Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[CH3:20][C:21](C)([O-:23])[CH3:22].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[CH2:22][O:23]1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccccc1CCCCc1ccccc1O
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1CCCCc1ccccc1OCC1CO1
Yield: 92.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), 230 mg of 2-[4-(2-methoxyphenyl)butyl]phenol (prepared as described in Preparation 4), 101 mg of potassium t-butoxide and 246 mg of epibromohydrin were reacted in 15 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 260 mg (yield 93%) of the title compound as an oil.
Reaction SMILES: N1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=O)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[NH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1>ClC(Cl)C>[C:11]([C:15]1[C:16](=[O:26])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19](=[N:27][C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:20]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1cnccn1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C
Yield: 58.3 %

Procedure:
A 1.62 ml quantity of pyridine was dissolved in 60 ml of dichloroethane. To the solution was added 0.89 g of aluminum chloride powder, and the mixture was refluxed with heating for 15 minutes. Then to the mixture were added 2.20 g of 2,6-di-tert-butyl-1,4-benzoquinone and 0.95 g of aminopyrazine, and the mixture was refluxed under heating for 17.5 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with dicloromethane. The filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=3:7), giving 1.73 g of Compound 1a.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[CH3:39])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:41]=[C:42]([CH:49]=[CH:50][CH:51]=2)[CH2:43][O:44]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.[CH2:58]1COCC1>C(Cl)Cl>[CH:43]([OH:44])=[O:55].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([C@@H:34]5[CH2:38][CH2:37][CH2:36][N:35]5[CH3:39])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:40]2[CH:51]=[CH:50][CH:49]=[C:42]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][CH2:53]3)[C:41]=2[CH3:58])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Solvent: ClCCl
Product: Cc1c(N2CCOCC2)cccc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc([C@@H]4CCCN4C)n3c2)c2ccccc21
Product: O=CO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 149b (104 mg, 0.15 mmol) and morpholine (64 μL, 0.73 mmol) in THF (2 mL) was stirred at 60° C. for 18 h. The reaction mixture was cooled to RT, diluted with DCM (5 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was passed through a phase separator and concentrated in vacuo and the resultant residue was purified by prep. HPLC, using 5-50% CH3CN in water, buffered with formic acid, on a Gemini C18 column, over 20 mins to afford the title compound as an off white solid (22 mg, 21%). LCMS (Method 5): Rt 2.66 min, m/z 704.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.84-2.11 (6H, m), 2.13 (3H, s), 2.15-2.26 (2H, m), 2.31-2.40 (5H, m), 3.10-3.17 (1H, m, obscured by water), 3.51 (2H, s, obscured by water), 3.55 (4H, t, J=4.6 Hz), 3.99 (1H, t, J=8.0 Hz), 4.78-4.86 (1H, m), 5.39 (1H, t, J=4.2 Hz), 6.33 (1H, s), 7.06 (1H, d, J=8.6 Hz), 7.24-7.49 (9H, m), 7.75 (1H, d, J=9.7 Hz), 8.10 (1H, s), 8.19 (0.6H, br s), 8.24 (1H, d, J=1.8 Hz).
