Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH:20]([CH3:22])[CH3:21])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(F)c1OC(C)C
Reaction time: 0.5 h

Procedure:
A solution of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (250 mg, 1.5 mmol) in DMF (2.5 mL) was treated with potassium carbonate (812 mg, 5.9 mmol) and stirred for 30 minutes. 2-Iodopropane (500 mg, 2.9 mmol) was added over 10 minutes and reaction mixture was stirred for 20 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium chloride solution. The organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 3-fluoro-4-isopropoxy-5-methoxybenzaldehyde. To the aldehyde was added tert-butanol (6.7 mL) and 2-methylbut-2-ene (4 mL, 38.2 mmol) and the reaction mixture was cooled to 0° C. A solution of chlorite (345 mg, 3.8 mmol) and sodium dihydrogen phosphate hydrate (527 mg, 3.8 mmol) in water (6.7 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred 30 minutes. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was basified with 1 N NaOH solution and extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 1 N HCl solution and extracted with EtOAc (4×50 mL). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo to afford 3-fluoro-4-isopropoxy-5-methoxy-benzoic acid (190 mg, 56%) as a white solid. ESI-MS m/z calc. 228.0. Found 229.3 (M−1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Cl:10][C:11]1[C:12]([F:37])=[C:13]([CH:34]=[CH:35][CH:36]=1)[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:32][CH3:33])=[C:22]([O:25][CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([O:25][C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][C:21]=2[O:32][CH3:33])[N:18]=[CH:17][N:16]=[C:15]3[NH:14][C:13]2[CH:34]=[CH:35][CH:36]=[C:11]([Cl:10])[C:12]=2[F:37])[CH2:27][CH2:28]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Yield: 58 %

Procedure:
Tert-butyl chloroacetate (1.43 ml, 10 mmol) was added dropwise to a mixture of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (4.02 g, 10 mmol), potassium iodide (1.66 g, 10 mmol) and potassium carbonate (1.66 g, 12 mmol) in dimethylacetamide (50 ml). The mixture was heated at 70° C. for one hour. After evaporation of the solvents under vacuum, the residue was triturated in water. The resulting solid was filtered, washed with water and purified by chromatography on silica gel (eluant: 2% 7N methanolic ammonia in dichloromethane) to give tert-butyl[4-({4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]acetate as a white solid (3.0 g, 60%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH:6]([S:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[C:27]4[O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:26]=4[CH:25]=[CH:24][CH:23]=3)[CH:17]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:7].Cl>O1CCCC1.CO.O>[CH:25]1[C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][C:27]=2[C:22]([C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:9][S:8][CH:6]([CH3:7])[C:5]([OH:35])=[O:4])[CH:15]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(SCc1cccc(-c2cccc(-c3cccc4c3oc3ccccc34)c2)c1)C(=O)O
Temperature: 25 °C

Procedure:
2N Sodium hydroxide solution (0.33 mL, 0.66 mmol) was added dropwise to a stirred solution of methyl-2-(3′-dibenzofuran-4-yl-biphen-3-ylmethylsulfanyl)-propionate (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) and methanol (1 mL). The clear reaction mixture was stirred at room temperature until the reaction was complete (TLC control), and then diluted with water (5 mL), and acidified to pH 3 with 2N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (2×20 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5-10% methanol in methylene chloride as eluent, afforded the title compound has a white solid (86 mg, 89%); Rf: 0.40 (10% methanol in dichloromethane); 1H NMR (DMSO-d6): □ 8.19 (2H, m, Ar—H), 8.02 (2H, d, J=9 Hz, Ar—H), 7.86 (2H, d, J=9 Hz, Ar—H), 7.75 (4H, m, Ar—H), 7.29-7.41 (5H, m, Ar—H), 3.96 (2H, s, PhCH2S), 3.36 (1H, q, J=7 Hz, SCHMe), 1.36 (3H, d, J=7 Hz, CHMe); ESI-LCMS e/z calcd for C28H22O3S 438.54, found 439 (M+H)+.
Reaction SMILES: C([S:18][CH2:19][CH2:20][NH:21][C:22](=[O:65])[CH2:23][CH2:24][NH:25][C:26](=[O:64])[C@H:27]([OH:63])[C:28]([CH3:62])([CH3:61])[CH2:29][O:30][P:31]([OH:60])(=[O:59])[O:32][P:33]([OH:58])(=[O:57])[O:34][CH2:35][C@H:36]1[O:40][C@@H:39]([N:41]2[C:50]3[N:49]=[CH:48][N:47]=[C:45]([NH2:46])[C:44]=3[N:43]=[CH:42]2)[C@H:38]([OH:51])[C@@H:37]1[O:52][P:53]([OH:56])([OH:55])=[O:54])(=O)CCCCCCCCCCCCCCC.N[C@H](C(O)=O)CO.N>C1N(CCO)CCN(CCS(O)(=O)=O)C1.[OH-].[Na+]>[CH3:62][C:28]([C@@H:27]([OH:63])[C:26]([NH:25][CH2:24][CH2:23][C:22]([NH:21][CH2:20][CH2:19][SH:18])=[O:65])=[O:64])([CH2:29][O:30][P:31]([O:32][P:33]([O:34][CH2:35][C@H:36]1[O:40][C@@H:39]([N:41]2[C:50]3[N:49]=[CH:48][N:47]=[C:45]([NH2:46])[C:44]=3[N:43]=[CH:42]2)[C@H:38]([OH:51])[C@@H:37]1[O:52][P:53]([OH:56])([OH:55])=[O:54])([OH:58])=[O:57])([OH:60])=[O:59])[CH3:61]
Reactant: CCCCCCCCCCCCCCCC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Agent: N
Agent: N[C@@H](CO)C(=O)O
Agent: O=S(=O)(O)CCN1CCN(CCO)CC1
Product: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS

