procedure:
The title compound was prepared from 2-cyanopyridine (0.94 g, 9 mmol) and 4-fluoroaniline (1 g, 9 mmol) by following the procedure described in preparation 10 (1.1 g, yield 56.81%). 1H-NMR (CDCl3):δ 6.98-7.09 (m, 2H), 7.26 (s, 2H), 7.39-7.42 (d, 1H), 7.82-7.84 (m, 1H), 8.38-8.4 (d, 1H), 8.57-8.58 (s, 1H). MS m/z: 216.3 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:11]([O-])=O)[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.CO>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O=[N+]([O-])c1cc(Br)c2[nH]ncc2c1
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(Br)c2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 39.5 %

Procedure:
A mixture of iron (Aldrich 99.99+%, 13.85 g, 248.0 mmol) and crude 7-bromo-5-nitro-1H-indazole (20.00 g, 82.63 mmol) in glacial acetic acid (100 mL) was heated at about 80° C. in a 2-neck round bottom flask equipped with a mechanical stirrer and a nitrogen line with a bubbler. After about 2.5 hours, MeOH (100 mL) was added, warmed, and filtered hot through Celite®. The Celite® pad was washed with additional MeOH (4×100 mL) and the combined organic layers were concentrated under reduced pressure. The residues were basified to pH ˜7 using aqueous Na2CO3 (2M) and the product was extracted into EtOAc (1 L) over about 16 hours. The layers were separated and the aqueous layer was further extracted with additional EtOAc (3×500 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, decanted, and concentrated. The resulting solid was pre-adsorbed onto silica and purified by silica gel chromatography using heptane/EtOAc (1:1) as the eluent to afford 7-bromo-1H-indazol-5-ylamine (6.92 g, 40%); 1H NMR (DMSO-d6, 400 MHz) 12.92 (br s, 1H), 7.87 (s, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.77 (d, J=1.2 Hz, 1H) 4.96 (br s, 2H); LC-MS (Table 1, Method e) Rt 0.83.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[S:24][CH:25]=1>>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[S:24][CH:25]=[C:21]([CH2:20][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH:1]3[CH2:2][CH2:3]3)[N:22]=2)=[CH:31][CH:30]=1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2csc(-c3ccc(Cl)cc3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole: MS (ES) m/z 458 (M+1) and 460 (M+1, isotope).
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])C1C=CC=CC=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])O.[Na+]>C(O)C>[F:25][C:24]([F:26])([F:27])[C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:29]([C:32]3[N:36]=[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]4[CH:33]=3)[CH:30]=[CH:31][C:9]=2[OH:8])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2cn3ccccc3n2)ccc1O
Yield: 56 %

Procedure:
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide (280 mg, 0.5 mmol), 2-aminopyridine (51.8 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (10 mL) was refluxed for 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2) to give the title compound (130.3 mg, 45.9%) as a white solid. Then, a mixture of this solid (108 mg, 0.19 mmol), 10% Pd—C (11 mg), ethanol (8 mL) and ethyl acetate (8 mL) was stirred for 7 hours under hydrogen atmosphere. The reaction mixture was filtered and the residue obtained by evaporation of the filtrate under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:3) to give the title compound (18.3 mg, 20.2%) as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][N:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11]2.CN(C)[CH:24]=[O:25].Cl>CCCCCC.CCOCC>[C:16]1([N:10]2[CH2:9][C:8]3[C:7]([CH:24]=[O:25])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc2c1CN(c1ccccc1)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1cccc2c1CN(c1ccccc1)C2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
2.3 ml (3.7 mmol) of a 1.6 molar solution of butyllithium in hexane are added to 14 ml of dry ether in a dry apparatus under argon. A solution of 930 mg (3.4 mmol) of 4-bromo-2-phenylisoindoline in 10 ml of dry ether is then added dropwise at -70° C. The mixture is stirred at -70° C. for 30 minutes, and 0.3 ml of dry dimethylformamide in 0.5 ml of ether is added. The mixture is stirred at 70° C. for 3 hours and heated to -5° C., and 13.6 ml of 1N hydrochloric acid are added dropwise. 50 ml of ether are added and the mixture is separated. The aqueous phase is extracted by shaking with ether and the combined ether phases are washed once with water, dried and concentrated. 600 mg of yellowish crystals of melting point 120°-122° C. are obtained.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>N1CCCCC1>[O:13]1[CH2:12][CH:11]1[CH2:9][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: ClCC1CO1
Reactant: Cc1ccccc1O
Solvent: C1CCNCC1
Product: Cc1ccccc1OCC1CO1