Reaction SMILES: C1(O[C:8](=[O:20])[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:20])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=O)Oc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 92 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:41])([C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)[CH:14]([CH3:16])[CH3:15])=[CH:9][C:8]=1[C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=1)(=O)=O.[C:51](=[NH:64])([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(=O)([O-])[O-]>C1(C)C=CC=CC=1>[C:52]1([C:51](=[N:64][C:7]2[C:8]([C:42]3[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=3)=[CH:9][C:10]([C:13]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:21]=3)([OH:41])[CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=2)[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(O)(c1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)C(O)(c1ccc(N=C(c2ccccc2)c2ccccc2)c(-c2ccc(F)cc2)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 85 °C
Reaction time: 16.5 h

Procedure:
To a solution of 4′-fluoro-5-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-2-yl trifluoromethanesulfonate (1.06 g), benzophenone imine (0.035 ml) and cecium carbonate (1.23 g) in toluene (15 ml) were added (RS)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (56.4 mg) and tri(dibenzylideneacetone)dipalladium(0) (27.7 mg), and the mixture was stirred at 80-90° C. for 26 h. (RS)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (112 mg) and tri(dibenzylideneacetone)palladium(0) (55.4 mg) were further added, and the mixture was stirred at 80-90° C. for 16.5 h, and at 105° C. for 3.5 h. The reaction mixture was filtered through Celite, and the filtrate was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent; hexane:ethyl acetate=5:1→1:1) to give the yellow amorphous title compound (115 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][C@@H:17]([CH3:20])[C@@H:16]([N:21]3[C:25]4=[C:26]5[CH:32]=[CH:31][NH:30][C:27]5=[N:28][CH:29]=[C:24]4[NH:23][C:22]3=[O:33])[CH2:15]2)=[CH:12][CH:13]=1)=[O:6].O1CCCC1.CC([O-])(C)C.[K+].C(Cl)(Cl)Cl>O>[CH3:20][C@@H:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][N:10]=2)[CH2:15][C@@H:16]1[N:21]1[C:25]2=[C:26]3[CH:32]=[CH:31][NH:30][C:27]3=[N:28][CH:29]=[C:24]2[NH:23][C:22]1=[O:33]
Reactant: C[C@@H]1CCN(c2ccc(NC(=O)CCCCl)cn2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C[C@@H]1CCN(c2ccc(N3CCCC3=O)cn2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a solution of rel-4-chloro-N-{6-[(3R,4R)—4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]pyridin-3-yl}butanamide (72 mg) and tetrahydrofuran (2.2 mL) was added potassium 2-methylpropan-2-olate (138 mg) at ambient temperature. The mixture was stirred for 0.5 hour then chloroform (10 mL) and H2O (4 mL) were added. The organic layer was separated and dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography to give rel-1-{(3R,4R)-4-methyl-1-[5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]piperidin-3-yl}-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (66 mg) as a colorless solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.Cl.[C:21]([O:25][C:26](=[O:29])[CH2:27][NH2:28])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.[H][H]>C(#N)C.[C].[Pd].O>[C:21]([O:25][C:26]([CH2:27][NH:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17])=[O:29])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)CN
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)CNc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (0.77 g, 3.0 mmol) in acetonitrile (10 mL) was added glycine tert-butyl ester hydrochloride (0.60 g, 3.6 mmol) and triethylamine (0.90 g, 9.0 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and the precipitated crystals were filtered, washed with water and then dried. To a tetrahydrofuran solution (50 mL) of the residue obtained was added 10% palladium-carbon (50 mg). A hydrogen atmosphere was substituted in the flask, and this was stirred overnight at room temperature. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.40 g, 40% yield) as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[F:12]>CCO.C1COCC1.[NH4+].[Cl-].O.[Fe]>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(Br)c(F)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)c(F)cc1F
Yield: 58.7 %

Procedure:
To a solution of 1-bromo-2,4-difluoro-5-nitrobenzene (5.04 g, 21.3 mmol) in EtOH (100 mL), THF (50 mL), NH4Cl (sat) (25 mL) and H2O (25 mL) was added iron powder (5.0 g, 89.5 mmol). The mixture was refluxed for 2 h and filtered through celite. The filter pad was washed with EtOAc (3×50 mL). The filtrate was concentrated and the residue was partitioned between EtOAc and brine. The organic layer was dried over MgSO4 and concentrated. Purification by flash chromatography (5–10% EtOAc/Hexane) provided 2.6 g (59%) of 5-bromo-2,4-difluoroaniline: ESMS m/e: 208.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:20](=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:3][CH2:2]1
