Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.CO[CH:18](OC)[N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH:20]([N:19]([CH:18]=[C:2]1[CH2:3][C@@H:4]([CH2:5][OH:6])[O:7][C@H:1]1[N:8]1[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]1=[O:10])[CH:23]([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Reactant: COC(OC)N(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(C=C1C[C@@H](CO)O[C@H]1n1ccc(N)nc1=O)C(C)C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
In a typical reaction--previously dried 2',3'-dideoxycytidine (153 mg, 0.724 mmoles) prepared by the literature procedures described above is treated with diisopropylformamide dimethylacetal (1.27 g, 7.24 mmoles) in anhydrous DMF (2 mL) under an argon atmosphere. The contents are stirred overnight and then the solvent and excess reagent are removed by rotary evaporation. The syrupy residue remaining is crystallized from ethanol-ether to give pale lemon-colored crystals (185 mg, 79%) of diisopropylaminomethylene 2',3'-dideoxycytidine.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:10][C:6]([CH3:11])([CH2:5][S:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(CCl)C(=O)O
Reactant: C[S-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC(C)(C)C(=O)O
Temperature: 23 °C
Reaction time: 24 h
Yield: 112.4 %

Procedure:
Sodium methanethiolate (1.0 g, 14 mmol, 2.0 equiv) was added to a stirred solution of 3-chloro-2,2-dimethylpropanoic acid (1.0 g, 7.2 mmol, 1.0 equiv) in N,N-dimethylformamide (3.7 mL) at 0° C. The resulting brown suspension was allowed to warm to 23° C. and stirred for 24 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (300 mL) and washed with diethyl ether (3×75 mL). The aqueous layer was acidified to pH≈1 with concentrated hydrochloric acid and extracted with diethyl ether (3×75 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation to afford the title compound as a colorless oil (1.2 g, 99%): 1H NMR (300 MHz, CDCl3) δ 2.76 (s, 2H), 2.16 (s, 3H), 1.30 (s, 6H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([S:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20](O)[CH3:21]>>[ClH:3].[CH2:20]([O:18][C:17](=[O:19])[C@H:15]([CH2:14][S:13][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:16])[CH3:21]
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](CSCCc1ccccc1)C(=O)O
Reactant: CCO
Product: CCOC(=O)[C@@H](N)CSCCc1ccccc1
Product: Cl
Temperature: 25 °C

Procedure:
Add thionyl chloride (2.0 ml) to absolute ethanol (25 ml) at 0°-5°. To this solution add S-phenethyl-L-cysteine (2.5 g, 1.11 mmole). Warm the resulting mixture to room temperature, and then heat at 60° for 5 hours. Concentrate the reaction mixture in vacuo, dissolve the resultant residue in dichloromethane (CH2Cl2), and concentrate the solution in vacuo. Dissolve the residue in absolute ethanol, treat with DARCO, filter and concentrate in vacuo to give the title compound, a white solid (2.90 g) m.p. 155°-156°, [α]D26 =-1.5° (MeOH).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.C([Li])CCC.CCCCCC.CN(C)[CH:27]=[O:28].[Cl-].[Na+]>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:27]=[O:28])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-bromo-6-methoxynaphthalene (4.00 g, 16.87 mmol) in 100 mL of anhydrous THF under nitrogen atmosphere at -78° C. was added a 1.6M solution of n-butyllithium in hexane (10.6 mL, 16.96 mmol). The reaction mixture turned into a yellow suspension 5 minutes after the addition of butyllithium. The suspension was stirred at -78° C. for 1 hour and then warmed to -23° C. Anhydrous N,N-dimethylformamide (4.0 mL, 51.7 mmol) was added. The reaction mixture was stirred at -23° C. for 30 minutes. Saturated sodium chloride solution (50 mL) was added to quench the reaction. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried with anhydrous magnesium sulphate, filtered, and concentrated under reduced pressure. The residue oil was chromatographed by 10% ethyl acetate in hexanes on silica gel to give 2.86 g (91%) of 6-methoxy-2-naphthaldehyde as a white solid. 1HNMR (300 MHz, CDCl3) δ10.10 (1H, s), 8.26 (1H, s), 7.95-7.78 (3H, m), 7.28-7.18 (2H, m), 3.97 (3H, s).
