Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2)OCC1=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1=C(N(C)c2ccc(F)cc2)OCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.5 %

Procedure:
A solution of ethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.38 mmol) which similarly prepared according to the procedure described in the Example 4, First step, potassium carbonate (0.063 g, 0.45 mmol) and methyliodide (0.026 mL, 0.42 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) was stirred at ambient temperature for 12 h. The reaction mixture was diluted with water then extracted with ethyl acetate for 3 times. The organic layer was dried over sodium sulfate and concentrated to afford ethyl 2-[(4-fluorophenyl)-N-methylamino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.13 g).
Reaction SMILES: [Na+].[OH:2][CH:3]([CH2:7][CH3:8])[C:4]([O-:6])=[O:5].CN(C)C=O.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>C(Cl)(Cl)Cl.O>[F:24][C:23]([F:26])([F:25])[C:19]1[N:18]=[C:17]([O:2][CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CCC(O)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCC(Oc1cccc(C(F)(F)F)n1)C(=O)O
Temperature: 105 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
2-hydroxybutyric acid sodium salt (10 g) was added to dry dimethylformamide (100 ml) and oil free sodium hydride (2 g) added in a single portion with stirring under nitrogen. The reaction mixture was stirred at ambient temperature for 30 minutes and then at about 80° C. for 10 minutes prior to addition of 2-chloro-6-trifluoromethylpyridine (10 g). The reaction mixture was then heated to 100-110° C. for 1 hour. The mixture was poured into an equal volume mixture of water and chloroform (1 liter) and the original layer made just acidic (pH4), followed by vigorous extraction into the organic phase which was separated, washed and dried. Chromatography gave a colorless solid which was recrystallized from hexane to give colorless crystals mp. 118° C. (11.9 g) of 2-(6-trifluoromethyl-2-pyridinyloxy)butyric acid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[NH2:10][C:9]1[C:8]2[C:7]([N:12]=[C:13]3[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18]3)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=2
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: O=C1CCCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Nc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2
Temperature: 25 °C
Yield: 33.3 %

Procedure:
To a mixture of 5-nitroanthranilonitrile (1.63 g, 10 mmol) and cyclohexanone (10.3 ml, 100 mmol) was added zinc chloride (1.36 g, 10 mmol) and the mixture was refluxed under heating for 20 min. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and chloroform was added to the obtained brown oil. The resulting yellow precipitate was collected by filtration and dried under reduced pressure at 80° C. This solid (1.56 g) was diluted with ethyl acetate and 1N aqueous sodium hydroxide solution, and ether was added. The insoluble matter was collected by filtration and dried under reduced pressure at 80° C. to give 9-amino-7-nitro-1,2,3,4-tetrahydroacridine (810 mg, 33%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].CCO>[Fe].O>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3ccsc23)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccsc23)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a vial containing tert-butyl [(3S)-1-(6-nitrothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate (210.1 mg, 0.5552 mmol), iron powder (306.1 mg, 5.481 mmol) and NH4Cl (491.9 mg, 9.196 mmol), EtOH (5.00 mL) was added, followed by water (1.00 mL). The mixture was stirred at 80° C. for 2 h. The reaction mixture was then filtered through a pad of diatomaceous earth. The diatomaceous earth pad was eluted with a 10% aq. K3PO4 (30 mL) and EtOAc (30 mL). The organic layer was washed with brine (30 mL), then dried over Na2SO4, and concentrated under reduced pressure. The resulting residue (197.9 mg) of the sub-title compound was used in the next step without further purification. LCMS calc. for C17H25N4O2S (M+H)+: m/z=349.2. found 349.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])[CH3:2].[Cl:28][Si](C)(C)C.CO>C1(C)C=CC=CC=1>[ClH:28].[ClH:28].[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CCOC(=O)[C@@H]1CCCN(CCOCCN(CC(C)C)c2ccccc2)C1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cl

