Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl(O)(=O)(=O)=O.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[N:17]=[C:18]([CH3:28])[S:19][C:20]=3[CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1>C(OC(C)(C)C)(=O)C>[C:10]([O:27][CH:21]([C:20]1[S:19][C:18]([CH3:28])=[N:17][C:16]=1[C:14]1[CH:13]=[CH:12][C:11]2[O:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:15]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:15])([CH3:11])[CH3:9]
Reactant: CCOC(=O)C(O)c1sc(C)nc1-c1ccc2c(c1)CCCO2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1sc(C)nc1-c1ccc2c(c1)CCCO2
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 700 μL) was added at −10° C. to a solution of ethyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-methyl-1,3-thiazol-5-yl]-2-hydroxyacetate (13b) (90 mg, 0.27 mmol) in terbutyl acetate (5 mL). After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 70/30) to afford the desired product (13c) as a white solid (50 mg, 0.13 mmol, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (2 gm) was suspended in methanol (48 ml) & water (12 ml) and then added sodium borohydride (0.236 gm.) at 25° C. and the reaction mixture was stirred for 1hr. To the reaction mixture was added water (12 ml) and stirred for 2 hours at 25-30° C. The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (1.70 gm).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][C:11]=1[O:18][C:19]([F:22])([F:21])[F:20].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[O:18][C:19]([F:20])([F:21])[F:22]
Reactant: COc1ccc(F)c(-c2ccc(C=O)cc2OC(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(CO)cc2OC(F)(F)F)c1
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 46.1 (0.165 g, 0.53 mmol) in MeOH (6 mL) was added sodium borohydride (0.040 g, 1.05 mmol) in one portion at room temperature. The mixture was stirred for 30 minutes, quenched with 1 N HCl, and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 46.2 (0.164 g, 99%) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[C:13]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH:23]([N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([F:10])([F:11])[F:12])[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CNc1ccccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.1 %

Procedure:
A mixture of 2-(methylamino)benzotrifluride (0.870 g, 5.000 mmol), 1-Boc-4-piperidone (1.500 g, 7.500 mmol)), acetic acid (1.5 mL, 17.5 mmol) and sodium triacetoxy borohydride (2.420 g, 11.000 mmol) in 1,2-dichloroethane (30 mL) was stirred at ambient temperature for 2 days. The reaction was quenched with water. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 4-[methyl-(2-trifluoromethylphenyl)amino]piperidine-1-carboxylic acid tert-butyl ester (0.360 g, 20%). 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, J=1.2, 7.8 Hz, 1H), 7.48-7.14 (m, 3H), 4.08-4.00 (m, 2H), 2.95-2.87 (m, 2H), 2.68-2.58 (m, 5H), 1.72-1:67 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](C#N)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:15][C:16]1C=C2C(=CC=1)N(C(=O)C)CC2>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]#[N:15])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(N)ccc21
Reactant: CC(=O)N1CCc2cc(C#N)ccc21
Product: CC(=O)N1CCc2ccc(C#N)cc21

Procedure:
The title compound was prepared following the procedure described for 1-acetoylindoline-5-carbonitrile but starting from 1-(5-aminoindolin-1-yl)ethanone (Aldrich, 844 mg; 4.79 mmol), to give 1-acetoylindoline-6-carbonitrile as an orange solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.31 (1H, s), 7.52-7.45 (2H, m), 4.18 (2H, t, J=8.6 Hz), 3.32-3.23 (2H, m), 2.23 (3H, s).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][C:5]=1[F:13].[CH3:14][C@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][C@@H:15]([OH:16])[CH3:17])=[CH:6][C:5]=1[F:13]
Reactant: Fc1cc2cc[nH]c2cc1Cl
Reactant: C[C@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](O)Cn1ccc2cc(F)c(Cl)cc21
Reaction time: 1 h
Yield: 79 %

Procedure:
A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.42 ml of (S)-methyloxirane the reaction mixture was stirred at room temperature for 85 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.54 g (79%) of (S)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as beige crystals (m.p. 99°-101°).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([NH2:12])=[N:7][CH:6]=1)[CH3:2].[C:14]1(=O)[CH2:19]CC[CH2:16][CH2:15]1>>[NH2:11][C:9]1[C:8]2[N:7]([C:14]([CH3:19])=[C:15]([CH3:16])[N:12]=2)[CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:10]=1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)c1cnc(N)c(N)c1
Product: CCOC(=O)c1cc(N)c2nc(C)c(C)n2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5,6-diamino-nicotinic acid ethyl ester (1 eq., 5.0 g) in cyclohexanone (50 ml) bromobutanone (1.4 equiv., 5.95 g) was added over 15 min. The dark brown mixture was heated to 100° C. (inner temperature) and stirred 1.5 h at this temperature. The mixture was cooled to room temperature and the light brown solid was filtered off and was washed with TBME (20 ml). Drying under reduced pressure at 45° C. Yield: 5.06 g (65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>O1CCCC1.[Cl-].[Na+].O>[CH2:18]([O:17][C:15](=[O:16])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:19]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOC1CCCCO1)(NC(=O)OC(C)(C)C)C(=O)OCC
Yield: 65.2 %