Procedure:
Palmitoyl CoA (10 mg) and 1 mg of L-serine were dissolved in 5 mL of 100 mM HEPES-NaOH buffer (containing 10 μM PLP; pH 8.0) and well stirred using a magnetic stirrer. While the stirring speed was reduced to such an extent that a mild mixing was resulted, 0.5 mL of a crude SPT enzyme solution was added and the mixture was made to react at 37° C. for 24 hours. The solution was made alkaline with 1 mL of 2N ammonia solution and the product in the solution was extracted and recovered with 5 mL of chloroform/methanol (2:1, (v/v)). The extract liquid was filtered, concentrated appropriately and analyzed by the same manner as in Example 3 whereupon the produced amount of 3-ketodihydrosphingosine was about 0.02 mg.
Reaction SMILES: S=[C:2]1[CH:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[NH:3]1.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH:28][C:2]1[CH:8]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[N:3]=1
Reactant: O=C(NC1CCc2ccccc2NC1=S)OCc1ccccc1
Reactant: COC(CN)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(CNC1=Nc2ccccc2CCC1NC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 112.8 %

Procedure:
Dissolve Benzyl N-(2-thioxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl)carbamate (1.78 Kg, 5.13 mol) and para-toluene sulfonic acid monohydrate (48.8 g, 256 mmol) in dichloromethane (12 L). Add aminoacetaldehyde dimethyl acetal (2.70 Kg, 25 mole) dropwise over 1 hour and stir for 36 hours at ambient temperature. Add additional aminoacetaldehyde dimethyl acetal (1.40 Kg, 13 mol) and stir for 12 hours at ambient temperature. Add water (5.0 L), separate the organic layer, and extract the aqueous with dichloromethane (2.0 L). Combine the organic layers and wash with water, saturated ammonium chloride (6.0 L), and brine (4.0 L). Filter the organic through diatomaceous earth and concentrate under reduced pressure to give the title compound (2.30 kg, 118%) as a yellow oil: MS (m/z): 398 (M+1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:32])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28]([O:30]C)=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:15][CH:14]=1.C[Si](C)(C)[O-].[K+].Cl>C1COCC1.CCOC(C)=O>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:32])[NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][N:26]=[C:27]([C:28]([OH:30])=[O:29])[C:22]3=[N:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1nccn2c(-c3ccc(NC(=O)Nc4ccccc4OC(F)(F)F)cc3)nnc12
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2nnc3c(C(=O)O)nccn23)cc1)Nc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 100.5 %

Procedure:
To a solution of methyl 3-(4-(3-(2-(trifluoromethoxy)phenyl)ureido) phenyl)-[1,2,4]triazolo[4,3-a]pyrazine-8-carboxylate (61F) (72 mg, 0.152 mmol) in THF (3 mL), was added potassium trimethylsilanolate (78 mg, 0.61 mmol). The mixture was stirred at room temperature for 70 min, and then acidified with 1 N aqueous HCl (0.62 mL). The mixture was diluted with EtOAc, washed with water (3×), brine, and dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as a brown solid (70 mg, 100%). HPLC/MS (Method C): retention time=1.83 min, [M+H]+=459.4.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10](C(OCC3C=CC=CC=3)=O)[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:21](Cl)(=[O:23])[CH3:22]>>[NH:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:21](=[O:23])[CH3:22])[C:7]=2[CH:8]=[CH:9]1
Reactant: CC(=O)Cl
Reactant: Nc1nccc2c1ccn2C(=O)OCc1ccccc1
Product: CC(=O)Nc1nccc2[nH]ccc12