Reactant: Nc1ccccc1NC1CC1
Reactant: COC(=O)CCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCC(=O)Nc1ccccc1NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of N1-cyclopropylbenzene-1,2-diamine (221 mg, 1.49 mmol) and triethylamine (0.3 mL, 2.2 mmol) in DMF was added a solution of methyl 8-chloro-8-oxooctanoate (260 mg, 1.3 mmol) in DMF at 0° C. drop-wise. The reaction was stirred overnight at room temperature, diluted with ethyl acetate and washed with 1 N HCl, saturated sodium bicarbonate solution and brine. The separated organic layer was concentrated to give crude methyl 8-(2-(cyclopropylamino)phenylamino)-8-oxooctanoate (390 mg)
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6]([C:7](N)=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[OH-:13].[Ba+2].[OH-]>>[CH3:1][C:2]1([CH3:12])[CH:6]([C:7]([OH:13])=[O:8])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1
Reactant: CC1(C)CC(C(N)=O)C(C)(C)N1
Reactant: [OH-]
Agent: [Ba+2]
Product: CC1(C)CC(C(=O)O)C(C)(C)N1

Procedure:
2,2,5,5-tetramethyl pyrroline-3-carboxylic acid was prepared by the hydrolysis of 2,2,5,5-tetramethyl pyrroline-3-carboxamide (Frinton; recrystallized from benzene) with barium hydroxide. The acid was recrystallized from water to provide an off-white solid. The measured mp was 300 (dec.) in a sealed tube; the reported mp was 300 dec. (Pauly 1902; Rozantsev 1970).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].C[S:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.N1C=CC=C[CH:18]=1>ClCCl>[Cl:7][CH2:6][CH2:5][O:4][C:2]([S:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:18])=[CH:12][CH:11]=1)=[O:3]
Reactant: O=C(Cl)OCCCl
Reactant: CSc1ccc(O)cc1
Reactant: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(SC(=O)OCCCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
A 250-mL, three-neck, round-bottomed flask equipped with a mechanical stirrer, a 50-mL pressure-equalizing addition funnel, an internal thermometer, and a nitrogen inlet was charged with chloroethyl chloroformate (10.8 g, 76 mmol) and 4-(methylthio)phenol (10 g, 71 mmol) in dichloromethane (75 mL). The resulting clear reaction mixture was cooled to 0° C. A solution pyridine (6.8 g, 86 mmol) in dichloromethane (10 mL) was slowly added over a period of 30 minutes. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was poured into a separatory funnel, washed with water (100 mL), brine (100 mL), dried over sodium sulfate, and evaporated under vacuum to give the title compound D1 as a viscous oil (˜17 g, quantitative yield). 1H NMR (CDCl3, 400 MHz): δ 1.89 (d, J=6 Hz, 3H), 2.47 (s, 3H), 6.46 (q, J=6 Hz, 1H), 7.11 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[O:3][CH2:2]1.[Li][CH3:13]>C1COCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:11])[CH3:13])[C:4]=2[O:3][CH2:2]1
Reactant: [Li]C
Reactant: O=Cc1cccc2c1OCO2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of benzo[1,3]dioxole-4-carbaldehyde (10 g, 66.7 mmol) in 200 mL THF at −78° C. was added, via addition funnel, 43.7 mL of a 1.6 M MeLi solution in diethyl ether. The reaction was slowly warmed to room temperature and stirred overnight. A TLC of an aliquot showed reaction was complete. The reaction was then cooled to −78° C. and quenched with saturated aqueous ammonium chloride and concentrated in vacuo. The residue was then extracted with ethyl acetate. The organics were combined, dried over magnesium sulfate, and concentrated in vacuo to give 11 g (99.4% yield) of 1-benzo[1,3]dioxol-4-ylethanol as a brown oil that crystallized upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH3:11]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Product: NC(=S)Nc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A stirred solution of 4-chlorophenyl isothiocyanate (10.0 g, 0.077 mol) in 100 ml ether was saturated with ammonia gas for five minutes. The reaction mixture was then stirred for 18 hr. The white solid which precipitated was collected by filtration and yielded 6.3 g of N-(4-chlorophenyl)thiourea, M.P. 147°-148° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.Cl.[CH3:60][N:61]([CH3:77])[CH:62]1[CH2:66][CH2:65][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:63]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:64]4[CH2:65][CH2:66][CH:62]([N:61]([CH3:60])[CH3:77])[CH2:63]4)=[CH:73][CH:72]=3)[CH3:76])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CNCc1ccc(CN2CCC(N(C)C)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(N(C)C)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (29 mg, 0.15 mmol), HOBt (22 mg, 0.16 mmol), DIPEA (0.04 mL, 0.22 mmol), N,N-dimethyl-1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-amine trihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8](=[S:10])=[S:9].[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]>C1C=CC=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:8](=[S:9])[S-:10])[CH:3]=1.[CH2:11]([NH+:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]
