Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(O)C.CC(C)=O.CCO[Si](OCC)(OCC)OCC.[C:22]1([Si:28]([O:35][CH2:36]C)([O:32][CH2:33]C)[O:29][CH2:30]C)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[N+]([O-])(O)=O.C(O)CCC.C(O)C>O>[C:22]1([Si:28]([O:35][CH3:36])([O:29][CH3:30])[O:32][CH3:33])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCO[Si](OCC)(OCC)c1ccccc1
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: CO[Si](OC)(OC)c1ccccc1

Procedure:
In a 1-liter flask 297 grams (4.798 moles) 2-propanol, 148 grams (2.558 moles) acetone, 123 grams (0.593 moles) TEOS, 104 grams (0.432 moles) phenyltriethoxysilane, 0.6 grams 0.1 M nitric acid and 72 grams (3.716 moles) deionized water were combined. The flask was refluxed for 4 hours. To the solution, 57 grams (0.769 moles) of Butanol, 88 grams (1.422 moles) 2-propanol, 44 grams (0.758 moles) of acetone, 59 grams (1.227 moles) of ethanol, 9.5 grams (0.528 moles) deionized water were added.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[O:11][CH:12]1[CH2:16][CH2:15][CH2:14]O1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:14]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:16][CH2:12][OH:11])=[CH:2]1
Reactant: COC1CCCO1
Reactant: c1ccc2[nH]ccc2c1
Product: OCCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12

Procedure:
The compound was prepared in the same way as described in example 2/4, starting from indole and 2-methoxy-tetrahydrofuran.
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([NH:22][C:23]2[C:32]([NH:33][C:34]3[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=3[CH2:42][CH2:43][CH2:44][OH:45])=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)(=[O:21])=[O:20])[CH:14]=1)=[O:11])C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[OH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([NH:22][C:23]2[C:32]([NH:33][C:34]3[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=3[CH2:42][CH2:43][CH2:44][OH:45])=[N:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)(=[O:21])=[O:20])[CH:14]=1)=[O:11]
Reactant: COc1ccc(CCCO)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)COCc3ccccc3)c2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(CCCO)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(=O)CO)c2)c1
Yield: 76.3 %

Procedure:
To a mixture of 2-(benzyloxy)-N-(3-{[(3-{[2-(3-hydroxypropyl)-5-methoxyphenyl]amino}quinoxalin-2-yl)amino]sulfonyl}phenyl)acetamide (69 mg; 0.1 mmol; 1 eq) in EtOH (12 mL) are added ammonium formate (69.3 mg; 1.1 mmol; 10 eq) and palladium on charcoal (10 mg, 10%). The reaction mixture is stirred at reflux for 2 h. The catalyst is filtered through celite, washed with EtOH and the filtrate is concentrated under reduced pressure to give a yellow residue. It is suspended in EtOH (2 mL), sonicated, filtered off and washed with EtOH (400 μL). The solid is dried in vacuo to give 41 mg (70%) of the title compound as a yellow solid 1H NMR (DMSO-d6) δ 12.53 (br s, 1H), 10.00 (s, 1H), 8.73 (s, 1H), 8.45 (s, 1H), 8.19 (br s, 1H), 7.99-7.91 (m, 2H), 7.75 (d, J=7.4 Hz, 1H), 7.57-7.48 (m, 2H), 7.42-7.32 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.68-6.61 (m, 1H), 5.75-5.62 (m, 1H), 4.45-4.30 (m, 1H), 4.00 (s, 2H), 3.70 (s, 3H), 3.28-3.15 (m, 4H), 1.58-1.45 (m, 2H). HPLC (max plot) 99%; Rt 3.71 min. UPLC/MS (ES−) 538.2, (ES−) 536.3.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:10]1[CH2:19][CH2:18][C:17]2[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=2[CH2:11]1)[CH3:2].[CH:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)=O>>[C:36]([CH2:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:27][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C@@H:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:30][CH:31]=1)([OH:38])=[O:37]
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: CCNc1ccccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CC(=O)O)cc1)C2
Yield: 87.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylaminophenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (182 mg) and (4-formylphenyl)acetic acid (420 mg) according to an analogous synthetic method to Example 212, the title compound (227 mg) was obtained.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([O:48]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1>C1COCC1.CCOC(C)=O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:44]3[C:39](=[CH:40][C:41]([S:45]([NH:6][C:7]4[S:11][N:10]=[CH:9][N:8]=4)(=[O:48])=[O:46])=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[C:31]([O:60][CH3:61])[CH:30]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.17 h
Yield: 41 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (33.3 mg, 0.172 mmol) and THF (718 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (172 μl, 0.172 mmol) was added drop wise. The flask was removed from the cooling bath for 3 min, then recooled in the bath. A solution of perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN, 74.12 mg, 0.144 mmol) in THF (0.6 mL with a 0.4 mL-flask wash) was added drop wise. After another minute, the flask was transferred to an ice-water bath. After 10 min of stirring, the mixture was concentrated, and the residue was taken up in DCM (1 mL) and TFA (0.5 mL). The mixture was stirred for 30 min, then diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (25-g Interchim column, 25-75% EtOAc/Heptane) to give white solid. The solid was taken up in EtOAc, filtered, washed with EtOAc (3×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (25.5 mg, 0.059 mmol, 41.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.69 (d, J=5.7 Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.48 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 7.89-7.89 (m, 0H), 7.91-7.81 (m, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=1.9 Hz, 1H), 7.20 (dd, J=1.9, 8.1 Hz, 1H), 3.68 (s, 3H). m/z (ESI) 433.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH3:27])[CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[S:7][C:6]=2[CH:35]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH3:27])[CH2:22]4)=[CH:16][CH:17]=3)[OH:11])=[C:8]([C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)[S:7][C:6]=2[CH:35]=1
Reactant: CC1CCCN(CCOc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CCCN(CCOc2ccc(C(O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 96 %