Procedure:
N-(1H-pyrrolo[3,2-c]pyridin-4-yl)acetamide (Intermediate 25) was prepared from benzyl 4-amino-1H-pyrrolo[3,2-c]pyridine-1-carboxylate in an analogous manner using acetyl chloride.
Reaction SMILES: [CH2:1]([OH:4])CO.[OH-].[K+].CSC1[N:18]2[C:12]([CH2:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[CH:16]=[CH:17]2)=[N:11][N:10]=1.Cl>O>[N:11]1[NH:10][C:1](=[O:4])[N:18]2[CH:17]=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[CH2:13][C:12]=12
Reactant: OCCO
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]nc2n1C=Cc1ccccc1C2
Reaction time: 2 h

Procedure:
To 2 ml of ethylene glycol was added 0.2 g of potassium hydroxide, followed by addition of 0.23 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine. The mixture was stirred at 150°-160° C. for 2 hours, after which water was added. The mixture was made acidic with 4N-hydrochloric acid and extracted with chloroform. The chloroform layer was washed with water and dried over Na2SO4. The solvent was evaporated off and the residue was treated with ethyl acetate. By the above procedure was obtained 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from methanol yielded light-brown needles melting at 207°-208° C. The following compounds were produced by procedures similar to that of the above Reference Example.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][OH:22])[N:14]=[CH:13][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([O:8][C:9]([NH:10][C@@H:11]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]([CH2:20][CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])[N:14]=[CH:13][C:12]1=2)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCCc2c1cnn2CCO)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1ncc2c1CCC[C@H]2NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.2 %

Procedure:
To a solution of (R)-[1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-carbamic acid benzyl ester (755 mg, 2.40 mmol) and pyridine (1.45 mL, 18.0 mmol) in dichloromethane was added methanesulfonyl chloride (1.40 mL, 18 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 6 hours The resulting mixture was poured into ice (10 g). The organic layer was then separated and washed with 0.1 N hydrochloric acid and saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (10% methanol in dichloromethane) to afford methanesulfonic acid 2-((R)-4-benzyloxycarbonylamino-4,5,6,7-tetrahydroindazol-1-yl)-ethyl ester (880 mg, 90%) as a white solid. MS calcd. for C18H23N3O5S 393, obsd. (ESI+) [(M+H)+] 394.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(-c2c(CCl)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CN3C(=O)c4ccccc4C3=O)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Yield: 95.9 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4-methylphenyl)-1(2H)-isoquinolinone (4.24 g, 9.5 mmol) and potassium phthalimide (2.65 g, 14.3 mmol) in N,N-dimethylformamide (50 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[[6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (5.07 g, 96.0%) as crystals.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[C:30]([C:34]1[N:35]=[CH:36][N:37]2[CH:41]=[CH:40][S:39][C:38]=12)(=[O:33])[CH2:31][CH3:32].[Cl-].[NH4+]>C1COCC1>[C:30]([C:34]1[N:35]=[CH:36][N:37]2[C:41]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:40][S:39][C:38]=12)(=[O:33])[CH2:31][CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCC(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1csc2c(C(=O)CC)ncn12
Reaction time: 1 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (6.17 ml) was added to 60 ml of THF. A solution of 2.12 ml of tri-n-butylstannyl chloride in 24 ml of THF and a solution of 1.11 g of 7-propionylimidazo[5,1-b]thiazole in 24 ml of THF were dropwise added in that order in an argon atmosphere at −73° C. to the mixture. The mixture was stirred at the same temperature for one hr. A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (6.17 ml) was added dropwise thereto. The mixture was stirred at the same temperature for 2 hr. An ammonium chloride solution (250 ml) was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1). Of two main components, the fraction, which had been eluted earlier, was collected to give 234 mg of 7-propionyl-3-(tri-n-butylstannyl)imidazo[5,1-b]thiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:21][C:22]2[CH:35]=[CH:34][C:25]3[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 25.9 %