Procedure:
Diethyl (t-butyloxycarbonyl)aminomalonate (52.3 g) was dissolved in tetrahydrofuran (400 ml), sodium t-butoxide (19.2 g) was added thereto, a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (40.4 g) in tetrahydrofuran (100 ml) was added to the reaction mixture at 70° C., and the mixture was stirred with heating for 10 hr. After cooling, the reaction mixture was poured into saturated brine. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the object product (50.0 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2cc(F)c(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2.09 g of 5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 2.10 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2,4,5-trifluorophenyl)pyridazine (hereinafter, referred to gas compound (vii) of the present invention).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[C:18]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[C:19]2[N:20]([C:22]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:26])=[CH:23][N:24]=2)[N:21]=1>CO.C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:16]2[CH:17]=[C:18]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:19]3[N:20]([C:22]([C:25]([NH:27][C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)=[O:26])=[CH:23][N:24]=3)[N:21]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(Cl)nn12
Reactant: N[C@H]1CCCN(Cc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(Nc1ccncc1)c1cnc2c(Nc3ccccn3)cc(N[C@H]3CCCN(Cc4ccccc4)C3)nn12
Temperature: 170 °C
Yield: 7.1 %

Procedure:
A vial containing a mixture of (S)-1-benzylpiperidin-3-amine (0.385 g, 2.021 mmol) and 6-chloro-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 37A (0.08 g, 0.135 mmol) was heated to 170° C. overnight. The mixture was dissolved in 3 mL methanol and 3 mL Solvent B (90% MeOH, 10% water, 0.1% TFA). One drop of TFA was added to the solution, the sample was split into 4 equal volumes and purified by reverse phase preparative HPLC on a Phenx Luna Axia Column 5u (21.2×100 mm) Solvent A (10% MeOH, 90% water, 0.1% TFA), Solvent B (90% MeOH, 10% water, 0.1% TFA) 20-100% solvent B gradient, 20 mL/min, 220 nM UV detection to provide (S)-6-(1-benzylpiperidin-3-ylamino)-8-(pyridin-2-ylamino)-N-(pyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (0.0082 g, 9.52 μmol, 7.06% yield). 1H NMR (500 MHz, CD3OD) δ ppm 8.42 (2H, m), 8.02-7.68 (5H, m), 7.49 (1H, m), 7.29-6.76 (9H, m), 4.2-3.95 (2H, m), 3.73-3.58 (1H, m), 3.37 (1H, m), 3.06-2.64 (2H, m), 2.32-1.78 (3H, m). LC/MS: HPLC Retention time: 2.15 min, MS: 520 (M+1) (Shimidazu LC, Waters Sunfire C-18 column (4.65×50 mm, 5 um, 0-100% Solvent B, 4 min gradient, 4 mL/min, 220 UV detection. Solvent A: 10% MeOH/90% Water/0.1% TFA, Solvent B 90% MeOH/10% Water/0.1% TFA.)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5](=[O:19])[C:6]([C:16]([OH:18])=O)=[N:7][N:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:24][O:23][N:22]([CH3:21])[C:16]([C:6]1[C:5](=[O:19])[C:4]([O:3][CH3:2])=[CH:9][N:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]=1)=[O:18]
Reactant: CNOC
Reactant: COc1cn(-c2cccnc2)nc(C(=O)O)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cn(-c2cccnc2)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (1.0 g, 3.5 mmol), N,O-dimethylhydroxylamine hydrochloride (0.52 g, 5.3 mmol), TEA (1.5 ml, 11 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.2 g, 3.9 mmol) in DMF (15 ml) was stirred at room temperature overnight. The mixture was diluted with AcOEt. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed on basic silica gel (0/100-20/80 MeOH/AcOEt) to give the title compound (0.81 g, 79% yield)
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([OH:14])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>[OH-].[Na+]>[C:15]([NH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(Cc1ccc(O)c(O)c1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC(Cc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1)C(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 25 ml of 0.1N NaOH, was dissolved 2 g of 2-amino-3-(3,4-dihydroxyphenyl)propanoic acid. To the resulting solution, 3.8 ml of benzoyl chloride was added dropwise. The reaction mixture was maintained at a temperature of 0° C. for the duration of the reaction. The pH was maintained in a range of approximately by the addition of 0.2N NaOH. After about 3 hours, the reaction mixture was acidified with concentrated hydrochloric acid. The precipitate was removed by filtration and taken up in boiling carbon tetrachloride. The precipitate was then crystallized to yield a 2-(benzoylamino)-3-(3,4-dibenzoyloxyphenyl)propanoic acid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC.Cl>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[OH:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:34](=[O:36])[CH3:35])=[CH:3][CH:4]=[C:5]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2n1
Temperature: 110 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 78, tributyl(1-ethoxyvinyl)tin (157 mg, 0.436 mmol) in anhydrous DMF (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added tetrakis(triphenylphosphine) palladium (0) (38 mg, 0.0327 mmol). The reaction vessel was sealed and the mixture was stirred at 110° C. for 2 h. After cooling to rt, 2 M aq HCl (0.5 mL) was added, and the mixture was stirred at rt for 1.5 h. The mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford crude 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone. The crude product was triturated with Et2O and the solid was collected by filtration and dried to afford 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)ethanone (19 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.00 (d, J=7.5 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.80 (s, 1H), 7.26-7.39 (m, 2H), 5.55 (s, 2H), 4.77 (d, J=4.9 Hz, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.74 (s, 3H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.12-1.32 (m, 4H). LCMS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([O-])=O.[ClH:20]>CO.[Pd]>[ClH:20].[NH2:1][CH2:4][CH2:5][C:6]1[CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[C:8]([CH:7]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(C=C[N+](=O)[O-])cc(C(=O)OC)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(CCN)cc(C(=O)OC)c1
Reaction time: 7 h