Reaction SMILES: O=[C:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[C:4](=O)[N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:8]=[CH:9][CH:10]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)C>C1COCC1>[CH2:2]1[C:11]2[C:6]3[C:7](=[CH:12][CH:13]=[CH:14][C:5]=3[CH2:4][N:3]1[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:8]=[CH:9][CH:10]=2
Reactant: NCCCCN1C(=O)c2cccc3cccc(c23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: NCCCCN1Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.0 g (18.6 mmol) 4-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-butylamine are dissolved in 200 ml THF and 6.1 g (160.7 mmol) LiAlH4 are added in portions under cooling. The suspension is stirred for 24 hours at RT and for 8 hours under reflux. After cooling, ethanol is carefully added dropwise until no more foam appears. The mixture is filtered and the filtrate is concentrated under vacuum. The residue is distributed between chloroform and water. The organic phase is dried over sodium sulfate and, after withdraw of the solvent, chromatographically purified over silica gel with CHCl3/CH3OH/NH4OH (90/10/0.5 to 90/10/1): Yield 2.2 g (49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(I)ccc1OC
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccccc2)ccc1OC

Procedure:
1.06 g (3.64 mmol) of methyl 2-Methoxy-5-iodobenzoate, 460 mg (3.78 mmol) of phenylboronic acid, 83 mg (2 molar %) of tetrakistriphenylphosphine palladium and 1.52 g (14.4 mmol) of sodium carbonate were heated under reflux in 12 ml of toluene/ethanol/water (2/1/1) solvent mixture for 2 hours. After the filtration through Celite followed by the after treatment conducted by an ordinary method, the obtained residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.O.[NH3:17]>O>[OH2:13].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13])=[CH:6][CH:7]=1.[NH4+:17]
Reactant: N
Reactant: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Solvent: O
Product: Nc1ccc(NC(=O)/C=C\C(=O)[O-])cc1
Product: [NH4+]
Temperature: 50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 12.1 g (58.7 mmol) of (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid and 50 ml of water. A solution prepared by dissolving 12 ml of 25% ammonia water in 12 ml of water was dropped into this under cooling with ice over a period of 15 minutes. After completion of dropping, the solvent was distilled off under reduced pressure to obtain a residue to which 100 ml of tetrahydrofuran was added, and the mixture was stirred at 50° C. for 1 hour. Thereafter, the mixture was cooled down to room temperature, the deposited solid was isolated by filtration, and washed three times with 20 ml of tetrahydrofuran. The resultant solid was dried to obtain 11.1 g of ammonium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate mono-hydrate as a gray-green powder. Yield: 79%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Mg].II.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].N#N>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCOC(=O)Cl
Reactant: c1ccc2cnccc2c1
Agent: II
Agent: N#N
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(=O)N1C=Cc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 4-trifluoromethylphenyl Grignard reagent was prepared by adding 1-bromo-4-(trifluoromethyl)benzene (1.3 mL, 9.2 mmol) to a suspension of magnesium turnings (240 mg, 10.0 mmol), a catalytic amount of iodine in THF (10 mL) and stirred at RT for 1.5 h. A separate round-bottomed flask containing isoquinoline (1.1 g, 8.3 mmol) in anhydrous THF (10 mL) was charged with ethyl chloroformate (0.88 mL, 9.2 mmol) under a stream of N2 and the mixture was stirred at RT for 15 min, and then cooled to 0° C. The previously made Grignard reagent was then cannulated into this solution dropwise and the reaction mixture was stirred for 1 h at 0° C. followed by 1 h at RT. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (10% EtOAc in hexanes) to give ethyl 1-(4-(trifluoromethyl)phenyl)isoquinoline-2(1H)-carboxylate as a white solid. MS (ESI pos. ion) m/z: 348 (M+1).
