Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH3:12][C:13]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH2:16][CH2:17][N:18]1[C@H:23]2[CH2:24][CH2:25][C@@H:19]1[CH2:20][CH:21]([N:26]1[C:30]([CH:31]([CH3:33])[CH3:32])=[N:29][N:28]=[C:27]1[CH3:34])[CH2:22]2)[CH2:14][NH2:15]>>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([NH:15][CH2:14][C:13]([CH3:12])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:16][CH2:17][N:18]2[C@H:23]3[CH2:24][CH2:25][C@@H:19]2[CH2:20][CH:21]([N:26]2[C:30]([CH:31]([CH3:33])[CH3:32])=[N:29][N:28]=[C:27]2[CH3:34])[CH2:22]3)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CN)c1ccccc1
Product: Cc1nnc(C(C)C)n1C1C[C@H]2CC[C@@H](C1)N2CCC(C)(CNC(=O)C1CCC(F)(F)CC1)c1ccccc1

Procedure:
The title compound was synthesized by coupling 4,4-difluorocyclohexanecarboxylic acid and (2-methyl-4-{(1R,5S)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-2-phenylbutyl)amine (intermediate 24) as described in example 21.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([N:10]=[C:11]=[O:12])([CH3:9])[CH3:8].[Cl:13][C:14]1[C:15]([O:24][C:25]2[C:29]([CH3:30])=[C:28]([CH3:31])[NH:27][N:26]=2)=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.Cl>CN(C=O)C>[CH:7]([NH:10][C:11]([N:27]1[C:28]([CH3:31])=[C:29]([CH3:30])[C:25]([O:24][C:15]2[C:14]([Cl:13])=[CH:19][C:18]([C:20]([F:23])([F:22])[F:21])=[CH:17][N:16]=2)=[N:26]1)=[O:12])([CH3:9])[CH3:8]
Reactant: CC(C)N=C=O
Reactant: Cc1[nH]nc(Oc2ncc(C(F)(F)F)cc2Cl)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ncc(C(F)(F)F)cc2Cl)nn(C(=O)NC(C)C)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
Potassium carbonate (0.62 g, 4.5 mmol) and isopropyl isocyanate (0.26 g, 3.0 mmol) were added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4,5-dimethylpyrazole (0.88 g, 3.0 mmol) in DMF (10 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-isopropyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-4,5-dimethylpyrazole-1-carboxamide (0.55 g, yield: 48.7%) mp: 78-80° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.24 (d, J=6.6 Hz, 6H), 1.78 (s, 3H), 2.58 (s, 3H), 3.95-4.15 (m, 1H), 6.70-6.95 (m, 1H), 8.02 (d, J=2.1 Hz, 1H), 8.32 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]#[N:11])=[C:4]([S:12][CH3:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([S:12]([CH3:13])=[O:22])[C:5]([C:10]#[N:11])=[C:6]([S:8][CH3:9])[N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(N)nc(SC)c1C#N
Solvent: ClCCl
Product: CSc1nc(N)nc(S(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4,6-bis-methylsulfanyl-pyrimidine-5-carbonitrile (7:212 mg, 1 mmol, 1.0 eq.), m-chloroperbenzoic acid (2 mmol), and dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 1 hr. The precipitate was filtered and gave to white solid. No further purification was necessary (282 mg). LC-MS: (ES+) m/z 229 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 2.85 (s, 3H), 2.47 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[F:21][C:22]([F:38])([F:37])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)=[CH:26][CH:25]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:38])([F:37])[F:21])=[CH:29][CH:28]=2)[CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: FC(F)(F)Oc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(OC(F)(F)F)cc2)[C@@H]1O
Yield: 47.3 %

Procedure:
The title compound (181 mg, 47%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (200 mg, 0.71 mmol) and 4-trifluoromethoxyphenyl-1H-imidazol-2-ylmethylamine (183 mg, 0.71 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[N:7]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].CC(O)C>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc3ccc(Cl)nn3c2C)cc1NC(=O)C(C)(C)C
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-c2nc3ccc(-c4ccccc4F)nn3c2C)cc1NC(=O)C(C)(C)C
Temperature: 80 °C
Yield: 62.6 %