Procedure:
Combined 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (73 mg, 0.232 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (57 mg, 0.279 mmol), DL-10-Camphorsulfonic acid (67 mg, 0.288 mmol) and isopropanol (4 mL) in a microwave tube. Microwaved reaction at 120° C. for 70 minutes. Evaporated off solvent and purified with normal phase chromatography to yield a yellow solid, 2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (29 mg, 26%). mp 153° C.; LCMS: m/z=483.37 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.61 (s, 1H), 7.53 (d, 1H, J=8.6 Hz), 7.27 (m, 3H), 6.70 (m, 2H), 6.40 (m, 1H), 2.92 (d, 3H, J=4.8 Hz), 2.32 (m, 2H), 2.04 (m, 2H), 1.30 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([NH:9]C(=O)C(F)(F)F)=[N:7][CH:8]=1)#N.C(O)=[O:18]>O.[Ni].[Al]>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([CH:1]=[O:18])=[C:4]([CH3:16])[CH:5]=1
Reactant: Cc1cc(NC(=O)C(F)(F)F)ncc1C#N
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Solvent: O
Product: Cc1cc(N)ncc1C=O

Procedure:
A solution of N-(5-cyano-4-methyl-2-pyridinyl)-2,2,2-trifluoroacetamide (D98) (0.050 g, 0.22 mmol) in formic acid (1.35 mL) was diluted with water (0.48 mL) and nickel/aluminium alloy (0.122 g) was added. The reaction mixture was heated at reflux under argon for 2 h then filtered while still hot, washing with further formic acid (3×5 mL). The filtrate and washings were concentrated, diluted with toluene (5 mL) and re-concentrated to give the crude title compound as a pale yellow solid (0.053 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 9.91 (1H, s), 8.34 (1H, s), 6.31 (1H, s), 5.49 (2H, br.s), 2.57 (3H, s). MS (ES): MH+ 137.2.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.Cl.[Cl:17][C:18]1[CH:19]=[C:20](/[CH:31]=[C:32](\[F:38])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:21]=[N:22][C:23]=1[NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]1.[CH:39]1([CH:45]=O)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:17][C:18]1[CH:19]=[C:20](/[CH:31]=[C:32](\[F:38])/[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:21]=[N:22][C:23]=1[NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:45][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:26]1
Reactant: O=CC1CCCCC1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCNC2)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium triacetoxyborohydride (0.56 g) was added a mixture of ethyl (2Z)-3-{5-chloro-6-[(3R)-3-piperidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (0.7 g), Et3N (0.49 mL) and cyclohexanecarboxaldehyde (0.23 mL) in CH2Cl2 (14 mL) and the mixture was stirred at ambient temperature for 20 hr. The reaction mixture was poured into a mixture of CHCl3 and aq NaHCO3. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoroacrylate (0.74 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:10]([N:13]1[C:17]2[C:18]([NH2:26])=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=2[N:15]=[C:14]1[CH3:27])([CH3:12])[CH3:11]>C1(C)C(C)=CC=CC=1>[CH3:2][C:1](=[N:26][C:18]1[C:17]2[N:13]([CH:10]([CH3:12])[CH3:11])[C:14]([CH3:27])=[N:15][C:16]=2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1nc2cc(C(F)(F)F)cc(N)c2n1C(C)C
Reactant: CC(=O)c1ccccc1
Solvent: Cc1ccccc1C
Product: CC(=Nc1cc(C(F)(F)F)cc2nc(C)n(C(C)C)c12)c1ccccc1

Procedure:
Acetophenone (2.8 g.) was reacted with 1-isopropyl-2-methyl-5-trifluoromethyl-7-aminobenzimidazole (4.0 g.) in 50 ml. of xylene for 21 hours according to the procedure of Example 1. After drying over sodium sulfate, the solvent was removed and the crude residue was recrystallized from benzene-cyclohexane (1:1) to give 3.38 g. of the desired product, m.p. 164°-166° C.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2([OH:42])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:30]([CH3:43])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]2([OH:42])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[C:30]([CH3:43])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCOCC2)c(C)c1
Agent: COCCO[Al+]OCCOC
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCOCC2)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt % solution in toluene, 1.06 mL, 3.516 mmol) was added to a solution of 4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethynyl}-tetrahydro-pyran-4-ol (Example 130-(1); 0.46 g, 1.172 mmol) in tetrahydrofuran (5 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for three hours. Then, ethyl acetate and brine were added to the reaction mixture, which was further diluted with ethyl acetate. Thereafter, celite was added and the mixture was stirred at room temperature for three hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 30:70, 40 minutes) to give the target compound as a colorless oil (0.46 g, 99%).