Reaction SMILES: [N+:1]([C:4]1([N+:8]([O-:10])=[O:9])[CH2:7][NH:6][CH2:5]1)([O-:3])=[O:2].[N+:11]([C:14]1[NH:15][CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1)([O-:13])=[O:12]>C(#N)C>[N+:11]([C:14]1[N-:15][CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[N:18]=1)([O-:13])=[O:12].[N+:1]([C:4]1([N+:8]([O-:10])=[O:9])[CH2:7][NH2+:6][CH2:5]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: O=[N+]([O-])C1([N+](=O)[O-])CNC1
Solvent: CC#N
Product: O=[N+]([O-])C1([N+](=O)[O-])C[NH2+]C1
Product: O=[N+]([O-])c1c[n-]c([N+](=O)[O-])n1
Yield: 95 %

Procedure:
3,3-Dinitroazetidine free base (1.0 g) was added to a solution of 2,4-dinitroimidazole (1.07 g) in 50 ml of warm acetonitrile. The solution was allowed to cool and the majority of the solvent evaporated. The remaining slurry was filtered and dried to give 1.98 g of the resultant product, 3,3-dinitroazetidinium 2,4-dinitroimidazolate (95% yield).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].C([O:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3([CH:46]=O)[CH2:42][CH2:41][C:40]([CH:43]([CH3:45])[CH3:44])=[C:31]32)[C:22]1([CH3:51])[CH3:50])(=O)C>CN(C)C=O.O1CCCC1>[OH:20][C@H:21]1[CH2:38][CH2:37][C@@:36]2([CH3:39])[C@@H:23]([CH2:24][CH2:25][C@:26]3([CH3:49])[C@@H:35]2[CH2:34][CH2:33][C@H:32]2[C@@:27]3([CH3:48])[CH2:28][CH2:29][C@@:30]3(/[CH:46]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:42][CH2:41][C:40]([CH:43]([CH3:44])[CH3:45])=[C:31]32)[C:22]1([CH3:50])[CH3:51]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)CC[C@]5(C=O)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/[C@]12CCC(C(C)C)=C1[C@H]1CC[C@@H]3[C@@]4(C)CC[C@H](O)C(C)(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a suspension of ethyl 2-(diethoxyphosphoryl)acetate (7.80 g, 34.8 mmol) in anhydrous N,N-Dimethylformamide (DMF) (20 ml) and Tetrahydrofuran (THF) (10 ml) stirred under nitrogen at 0° C. was added NaH (1.288 g, 32.2 mmol) dropwise during 5 min and stirred for 10 mins. The solution was warmed to rt and stirred for 30 mins before (3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-formyl-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (4.2 g, 8.70 mmol) was added to above mixture. After sitting overnight, the reaction was quenched by water and washed with saturated NaHCO3, water and brine. The organic fraction was dried over sodium sulfate, filtered and concentrated to give a residue, which was purified on a silica gel column (petrol ether/EtOAc=10:1) to obtain the pure product (E)-ethyl 3-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylate (3.1 g, 69%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.01-6.84 (m, 2H), 5.64 (d, J=16.1 Hz, 1H), 4.20 (q, J=7.3 Hz, 2H), 3.26-3.07 (m, 3H), 2.40-2.11 (m, 5H), 2.08-1.91 (m, 2H), 1.89-0.61 (m, 43H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:16][CH3:17]>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:16]([C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[F:6])[CH3:17])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNc1ccc([N+](=O)[O-])cc1F
Solvent: Cc1ccccc1
Product: CN(C(=O)CCl)c1ccc([N+](=O)[O-])cc1F

Procedure:
Chloroacetyl chloride (1.87 ml, 0.0235 mol) is added to (2-fluoro-4-nitro-phenyl)-methyl-amine (14, 2.00 g, 0.0118 mol) in toluene (20 ml) and the mixture refluxed for 3 hours. The mixture is evaporated under vacuum and the residue triturated with ethanol to give the title compound as a white solid. HPLC r.t. 4.57 min; MS for C9H8ClFN2O3 m/z 247 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:2]1.[CH3:23][O:24][C:25]1[CH:50]=[CH:49][C:48]([N:51]2[CH:55]=[N:54][N:53]=[N:52]2)=[CH:47][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][C:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:34][CH2:35]OS(C)(=O)=O)[CH2:30]1)=[O:28]>>[CH3:23][O:24][C:25]1[CH:50]=[CH:49][C:48]([N:51]2[CH:55]=[N:54][N:53]=[N:52]2)=[CH:47][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][C:31]([CH2:34][CH2:35][N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:8]3[N:7]([CH2:6][C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:22][CH2:21]2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30]1)=[O:28]