Procedure:
To a mixture of N-(5-(6-chloro-3-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (0.100 g, 0.280 mmol), 4-fluorophenylboronic acid (0.420 mmol), Na2CO3 (0.840 mmol), 2-propanol (9 mL) and water (3 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0280). The mixture is heated at 80° C. for 12 hours, diluted with sat. aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×25 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of hexanes to EtOAc to afford the title compound (0.073 g, 62%) as a yellow solid: Rf 0.29 (1:1 EtOAc:hexanes); LCMS (m/z)=417.5 [M+H]+, tR=2.71 min. (compound same as Example 312)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([C:14]2([CH3:21])[O:20][CH:15]2[C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[O:7]([C:14]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:21])[CH:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Reactant: Oc1ccccc1
Product: COC(=O)C(O)C(C)(Oc1ccccc1)c1ccccc1

Procedure:
28.2 g (0.3 mol) of phenol and 19.2 g (0.1 mol) of methyl 3-phenyl-2,3-epoxybutyrate are heated together for 6 hours at 100° C. After the excess phenol has been distilled off under greatly reduced pressure and the residue has been purified by chromatography over silica gel using a hexane/ethyl acetate mixture, 17.9 g of a slightly yellow oil are obtained.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f4) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][OH:22])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([CH2:20][CH2:21][O:22][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CC[C@@H](CCO)CCCCOCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CC[C@H](CCCCOCc1ccccc1)CCOc1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl (S)-8-(benzyloxy)-4-(2-hydroxyethyl)octanoate (1.61 g, 5.2 mmol) in methylene chloride (20 ml) is added 3-hydroxypyridine (0.51 g, 5.4 mmol) and triphenylphosphine (1.82 g, 7 mmol). The mixture is stirred at room temperature for 10 minutes and then diisopropyl azodicarboxylate (1.05 ml, 5.3 mmol) is added slowly. The mixture is allowed to stir for 2 hours and the solvent is evaporated. The residue is purified by flash chromatography on silica gel using 1:1 ethyl acetate/hexane as eluent to obtain methyl (S)-8-(benzyloxy)-4-[2-(3-pyridyloxy)ethyl]octanoate; IR (CH2CL2): 1732, 1280, 1230, 1102 cm-1.
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.N[C@@H](CCN1CC([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)C1)CO>>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:26][CH2:27]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:43][CH:44]=1
Reactant: N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1
Reactant: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Product: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1