Procedure:
A solution of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(3-methyl-1-piperidinyl]ethoxy]phenyl]methanone, as described in United Kingdom Patent Application GB 2097 788 H (0.300 g, 0.633 mmol), was stirred in THF (40 mL) at ambient temperature. Lithium aluminum hydride (0.100 g, 2.64 mmol) was added gradually over a 15 minute period and the reaction mixture was stirred at ambient temperature for 1.75 hours. Subsequently, the reaction was quenched with cold ethyl acetate. The mixture was evaporated and then taken up in methanol (10 mL) an ethyl acetate (30 mL). The organic layers were washed with sodium bicarbonate (25 mL of a saturated aqueous solution), potassium sodium tartrate (3×20 mL, saturated aqueous solution), and dried (magnesium sulfate). Concentration gave 0.290 g (96%) of the title compound which was used without further purification:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.N[C@@H]1CCCC[C@H]1O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH:30]1[C:35](OC)([O:36]C)[CH2:34][CH2:33][O:32][CH2:31]1>C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[C:1]1([CH:30]2[C:35](=[O:36])[CH2:34][CH2:33][O:32][CH2:31]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: COC1(OC)CCOCC1I
Agent: Cl[Ni]Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCOCC1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a stirred mixture of phenylboronic acid (16.81 g, 138 mmol), trans-2-Aminocyclohexanol hydrochloride (1.393 g, 9.19 mmol), and Nickel(II) chloride hexahydrate (1.092 g, 4.59 mmol) in THF (92 mL) at 0° C. was added Sodium bis(trimethylsilyl)amide (1.0 M in THF) (184 mL, 184 mmol) dropwise over 10 min. When the addition was complete, the reaction mixture was sparged with N2 for 15 min. To the reaction mixture at 0° C. was then added 2-Propanol (375 mL)(previously sparged with N2). The resulting mixture was allowed to come to RT at which time 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate I(1)) (25 g, 92 mmol) was added dropwise over 5 min. The reaction mixture was then brought to 60° C. and stirred overnight. The reaction mixture was then cooled to 0° C. and quenched by the careful addition of aqu. 1 N HCl until acidic. The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic extracts were washed with Brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 3-phenyldihydro-2H-pyran-4(3H)-one (8.37 g, 47.5 mmol, 51.7% yield) as a slightly orange oil. 1H NMR (500 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.26-7.31 (1H, m), 7.21-7.26 (2H, m), 4.17-4.31 (2H, m), 3.91-4.05 (2H, m), 3.78 (1H, dd, J=8.55, 6.10 Hz), 2.61-2.74 (1H, m), 2.51-2.61 (1H, m).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:13][CH:12]2[CH:8]([CH2:9][N:10]([C:14](=[O:24])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:11]2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])([OH:25])[CH2:6]1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][CH:5]1[CH2:13][CH:12]2[CH:8]([CH2:9][N:10]([C:14](=[O:24])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:11]2)[C:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])([OH:25])[CH2:6]1
Reactant: COc1ccccc1CC(=O)N1CC2CC(CN=[N+]=[N-])CC(O)(c3ccccc3OC)C2C1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1CC(=O)N1CC2CC(CN)CC(O)(c3ccccc3OC)C2C1
Temperature: 60 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of 6.05 g of (3aRS,4RS,6SR,7aSR)-6-azidomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol, 0.6 g of 10% palladium on carbon and 300 cm3 of ethanol is heated to 60° C. Hydrogen is bubbled through for 3 hours, and then the reaction mixture is left at 20° C. for 20 hours and then purged with a stream of nitrogen, filtered and concentrated under reduced pressure (2.7 kPa). 5.7 g of (3aRS,4RS,6SR,7aSR)-6-aminomethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]perhydroisoindol-4-ol are obtained in the form of a thick white foam.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:12][S:13][CH3:14]>O.CO>[OH:7][CH2:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:11][CH2:12][S:13]([CH3:14])=[O:2]
Reactant: CSCC[C@@H](CCO)NC(=O)OC(C)(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)CC[C@@H](CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
A suspension of sodium periodate (7.0 g) in water (32 ml) was added to a solution of (R)-tert-butyl (1-hydroxy-5-(methylthio)pentan-3-yl)carbamate (8.16 g) obtained in Step 1 in methanol (98 ml) at a temperature 10° C. or lower, and the mixture was stirred at room temperature for 2 hours. The generated insoluble matter was filtered off, and the filtrate was distilled off under reduced pressure. The resulting residue was dissolved in a saturated sodium chloride solution, followed by extraction with chloroform for 3 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow solid (9.38 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=[O:24])(=O)=O>CN(C)C=O>[O:7]([CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:23]=[O:24])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(COc2ccccc2)c1
Yield: 75.5 %