Reactant: CCN(CC)CC
Reactant: Nc1cccnc1
Reactant: S=C=S
Solvent: c1ccccc1
Product: CC[NH+](CC)CC
Product: S=C([S-])Nc1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 9.4 g 3-aminopyridine and 7.6 g carbon disulfide in 100 ml benzene, was added dropwise 14 ml triethylamine, the mixture was stirred at room temperature for three hours, and the two separate layers thus formed were allowed to stand overnight. The benzene layer was removed by decantation, the oily product was washed four times with 30 ml ether, and the solvent was distilled off under reduced pressure, affording triethylammonium (3-pyridyl)dithiocarbamate. This crude salt was dissolved in 75 ml chloroform, 14 ml triethylamine was added, and the resulting solution was cooled in ice. Ethyl chloroformate (10.2 ml) was then added dropwise, the reaction was allowed to proceed at room temperature for one hour, and the reaction mixture was washed with 50 ml water, dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 13.2 g of rude 3-pyridyl isothiocyanate as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[C:25]=3[CH3:33])=[CH:18][CH:17]=2)=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:30][C:26]1[C:25]([CH3:33])=[C:24]([N:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:12]3[CH:13]=[CH:14][C:2]([Cl:1])=[C:3]([CH:11]=3)[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:18]=2)[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccccc3F)c3cccc(N)c3C)cc2)ccc1Cl

Procedure:
The product from Example 306B in ethanol (1.2 mL) and H2O (0.6 mL) was treated with iron powder (100 mg, 1.8 mmoles) and NH4Cl (10 mg, 0.18 mmoles) at 80° C. overnight. The reaction mixture filtered, residue washed with methanol and dichloromethane, the filtrate concentrated in vacuo to provide the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4](=[O:17])[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C.O>[Cl:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27][N:3]1[C@@H:2]([CH3:1])[CH2:7][N:6]2[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[CH:13][N:12]=3)=[N:9][N:10]=[C:5]2[C:4]1=[O:17]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1Cn2c(nnc2-c2cnccn2)C(=O)N1Cc1ccc(F)cc1Cl
Reaction time: 18 h
Yield: 64.7 %

Procedure:
To a solution of Example 77 (40 mg, 0.17 mmol) in DMF (1.7 mL) was added cesium carbonate (226 mg, 0.70 mmol) and 2-chloro-4-fluorobenzyl bromide (58 mg, 0.26 mmol) and the reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried with Na2SO4, filtered, concentrated and purified by flash column chromatography (0-20% iPrOH in EtOAc) to provide the desired compound (41 mg, 65%). MS (ESI): mass calcd. for C17H14ClFN6O, 372.8; m/z found, 373.1 [M+H]+. 1H NMR (400 MHz, DMSO) δ 9.47 (d, J=1.3 Hz, 1H), 8.84-8.80 (m, 2H), 7.61-7.55 (m, 1H), 7.55-7.50 (m, 1H), 7.26-7.19 (m, 1H), 5.10 (d, J=15.9 Hz, 1H), 5.01-4.89 (m, 1H), 4.70 (dd, J=13.9, 4.6 Hz, 1H), 4.48 (d, J=16.0 Hz, 1H), 4.13-4.03 (m, 1H), 1.18 (d, J=6.7 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=O)[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.Cl.[NH2:32][OH:33].N1C=CC=CC=1>CCO>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]3[N:23]4[CH:24]=[CH:25][C:26]([C:28](=[N:32][OH:33])[CH3:29])=[CH:27][C:22]4=[N:21][CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: NO
Reactant: CC(=O)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccn2c(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cnc2c1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To a stirred solution of 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone (40 mg, 0.095 mmol) from Example 200 in EtOH (2 mL) at rt were added hydroxylamine hydrochloride (120 mg, excess) and pyridine (200 μL, excess). The mixture was heated at 90° C. for 1 h, and then cooled to rt. Purification by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH), CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase afforded 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)imidazo[1,2-a]pyridin-7-yl)ethanone oxime (23 mg, 61%) as yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 11.46 (br s, 1H), 8.13 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.44-6.58 (m, 1H), 5.89 (s, 1H), 4.78 (d, J=2.5 Hz, 1H), 4.29 (s, 2H), 3.50 (br s, 1H), 2.18 (s, 3H), 2.04 (d, J=12.3 Hz, 1H), 1.87 (d, J=10.8 Hz, 1H), 1.56-1.67 (m, 2H), 1.15-1.32 (m, 4H). LCMS (ESI) m/z 436 (M+H)+.