Procedure:
This compound is prepared in a manner analogous to that used to prepare 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 83 except using (S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:29]4[CH:30]=[CH:31][C:32]([N:35]5[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]5)=[N:33][CH:34]=4)=[C:14]([C:16](=[O:28])[NH:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:29]4[CH:34]=[N:33][C:32]([N:35]5[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]5)=[CH:31][CH:30]=4)=[C:14]([C:16]([NH:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[O:28])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3c(C(=O)Nc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2ccccc2n1)c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 20d (191 mg, 0.300 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added. Once the solution was homogeneous, TFA (1 mL) was added dropwise. The mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in DCM (10 mL) and then the solvent was removed under reduced pressure again. The residue was triturated with Et2O (20 mL), resulting in a yellow precipitate, which was isolated by filtration and washed with Et2O (2×10 mL). The residual solvent was removed under reduced pressure to afford the title compound 3. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 10.35 (s, 1H), 8.78 (br. s., 2H), 8.50 (d, J=2.2 Hz, 1H), 8.41 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.21 (d, J=5.9 Hz, 1H), 7.92-8.00 (m, 2H), 7.89 (d, J=8.6 Hz, 1H), 7.70-7.79 (m, 1H), 7.48-7.58 (m, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.50 (d, J=5.9 Hz, 1H), 4.04-4.16 (m, 4H), 3.80-3.91 (m, 8H), 3.20-3.29 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H29N9O2: 536.3 (M+H). Found: 536.3.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:15]3[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:5][CH2:4]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C1COCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:14]1[N:15]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:4][CH2:5]1)[N:19]=[CH:18][N:17]=2
Reactant: NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of N-{[4-(aminomethyl)cyclohexyl]methyl}-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-amine (6 mg, 0.013 mmol, 1 eq.) in 5 mL of THF was added methanesulfonyl chloride (0.02 mL) and triethylamine (0.05 mL) The reaction was stirred at room temperature 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 5 mg (71%) of N-{[4-({[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}methyl)cyclohexyl]methyl}methanesulfonamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-1.16 (m, 2 H) 1.33-1.75 (m, 6 H) 1.77-2.02 (m, 2 H) 2.84-3.00 (m, 4 H) 3.00-3.16 (m, 1 μl) 3.43-3.80 (m, 2 H) 4.40-4.63 (m, 1 H) 5.89-6.18 (m, 1 H) 7.08-7.60 (m, 8 H) 8.44 (s, 1H), [M+H]+ 559.6.
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[NH:8][CH:7]=[CH:6][S:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].O>O1CCCC1>[CH:1]([CH:4]1[C:9](=[O:10])[N:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:6][S:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1SC=CNC1=O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CN1C=CSC(C(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (2RS)-2-isopropyl-3,4-dihydro-2H-1,4-thiazin-3-one (70 mg, Reference compound No. 42-1) in anhydrous tetrahydrofuran (1 ml) is added to a solution of sodium hydride (39 mg) in anhydrous tetrahydrofuran (1 ml) under ice cooling, and the mixture is stirred for 10 minutes. Methyl bromoacetate (74.3 mg) is added to the mixture, the temperature is raised to room temperature, and the whole is stirred for 20 minutes. The reaction mixture is cooled with ice, water is added to the mixture, and the whole is extracted with ethyl acetate. The extract is washed with 1 N hydrochloric acid, water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (90.2 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([O:22]C)=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C)cnc(Cn2nc3cc(CC(=O)O)c4c-3c(n2)C(NC(=O)OC(C)(C)C)=NSC4)c1C
Yield: 97 %

Procedure:
A mixture composed of methyl {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetate of Example 111 (218 mg), methanol (8 ml) and a 1 N sodium hydroxide solution (0.22 ml) was stirred at room temperature for eight hours. A 1 N hydrochloric acid solution (2.5 ml) was added dropwise to the reaction mixture under ice-cooling, and methanol in the reaction mixture was evaporated under reduced pressure. A 0.5 N hydrochloric acid solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was concentrated to dryness under reduced pressure to obtain the title compound (173 mg, 97%) as an amorphous.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[N:2]1.[Cl:9][C:10]1[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=1[CH:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15].N1CCCCC1>CCO>[NH2:17][C:16]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]([C:7]#[N:8])=[C:12]([C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[Cl:9])[C:13]=1[C:14]#[N:15]
Reactant: N#CCc1cc[nH]n1
Reactant: N#CC(C#N)=Cc1ccccc1Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1c(-c2ccccc2Cl)c(C#N)c2ccnn2c1N
Yield: 14.5 %