Procedure:
A solution of ortho-cresol (64.8 g., 0.6 mole), epichlorohydrin (330 g., 3.6 mole), and piperidine (5 drops) was allowed to react and the product was isolated using the same methods outlined hereinabove in Example 1. Concentration of the methylene chloride extract gave 95 g. of crude epoxide (IIb) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]2[C:13]3[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:9][C:8]=3[N:7]=[C:6]([NH2:23])[C:5]=2[N:24]=1.[CH:29]1([N:35]=[C:36]=[O:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[NH2:23][C:6]1[C:5]2[N:24]=[C:2]([CH3:1])[N:3]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:4]=2[C:13]2[CH:12]=[CH:11][C:10]([O:14][CH2:15][CH2:16][CH:17]3[CH2:18][CH2:19][N:20]([C:36]([NH:35][CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:37])[CH2:21][CH2:22]3)=[CH:9][C:8]=2[N:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1nc2c(N)nc3cc(OCCC4CCNCC4)ccc3c2n1CC(C)C
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(N)nc3cc(OCCC4CCN(C(=O)NC5CCCCC5)CC4)ccc3c2n1CC(C)C
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
A solution of 2-methyl-1-(2-methylpropyl)-7-(2-piperidin-4-ylethoxy)-1H-imidazo[4,5-c]quinolin-4-amine (0.300 g, 0.786 mmol) in chloroform was cooled to 0° C. Cyclohexyl isocyanate (0.100 mL, 0.783 mmol) was added dropwise, and the reaction was stirred for 30 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with dichloromethane:methanol ranging in ratios from 99:1 to 95:5). The resulting product was recrystallized from ethanol to provide 0.130 g of 4-(2-{[4-amino-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)-N-cyclohexylpiperidine-1-carboxamide as a white powder, mp 213.7-215.7° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])[CH3:2].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+]>C(O)(=O)C.O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]=[N+:31]=[N-:32])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N)ccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N=[N+]=[N-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole (466 mg) in acetic acid (8 mL) a solution of sodium nitrite (1.1 eq) in water (4 mL) is added dropwise. After stirring at 0° C. for 1 h, a solution of sodium azide (1.3 eq) in water (5 mL) is added dropwise. Stirring is continued for 0.5 h at 0° C., and then at room temperature for 0.5 h. The reaction mixture is concentrated to ⅓ volume, water (10 mL) is added and then mixture is then extracted with ethyl acetate (3×). The combined organic layers are washed with aqueous sodium bicarbonate (2×), then washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 641 mg of crude 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[O:5]1[CH2:9][CH2:8][CH:7]([CH2:10]OS(C)(=O)=O)[CH2:6]1>CN(C=O)C.O>[N:1]([CH2:10][CH:7]1[CH2:8][CH2:9][O:5][CH2:6]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCOC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CCOC1
Temperature: 50 °C
Yield: 61.7 %

Procedure:
Add sodium azide (1.5 g, 23 mmol, 1.5 equiv) to a solution of methanesulfonic acid tetrahydro-furan-3-ylmethyl ester (2.76 g, 15.3 mmol, 1 equiv) in anhydr DMF (10 mL). Heat the reaction mixture at 50° C. for 16 h. Dilute the reaction mixture with H2O (100 mL) and extract with Et2O (2×50 mL). Wash the combined organic layers with H2O (2×50 mL), dry (anhydr Na2SO4), and rotary evaporate (40° C.) to yield 1.20 g (61.6%) of 3-azidomethyl-tetrahydro-furan as a nearly-colorless liquid.