Procedure:
To a solution of the above ester (8.0 g, 21 mmol) in anhydrous toluene (30 ml) was added a solution of chlorotrimethylsilane (4.6 g, 42 mmol) in anhydrous toluene (10 ml). Methanol (1.7 ml, 42 mmol) was carefully added and the resulting mixture left for crystallisation to give 6.2 g of (R)-1-(2-(2-(N-(2-methyl-1-propyl)-N-phenylamino)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester dihydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([S-:6])=[S:5])[CH3:2].[K+].Cl[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CC(C)=O>[C:4](=[S:6])([O:3][CH2:1][CH3:2])[S:5][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=S)SCC(=O)OC(C)(C)C
Yield: 102 %

Procedure:
Potassium ethylxanthate (58.0 g, 364 mmol) was suspended in 200 mL of dry acetone at room temperature. tert-Butyl chloroacetate (50 g, 332 mmol) was added dropwise with stirring. After 18 hrs potassium chloride was removed by fitration, and the solvent was evaporated. The residue was taken up into ether, washed with 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and evaporated to leave 80 g of O-ethyl S-(tert-butoxycarbonyl)methyl dithiocarbonate as a thick oil. This oil was stirred with ethanolamine (323 mmol) for 2 hrs at room temperature. The reaction mixture was taken up into ethyl acetate, washed with 1.2N HCl, water, and brine, dried over MgSO4, filtered, and evaporated. The residue was vacuum dis-tilled to give 30 g of mercapto-acetic acid tert-butyl ester as a clear oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C@@:4]12[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:22])=[CH:12][C:13]=3[CH2:14][CH2:15]1)[CH2:6][CH2:5]2.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)C>[OH:22][C:11]1[CH:10]=[CH:9][C:8]2[CH:7]3[CH:16]([CH2:15][CH2:14][C:13]=2[CH:12]=1)[CH:17]1[C:4]([CH3:3])([C:20](=[O:21])[C:19](=[CH:29][C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH2:18]1)[CH2:5][CH2:6]3
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: O=Cc1ccncc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC12CCC3c4ccc(O)cc4CCC3C1CC(=Cc1ccncc1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (1.0 g, 25 mmol) was added to a suspension of estrone (1.35 g, 5.0 mmol) and pyridine-4-carbaldehyde (595 mg, 5.0 mmol) in ethanol (40 mL) at room temperature. The resulting dark orange solution was stirred at room temperature for 4 hours. Then glacial acetic (ca. 10 mL) acid was added with stirring. The colour changed to light yellow and a light yellow solid precipitated. The solid was filtered off and washed with water (50 mL), ethanol (20 mL), diethyl ether (50 mL) and hexane (50 mL) and dried under high vacuum. Yield: 1.588 g (88%) light yellow solid. 1H-NMR (DMSO-d6, 400 MHz), δ: 0.92 (s, 3H, —CH3), 1.30-1.68 (m, 5H), 1.82-1.92 (m, 1H), 1.96-2.04 (m, 1H), 2.14-2.24 (m, 1H), 2.31-2.38 (m, 1H), 2.61-2.69 (m, 1H), 2.71-2.84 (m, 2H), 2.87-2.96 (m, 1H), 6.47 (d, J=2.3 Hz, 1H), 6.53 (dd, J=8.6, 2.3 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.28 (s, 1H), 7.60 (d, J=6.2 Hz, 2H), 8.65 (d, J=6.2 Hz, 2H), 9.05 (s, 1H, —OH). LRMS (FAB+): 360.2 (100, [M+H]+). LRMS (FAB−): 358.2 (100, [M−H]−). HRMS (FAB+): 360.196986 C24H26NO2 requires 360.196354.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.F[C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>>[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:22]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Nc1ccc(O)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(O)cc1
Yield: 99.8 %