Procedure:
Phenol (100 mg), cesium carbonate (100 mg) and 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (120 mg) were heated in dimethylformamide (1 ml) at approx. 80° C. for about 30 minutes. TLC showed that the reaction was almost complete so the reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give an oil. The residue was purified via flash column chromatography, using dichloromethane:diethyl ether (10:1) as eluant to give 3-[(phenoxy)methyl]-4-phenylmethoxybenzaldehyde (90 mg) as off-white crystals. 1H NMR (CDCl3) δ 9.95 (s, 1H, CHO); 5.27 (s, 2H); 5.24 (s, 2H). TLC (silica gel): Rf=0.7 (petroleum ether: diethyl ether, 1:1).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:37])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (80 mg, 65%), MS (ISP) m/z=491.5 [(M+H)+], mp 186.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-tert-butyl-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 140 °C
Yield: 14.7 %

Procedure:
A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (130 mg, 0.332 mmol) from Step 4 of Example 78, (1R,2R)-(−)-trans-1-amino-2-indanol (198 mg, 1.33 mmol), and DIEA (214 mg, 1.66 mmol) in anhydrous DMA (2 mL) in a sealed reaction vessel was heated in a Biotage microwave synthesizer at 140° C. for 1.5 h. LCMS indicated that the reaction was incomplete. Additional (1R,2R)-(−)-trans-1-amino-2-indanol (50 mg, 0.335 mmol) was added, and the mixture was heated in a Biotage microwave synthesizer at 140° C. for a further 45 min. The reaction mixture was cooled to rt and 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 (1R,2R)-1-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (24 mg, 15%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.47 (d, J=7.9 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.69 (s, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.11-7.28 (m, 5H), 5.45-5.54 (m, 3H), 5.18 (t, J=7.1 Hz, 1H), 4.24-4.35 (m, 1H), 3.16 (dd, J=6.9, 15.5 Hz, 1H), 2.74 (dd, J=7.1, 15.5 Hz, 1H). LCMS (ESI) m/z 492 and 494 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([N:9]=[C:10]=[S:11])[CH:8]=1)#[N:2].[NH3:18]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([NH:9][C:10]([NH2:18])=[S:11])[CH:8]=1)#[N:2]
Reactant: N
Reactant: N#Cc1ccc(N2CCOCC2)c(N=C=S)c1
Solvent: CCO
Product: N#Cc1ccc(N2CCOCC2)c(NC(N)=S)c1