Reactant: c1ccc2c(c1)nc(NC1CCNCC1)n2Cc1ccoc1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCC(Nc3nc4ccccc4n3Cc3ccoc3)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 102.1 using (1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine and 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[SH:18])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].[CH2:22]([Cl:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[ClH:29].[CH2:22]([S:18][C:6]1[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)Cn1c(S)nc2cnc3ccccc3c21
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Cn1c(SCc2ccccc2)nc2cnc3ccccc3c21
Product: Cl

Procedure:
To a solution of 4.4 g (0.071 mole) of 1-isobutyl-2-mercapto-1H-imidazo[4,5-c]quinoline (from Example 164, Part B below) in 45 ml of methanol and was added 4.1 g (0.0188) of 25% sodium methoxide in methanol, then 2.4 g (0.0188 mole) of benzyl chloride. The solution was heated at reflux for 0.5 hour, then evaporated. Water was added to the residue, and the mixture was extracted with dichloromethane. The extracts were dried over sodium chloride, and then evaporated. The residue was dissolved in diethyl ether, and the solution was saturated with hydrogen chloride. The precipitate was separated by filtration, washed with ether and recrystallized from a mixture of ethanol and diethyl ether to provide 2-benzylthio-1-isobutyl-1H-imidazo[4,5-c]quinoline hydrochloride, m.p. 205°-207° C. Analysis: Calculated for C21H21N3S.HCl: %C, 65.7; %H, 5.8; %N, 10.9; Found: %C, 65.4; %H, 5.6; %N, 10.9.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([N+:17]([O-])=O)[CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Ni].C(O)C>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)c([N+](=O)[O-])c1)n1ccnc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Yield: 100 %

Procedure:
A mixture of 31 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2-nitrobenzenamine and 240 parts of ethanol was hydrogenated at 0.5.105Pa in a Parr apparatus and at room temperature with 30 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated, yielding 27.4 parts (100%) of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine as a residue (interm. 117).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[CH:4][N:3]=1.[F:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[F:15][CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1)=[O:20]
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1ccnc(Cl)n1
Product: C[C@H]1COCCN1c1ccnc(-c2ccc(NC(=O)NCCF)cc2)n1

Procedure:
Method as described for example 49 using (S)-4-(2-chloropyrimidin-4-yl)-3-methylmorpholine (intermediate 3) and 1-(2-fluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 19). The mixture was purified by prep HPLC at high pH to afford the title compound. (15 mg, 9%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>CS(C)=O>[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:27][CH2:26]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Br)c(Cl)cn1
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Br)c(Cl)cn2)CC1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To a solution of 3-bromo-5′-chloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (100 mg, 0.250 mmol) in DMSO (1 mL) was added trans-1,4-diaminocyclohexane (114 mg, 0.998 mmol). The mixture was stirred at 110° C. for 19 hr. The crude reaction mixture was purified by reverse phase HPLC and lyophilized to give 51 mg of N2′-(trans-4-aminocyclohexyl)-3-bromo-5′-chloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 494.2/496.1 (MH+), retention time=0.61 min; 1H NMR (400 MHz, DMSO-d6) d