Procedure:
To a solution of 365 mg (1.38 mmol) of dimethyl 5-(2-nitrovinyl)isophthalate in 15 mL of methanol and 0.46 mL of 12 N HCl, was added 80 mg of 10% palladium on carbon. The mixture was stirred under a hydrogen balloon atmosphere for 7 h then filtered through celite and evaporated to give dimethyl 5-(2-aminoethyl)isophthalate hydrochloride as a white solid which was used as such immediately in the next step.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:12]2[S:13][C:14]([C:17]3[CH:18]=[C:19]([N:24]([C:32]4[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=4)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:15][N:16]=2)[CH2:10][CH2:9][C:8](=[O:11])[NH:7][CH2:6][CH2:5]1.Br[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][O:3][C:4]1([C:12]2[S:13][C:14]([C:17]3[CH:18]=[C:19]([N:24]([C:32]4[N:37]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:35]=[CH:34][N:33]=4)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:15][N:16]=2)[CH2:10][CH2:9][C:8](=[O:11])[NH:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1cc(-c2cnc(C3(O)CCNC(=O)CC3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnc(C3(OCCO)CCNC(=O)CC3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Temperature: 125 °C
Yield: 46.1 %

Procedure:
A flame dried microwave vessel was charged with a solution of sodium hydride (4.26 mg, 0.106 mmol, 2.0 equiv) in anhydrous DMF (1 ml). tert-butyl {3-[2-(4-hydroxy-7-oxoazepan-4-yl)-1,3-thiazol-5-yl]-5-methylphenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (30 mg, 0.05 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (19.1 mg, 0.08 mmol, 1.5 equiv) were added, causing an exotherm and color change from tan to dark orange. This mixture was heated at 125° C. for 30 min. The resulting mixture of products was purified via reverse-phase HPLC (acetonitrile/water gradient with 0.05% TFA present), to afford tert-butyl (3-{2-[4-(2-hydroxyethoxy)-7-oxoazepan-4-yl]-1,3-thiazol-5-yl}-5-methylphenyl)[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (14 mg, 33%), as an orange oil. MS ESI: [M+H]+ m/z 7222
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(#N)C.[NH2:28][C:29]1[CH:56]=[CH:55][CH:54]=[CH:53][C:30]=1[O:31][CH2:32][C:33]([OH:52])([CH3:51])[CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[NH:43][C:42]2=[O:50])[CH2:37][CH2:36]1.[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[C:63](O)=[O:64].CCN(C(C)C)C(C)C>C1COCC1>[OH:52][C:33]([CH3:51])([CH2:34][N:35]1[CH2:36][CH2:37][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[NH:43][C:42]2=[O:50])[CH2:39][CH2:40]1)[CH2:32][O:31][C:30]1[CH:53]=[CH:54][CH:55]=[CH:56][C:29]=1[NH:28][C:63]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][N:57]=1)=[O:64]
Reactant: O=C(O)c1ccccn1
Reactant: CC(O)(COc1ccccc1N)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(COc1ccccc1NC(=O)c1ccccn1)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
HATU in acetonitrile (0.2 M, 0.375 ml, 0.075 mmol) was added to a solution of 1-{1-[3-(2-aminophenoxy)-2-hydroxy-2-methylpropyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one (0.020 g, 0.05 mmol), 2-pyridinecarboxylic acid (0.006 g, 0.05 mmol) and Hünigs base (0.013 ml, 0.075 mmol) in THF (0.5 ml). After 0.5 h at 40° C. and 2 h at room temperature the reaction mixture was concentrated, and the residue purified on silica (dichloromethane-methanol, 12:1, containing 1% of NH4OH (25%)). Yield 20 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:33])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]3)=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with 4-phenoxyphenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (7.4 mg, 11%) having the following characteristics.