Procedure:
Using General Method 1, the reaction of 2.5 M solution of n-BuLi in hexanes (29 mL, 73 mmol), diisopropylamine (9.5 mL, 68 mmol), 4-hydroxyaniline (1.85 g, 17 mmol), and 2,4,5-trifluorobenzoic acid (3 g, 17 mmol) provided 4.5 g of the crude title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:15][CH:16]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.C(Cl)[Cl:29].CO.[ClH:33]>O1CCOCC1>[ClH:29].[ClH:33].[Br:1][C:2]1[CH:3]=[C:4]([O:15][CH:16]2[CH2:20][CH2:19][NH:18][CH2:17]2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OC2CCN(C(=O)OC(C)(C)C)C2)n1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1csc(Nc2ncc(Br)cc2OC2CCNC2)n1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A mixture of tert-butyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)pyrrolidine-1-carboxylate (prepared according to Example 61; 550 mg, 1.21 mmol) and CH2Cl2 (10 mL) and MeOH (2 mL) was stirred at room temperature. 4N HCl in dioxane (5 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction was concentrated and dissolved in small amount of CH2Cl2/methanol and added to vigorously stirred ether and filtered to afford N-(5-bromo-3-(pyrrolidin-3-yloxy)pyridin-2-yl)-4-methylthiazol-2-amine dihydrochloride (478 mg, 92.4% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.18 (bs, 1H), 9.80 (bs, 1H), 9.27 (bs, 1H), 8.09 (d, 1H), 7.83 (d, 1H), 6.80 (s, 1H), 5.42 (m, 1H), 3.62-3.30 (m, 4H), 2.31 (s, 3H), 2.22 (m, 2H); Mass spectrum (apci) m/z=357.0 (M+H-2HCl).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.C(N(CC)CC)C.[O:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([NH:12][C:30]([CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[O:31])[CH:13]=[CH:14][CH:15]=2)[O:5]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: O=C(Cl)C1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cccc(NC(=O)C3CCOCC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (220 mg) and triethylamine (0.182 mL) in N,N-dimethylacetamide (1.5 mL) chilled to 0° C. was added tetrahydro-2H-pyran-4-carbonyl chloride (prepared from tetrahydro-2H-pyran-4-carboxylic acid (156 mg) and oxalyl chloride (0.15 mL) in dichloromethane (2.5 mL)) dropwise. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid aqueous solution (3 times) then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (267 mg, 81%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:7][CH:8]=2)[NH:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[N:12]1([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][NH:11][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)NC(=O)NC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1NCc2ccc(N3CCNCC3)cc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.7 %

Procedure:
To a solution of 16 (0.7 g, 2.11 mmol) in a mixture of CH2Cl2 (15 mL) and THF (5 mL) at 0° C. was added TFA (5 mL) and the mixture was stirred at room temperature for 6 h. The solvent was evaporated under vacuum to afford 0.66 g (96%) of compound 5 as a dark brown gum. IR (KBr) νmax. cm−1: 3261 (NH), 3032 (Ar—H), 1691 (C═O), 1613, 1513, 1415 (C═C). 1H NMR (500 MHz, DMSO-d6) δ=3.18 (m, 4H, 2CH2); 3.42 (m, 4H, 2CH2); 4.23 (s, 2H, CH2); 6.66 (m, 2H, aromatic-H); 6.73 (m, 1H, aromatic-H); 8.80 (br. s, 1H, NH); 8.86 (br. s, 1H, NH); 13C NMR (125.7 MHz, DMSO-d6) δ=46.35 (CH2), 46.73 (CH2), 48.63 (CH2), 114.19 (aromatic-C), 114.38 (aromatic-C), 116.49 (aromatic-C), 118.83 (aromatic-C), 131.87 (aromatic-C), 144.81 (aromatic-C), 154.72 (C═O). Calculated (%) for C14H16F3N4O2 (329.12); C: 48.56, H: 4.95, N: 16.18. found (%); C: 48.45, H: 5.05, N: 16.15.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(#N)C>[CH3:21][C:18]1[O:17][C:16]([CH2:15][NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:23]=[CH:22][C:9]=3[N:10]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(CNC2=Nc3ccc(NC(=O)CCl)cc3CO2)o1
Reactant: C1COCCN1
Solvent: CC#N
Product: Cc1ccc(CNC2=Nc3ccc(NC(=O)CN4CCOCC4)cc3CO2)o1
Yield: 86.7 %