Procedure:
To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (1.56 g, 14.5 mM) from Preparative Example 3 Step C in absolute EtOH (73 mL) at 25° C. was added o-chlorobenzylidene malononitrile (2.74 g, 14.5 mM) and piperidine (0.14 mL, 1.45 mM). The mixture then refluxed for 1.75 hr. The solvent evaporated. Chromatography on silica gel (30×5 cm) with CH2Cl2 afforded 7-Amino-5-(2-chloro-phenyl)-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (0.62 g, 15%). HRMS: m/z 293.0472 (M+), Calcd. C15H8N5Cl1: m/z 293.0468; δC (CDCl3) CH: 99.3, 127.6, 129.6, 130.8, 131.6, 145.5; C: 75.7, 86.9, 114.8, 115.1, 131.5, 133.8, 138.4, 145.6, 149.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O1CCCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
28.3 g (0.10 mol) of p-bromoiodobenzene, 10.2 g (0.10 mol) of phenylacetylene, 701 mg (1 mmol) of bis(triphenylphosphine)palladium(II)dichloride, and 190 mg (1 mmol) of copper (I) iodide were placed in a 1000-mL three-neck flask, and nitrogen substitution was carried out. Then, 350 mL of tetrahydrofuran and 18 mL of triethylamine were added thereto, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction mixture was washed with a 3% hydrochloric acid aqueous solution, and the aqueous phase was extracted with ethyl acetate. The extracted solution combined with the organic phase was washed with brine and dried with magnesium sulfate. The mixture was filtered through celite, florisil, and alumina, and a solid obtained by the concentration of the filtrate was recrystallized with hexane to give 15 g of a solid that was the target substrate in the yield of 58%.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[CH3:20][O:21][CH2:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>>[CH3:20][O:21][CH2:22][C:23]1[N:24]=[C:25]([NH:28][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[S:26][CH:27]=1
Reactant: COCc1csc(N)n1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Product: COCc1csc(NC(=O)c2cc(-c3cncc(F)c3)cc(C)n2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Methoxymethyl-thiazol-2-ylamine instead of 3-Chloroaniline to yield the final compound as a off-white solid, MS (ISP): m/e=359.1 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]1[C:10]2[C:5](=CC=CC=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.O[CH:24]1[C:32]2C(=NC=C[N:31]=2)C(=O)[N:25]1C1C=CC2C(=NC(OC)=CC=2)N=1.S(Cl)(Cl)=O>CN(C)C=O>[Cl:1][CH:2]1[C:10]2[C:5](=[N:25][CH:24]=[CH:32][N:31]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: COc1ccc2ccc(N3C(=O)c4nccnc4C3O)nc2n1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2nccnc2C(Cl)N1c1ccc2ccc(Cl)nc2n1

Procedure:
5-Chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazine is prepared in a manner similar to that described in Example 6 for the preparation of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone, but starting with 5-hydroxy-6-(7-methoxy-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (23.2 g), sulphinyl chloride (300 cc) and dimethylformamide (1 cc). 5-Chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]-pyrazine (21 g ) m.p. 264° C., is thereby obtained.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][C@H:11]2[C:16]([OH:18])=[O:17])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:20]1([CH:26](O)[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]1([CH:26]([O:17][C:16]([C@@H:11]2[CH2:12][S:13][CH2:14][CH2:15][N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:19])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[O:18])[CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OC(CCc1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCSC[C@H]2C(=O)OC(CCc2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
0.301 g (1 mmol) of (3R)-4-(4-toluenesulfonyl)thiomorpholine-3-carboxylic acid, 0.318 g (1.5 mmol) of (1,3-diphenyl)-propanol, 0.088 g (0.33 mmol) of CAS, 0.227 g (1.2 mmol) of DCC and 0.04 g (0.33 mmol) of DMAP were dissolved in 15 mL of CH2Cl2. The mixture was stirred for 24 h at room temperature. The solid was filtrated and the solvent was evaporated. The residual was dissolved in a suitable amount of ethyl acetate (20 ml) and then the mixture was filtered to remove insoluble substance. The ethyl acetate was added to 60 ml and then the liquid was washed with 10% NaHCO3 solution, saturated NaCl solution and dried over Na2SO4. After the drying agent was removed and part of ethyl acetate was evaporated, the crude product was purified by flash column chromatography (eluent: ethyl acetate:cyclohexane=1:3) to obtain the product as a oil (0.15 g). 1H-NMR (400 MHz, CDCl3): δ 7.5040(d, 2H, J=8.32 Hz), 7.3751-7.0634 (m, 12H), 5.7186-5.6846 (m, 1H), 5.0645 (t, 1H, J=3.42 Hz), 4.0136-3.9800 (m, 1H), 3.4760-3.4052 (m, 1H), 3.1031-3.0773 (m, 2H), 2.8562-2.7914 (m, 1H), 2.6613-2.5414 (m, 2H), 2.4304-2.3855 (m, 1H), 2.3333 (s, 3H), 2.2283-2.2041 (m, 1H), 2.0565-2.0328 (m, 1H); MS (EI) m/z: 495.8, 449.8, 391.8, 339.8, 299.7, 255.7, 193.8, 154.8, 138.8, 116.9, 90.8, 64.9.