ppm 1.06-1.31 (m, 4 H) 1.31-1.49 (m, 2 H) 1.49-1.64 (m, 2 H) 1.64-1.82 (m, 1 H) 1.85-2.11 (m, 4 H) 2.93-3.12 (m, 3 H) 3.22 (t, J=10.96 Hz, 2 H) 3.61 (t, J=10.76 Hz, 1H) 3.81 (dd, J=11.35, 2.74 Hz, 2 H) 6.39 (s, 1 H) 6.48 (d, 1 H) 6.82 (br. s., 1 H) 6.94 (br. s., 1 H) 7.59 (d, J=9.00 Hz, 1 H) 7.78 (d, J=3.91 Hz, 2 H) 8.02 (s, 1H)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].N[CH2:7][CH2:8][CH2:9][Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C([N:22](CC)CC)C>ClCCl>[CH2:12]([O:11][Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[CH2:9][CH2:8][CH2:7][C:2](=[CH2:3])[C:1]([NH2:22])=[O:4])[CH3:13]
Reactant: CCN(CC)CC
Reactant: C=CC(=O)Cl
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: ClCCl
Product: C=C(CCC[Si](OCC)(OCC)OCC)C(N)=O
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of acryloyl chloride (8.5 mL, 105 mmol) in dry dichloromethane (250 mL) cooled to 0° C. was added dropwise a mixture of 3-aminopropyltriethoxysilane (23.5 mL, 100 mmol) and triethylamine (13.9 mL, 100 mmol) in dichloromethane (50 mL). After completion of addition the reaction mixture was stirred for 30 min, then filtered. The filtrate was concentrated to an oil, diluted with hexane (100 mL) and filtered. The resulting filtrate was concentrated to oil and distilled in vacuo. The product was obtained as a viscous liquid (21.2 g, 77%), b.p. 142-145/1 mm Hg.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[C:17](=[CH:18][C:19]4[O:20][CH2:21][O:22][C:23]=4[CH:24]=3)[C:16](=[O:26])[CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5].[N-:28]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O>O>[CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[CH:24]=[C:23]4[O:22][CH2:21][O:20][C:19]4=[CH:18][C:17]=3[C:16](=[O:26])[NH:28][CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN1C(=O)C2(CNC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
A mixture of 1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione (0.10 g, 0.28 mmol), sodium azide (0.09 g, 1.40 mmol) and trifluoroacetic acid (2.00 mL) was stirred at 50° C. overnight. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.08 g, 74%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), 7.30 (td, 1H), 7.20 (dd, 1H), 6.98 (td, 1H), 6.93 (d, 1H), 6.32 (br, 1H), 6.21 (s, 1H), 5.97-5.92 (m, 2H), 4.02 (dd, 1H), 3.87-3.70 (m, 2H), 3.47 (dd, 1H), 1.80-1.66 (m, 2H), 1.42-4.30 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 175.8, 165.2, 151.6, 147.9, 141.7, 134.3, 130.9, 129.0, 124.5, 123.2, 122.9, 109.0, 108.5, 105.4, 101.9, 51.9, 48.2, 40.4, 29.1, 27.1, 22.3, 14.0; MS (ES+) m/z 379.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([CH2:12][C:13]([OH:15])=O)[NH:11][CH:10]=[CH:9][S:8]2)=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].C(Cl)CCl.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[NH:16][C:13](=[O:15])[CH2:12][C:7]1([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[NH:11][CH:10]=[CH:9][S:8]1)=[O:20]
Reactant: Nc1ccccc1C=O
Reactant: O=C(O)CC1(c2ccncc2)NC=CS1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=Cc1ccccc1NC(=O)CC1(c2ccncc2)NC=CS1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In an oven-dried, 50-mL, round-bottomed flask were placed 2-(4-pyridyl)-thiazole acetic acid (Step b, 140 mg, 0.64 mmol), 2-aminobenzaldehyde (Aldrich, 270 mg, 2.22 mmol), EDC (Aldrich, 244 mg, 1.27 mmol), and DIEA (Aldrich, 148 mg, 0.20 mL, 1.15 mmol) in CH2Cl2 (20 mL). The mixture was cooled to 0° C., and 1-hydroxy-7-azabenzotriazole (Aldrich, 173 mg, 1.27 mmol) was added in one portion. The reaction was warmed to RT slowly, stirred for 12 h, and concentrated in vacuo. The resulting crude product was purified by flash chromatography (EtOAc/hexanes, 50:50) to afford N-(2-formylphenyl)-2-(4-pyridyl)-thiazole acetamide as a white solid. Mp: 136-137° C. MS m/z: 324 (M+1). Calc'd for C17H13N3O2S: 323.07.