Procedure:
Prepared from the above described 2-chloro-N-{2-[(5-methyl-furan-2-ylmethyl)-amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (100 mg, 0.300 mmol) and morpholine (0.260 ml 2.996 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (100 mg, 87%), MS (ISP) m/e=385.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+].[C:43]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:47])[C:44]([CH3:46])=[CH2:45]>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].C1(C)C=CC=CC=1.CC(N(C)C)=O>[CH3:9][O:8][C:6]1[N:7]=[C:2](/[CH:45]=[C:44](\[CH3:46])/[C:43]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: C=C(C)C(=O)OC(C)(C)C
Reactant: COc1nc(Cl)ccc1-n1cnc(C)c1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1nc(/C=C(\C)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (400 mg), an allylpalladium chloride dimer (32.8 mg), tri-o-tolylphosphine (54.4 mg), sodium acetate (441 mg), dimethylacetamide (0.640 mL), tert-butyl methacrylate (0.724 mL) and toluene (2 mL) was stirred in a nitrogen atmosphere at 120° C. for 3.5 hours. The reaction solution was left to cool to room temperature. Then, a silica gel was added and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 313 mg of tert-butyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacrylate. The ester was diluted with trifluoroacetic acid (2.48 mL) and methylene chloride (2.48 mL), and the reaction solution was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure to obtain 260 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[OH:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CCO)cc1
Reaction time: 0.5 h

Procedure:
4-(4-tert-butyldimethylsilyloxybutyl)phenylacetic acid (0.25 g, 0.775 mmol) dissolved in dry ether is added dropwise to a suspension of lithium aluminum hydride in ether (44.2 mg, 1.16 mmol). The reaction mixture is stirred for 5 hours after which water (45 μl), NaOH (15% solution, 45 μl) and water (135 μl) are successively added and the reaction mixture is stirred for a further 30 minutes. The resulting precipitate is filtered
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13]CCO1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22]3=[C:23]([CH2:25][S:26][CH2:27][CH2:28][N:21]3[C@H:20]3[CH2:29][CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][C@@H:19]23)[CH:24]=1>>[CH2:28]1[N:21]2[C:22]3[C:18]([C@@H:19]4[CH2:32][NH:31][CH2:30][CH2:29][C@@H:20]42)=[CH:17][C:16]([NH:15][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:13])[CH3:14])=[CH:24][C:23]=3[CH2:25][S:26][CH2:27]1
Reactant: CC1(c2cc(Cl)ccc2Br)OCCO1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: CC(=O)c1cc(Cl)ccc1Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(2-bromo-5-chlorophenyl)-2-methyl-1,3-dioxolane and following the procedures described in EXAMPLE 116, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 150. 1H NMR (CDCl3) δ: 10.26 (s, 1H), 7.72 (d, 1H, J=2.2 Hz), 7.20 (dd, 1H, J=9.2, 2.6 Hz), 6.96 (d, 1H, J=9.2 Hz), 6.84 (d, 1H, J=1.8 Hz), 6.77 (d, 1H, J=1.9 Hz), 6.87 (s, 1H), 3.74 (ABq, 2H, JAB=15.6 Hz), 3.63-3.57 (m, 1H), 3.50-3.42 (m, 1H), 3.40-3.30 (m, 1H), 3.20-3.02 (m, 5H), 2.98-2.90 (m, 1H), 2.66-2.58 (m, 1H), 2.61 (s, 3H), 2.05-1.97 (m, 2H). LRMS (ES)+: 391.4 (M+H)+. LRMS (ES)+: 414.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][CH:22]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Product: C=Cc1ccc(CN2CCOC(CNC(=O)Nc3ccc(Cl)cc3)C2)cc1
Yield: 49.6 %