Procedure:
Reaction of 5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) with 25% aqueous ammonia solution (1 ml) at room temperature for 3 hours gave 1-(5-cyano-2-morpholinophenyl)thiourea (m.p. 193°-194° C.)
Reaction SMILES: [C:1]1([C:7]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[C].[Pd]>[CH:1]1([C:7]2([C:12]#[N:13])[CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CC1(C2=CCCCC2)CCCC1
Agent: [Pd]
Solvent: CO
Product: N#CC1(C2CCCCC2)CCCC1

Procedure:
1-Cyclohex-1-en-1-ylcyclopentanecarbonitrile was reacted in methanol at room temperature in the presence of palladium-carbon under a hydrogen atmosphere to obtain 1-cyclohexylcyclopentanecarbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]([C:21]1(Br)[CH2:24][CH2:23][CH2:22]1)=[O:20].O>CN(C=O)C.COC(C1(Br)CCC1)=O>[CH3:17][O:18][C:19]([C:21]1([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:24][CH2:23][CH2:22]1)=[O:20]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COC(=O)C1(Br)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Temperature: 140 °C

Procedure:
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (10 g, 64 mmol) and K2CO3 (13 g, 94 mmol) in DMF (100 mL) was added 1-bromo-cyclobutanecarboxylic acid methyl ester (15 g, 77 mmol, prepared according to Bulletin of the Chemical Society of Japan, 36, 145-7; 1963). The mixture was heated at 140° C. for 1.5 h. Then additional 1-Bromo-cyclobutanecarboxylic acid methyl ester (0.5 g, 2.6 mmol) was added and the mixture was heated at 140° C. for additional 10 min. The mixture was cooled to room temperature and poured into water (200 mL). The mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with water (4×), dried over Na2SO4, concentrated to afford crude product 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester as a dark oil (18 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[CH:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][C:45]([OH:47])=[O:46])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)=O>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:30][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][C:41]([CH2:44][C:45]([OH:47])=[O:46])=[CH:40][CH:39]=4)=[CH:34][CH:33]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Product: O=C(O)Cc1ccc(-c2ccc(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)cc2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and (4′-formyl-biphenyl-4-yl)-acetic acid according to the procedure of Example 66. MS (ES) m/z 617.2.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[OH:13])[C:7]=1Br.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:27][NH2:28]>C(N(CC)CC)C>[Br:1][C:2]1[C:3](=[O:21])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[OH:13])[C:7]=1[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=c1[nH]nc(OCCC(O)c2ccc(Cl)cc2)c(Br)c1Br
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2c(OCCC(O)c3ccc(Cl)cc3)n[nH]c(=O)c2Br)cc1OC
Yield: 68.5 %

Procedure:
From 300 mg of 4,5-dibromo-6-[3-(4-chlorophenyl)-3- hydroxypropyloxy]-3(2H)pyridazinone, 228 mg of 3,4-dimethoxybenzylamine and 69 mg of triethylamine, 246 mg of the title compound was prepared in the same manner as in Example 1, as white crystals having a melting point of 190°-196° C.
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH2:14][O:1][NH2:2])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCc1cccc2ccccc12

Procedure:
Prepared by a similar procedure as described for preparation 13. Starting materials: N-Hydroxyphthalimide and 1-chloromethyl-naphthalen. 13C-NMR (DMSO-d6) δ 133.5, 133.2, 131.4, 128.2, 126.8, 126.7, 126.0, 125.6, 125.2, 124.1, 75.4.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:33]([CH3:34])=[C:25]([F:24])[CH:26]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(OCCN3CCOCC3)c(-c3c(Cl)cnn3C)c2)cc1F
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a solution of 3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (0.040 g, 0.12 mmol) in CH2Cl2 (1.8 mL) was added 3-fluoro-4-methylbenzoyl chloride (0.025 mL, 0.14 mmol) and triethylamine (0.022 mL, 0.15 mmol). The reaction was stirred for 1 h, and concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown oil (0.0096 g, 14%). LCMS m/z (%)=473 (M+H35Cl, 100), 475 (M+H37Cl, 27). 1H NMR (400 MHz, DMSO-d6) δ: 10.31 (s, 1H), 7.96 (dd, J=2.6, 11.6 Hz, 1H), 7.76-7.72 (m, 3H), 7.67 (s, 1H), 7.49-7.44 (m, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.48-4.44 (m, 1H), 4.38-4.30 (m, 1H), 3.66 (s, 3H), 4.00-2.90 (m, 10H), 2.32 (s, 3H).