Procedure:
Example 38 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 1-(chloromethyl)-4-vinylbenzene (0.0062 g) to give the title compound (0.0071 g). LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 386 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10][C:9]([C:17](OCC)=[O:18])=[N:8]2)=[CH:4][CH:3]=1.[NH3:24]>CO>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10][C:9]([C:17](=[O:18])[NH2:24])=[N:8]2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CCCCOc1cc(C(=O)OCC)nn1Cc1ccc(Cl)cc1
Solvent: CO
Product: CCCCOc1cc(C(N)=O)nn1Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 86.2 %

Procedure:
A mixture consisting of 6.7 g of 1-(p-chlorobenzyl)-3-ethoxycarbonyl-5-n-butoxypyrazole, 30 ml of a 28% aqueous ammonia solution and 30 ml of methanol was placed in an autoclave and heated at a temperature of 60°C for 2 hours. After completion of the reaction, the solvent was removed by distillation and the residue was recrystallized from methanol-petroleum ether to give 5.3 g (86.2% yield) of 1-(p-chlorobenzyl)-3-carbamoyl-5-n-butoxypyrazole as colorless needles having a melting point of 137° - 138°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10](Cl)=[O:11].[NH2:14][N:15]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]=[C:16]1[CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:13])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@H:6]2[CH2:9][C:10]([NH:14][N:15]1[C:20](=[O:21])[C:19]2[CH:22]=[CH:23][S:24][C:18]=2[N:17]=[C:16]1[CH2:25][CH3:26])=[O:11]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)Cl)[C@@H]1C2
Reactant: CCc1nc2sccc2c(=O)n1N
Product: CCc1nc2sccc2c(=O)n1NC(=O)C[C@@H]1CC[C@H]2C[C@@H]1C2(C)C

Procedure:
The product from Example 1C and 3-amino-2-ethylthieno[2,3-d]pyrimidin-4(3H)-one (Enamine) were processed using method analogous to that described in Example 1D to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88-0.96 (m, 1H) 1.07 (s, 3H) 1.16-1.23 (m, 6H) 1.45-1.64 (m, 1H) 1.79-2.06 (m, 6H) 2.27-2.46 (m, 2H) 2.53-2.67 (m, 1H) 2.66-2.82 (m, 1H) 7.38 (d, J=7.1 Hz, 1H) 7.59 (d, J=5.6 Hz, 1H); MS (ESI+) m/z 360 (M+H)+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:26]([F:29])([F:28])[F:27])=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:11]=1)(=O)=O.[F:30][C:31]1[CH:36]=[C:35]([N:37]2[CH:41]=[N:40][N:39]=[N:38]2)[CH:34]=[CH:33][C:32]=1O>>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([N:10]3[CH:11]=[C:7]([CH2:6][O:5][C:32]4[CH:33]=[CH:34][C:35]([N:37]5[CH:41]=[N:40][N:39]=[N:38]5)=[CH:36][C:31]=4[F:30])[C:8]([C:26]([F:29])([F:28])[F:27])=[N:9]3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: Oc1ccc(-n2cnnn2)cc1F
Reactant: CCc1cnc(N2CCC(n3cc(COS(C)(=O)=O)c(C(F)(F)F)n3)CC2)nc1
Product: CCc1cnc(N2CCC(n3cc(COc4ccc(-n5cnnn5)cc4F)c(C(F)(F)F)n3)CC2)nc1

Procedure:
The compound was synthesized using (1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl methanesulfonate and 2-fluoro-4-(1H-tetrazol-1-yl)phenol in a manner similar to that described in Example 1. 1H NMR (CDCl3): δ 8.99 (1H, s), 8.15 (2H, s), 7.64 (1H, s), 7.50 (1H, m), 7.41 (1H, m), 7.17 (1H, m), 5.13 (2H, s), 4.86 (2H, m), 4.42 (1H, m), 2.99 (2H, m), 2.44 (2H, q), 2.20 (2H, m), 1.93 (2H, m), 1.16 (3H, t).