Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:39]([O:38][C:36](=[O:37])[C:28]1[CH:29]=[C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:25])[C:10]([C:16]3[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)([OH:15])[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)[CH:31]=[CH:32][C:27]=1[Cl:26])[CH3:40]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1Cl

Procedure:
In analogy to Example 151, step 8, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid, copper-(II)-acetate and pyridine to give the title compound as an off-white solid. MS (m/e)=558.2 [M+H+].
Reaction SMILES: [CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:39]([O:43]C=C)[CH:40](C)C.C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([N:4]([CH:29]([CH3:31])[CH3:30])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([C:39](=[O:43])[CH3:40])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=COCC(C)C
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(OCc2ccccc2)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanamine (Example 12) (10.2 g, 21.23 mmol) in DMF (100 mL) under nitrogen atmosphere at room temperature were sequentially added triethylamine (2.58 g, 25.47 mmol), TlOAc (6.15 g, 23.35 mmol), isobutylvinylether (14 mL, 106.14 mmol), DPPP (0.87 g, 2.12 mmol) and Pd(OAc)2 (0.24 g, 1.06 mmol). The reaction temperature was raised to 100° C. and stirred for 3 hours, cooled to room temperature, filtered and treated with HCl (5%, 250 mL) and stirred for another 2 hours. The reaction mixture was repeatedly extracted with dichloromethane and the combined organic layers were dried (MgSO4), filtered and the solvent evaporated. Triethylamine and DMF were destined off under reduced pressure to yield 9 g (98%); 1H NMR (CDCl3) δ1.22 (m, 12H), 2.52-2.70 (m, 7H), 3.40 (br, 2H), 4.34 (t, 1H), 5.10 (s, 1H), 6.90 (d, 1H), 7.17-7.40 (m, 10H), 7.82 (m, 1H) and 7.92 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][C:25]1[N:20]2[CH:21]([CH3:40])[C:22](=[O:39])[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:24]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:17]2[CH:18]=[C:19]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][C:25]2[N:20]3[CH:21]([CH3:40])[C:22](=[O:39])[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[N:24]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N4C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]4C)cc3N21
Temperature: 100 °C
Yield: 19.1 %

Procedure:
A mixture of (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 7.00 mmol), 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step E, 1.990 g, 4.67 mmol), Pd(OAc)2 (0.210 g, 0.933 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisoproplylbiphenyl (0.667 g, 1.400 mmol) and t-BuONa (0.897 g, 9.33 mmol) in toluene (120 mL) was heated at 100° C. for 3 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-50% EtOAc in petroleum ether) to give (2S,5R)-2,5-dimethyl-4-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.5 g, 19%) as a solid. LC/MS (Table 1, Method 25) Rt=1.072 min.; MS m/z: 560 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:41][N:42]([CH2:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1)[CH3:43]>ClCCl>[CH3:43][N:42]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([NH:49][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:30])=[CH:50][CH:51]=1)[CH3:41]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)Cc1ccc(NC(=O)C2NC(CC(C)(C)C)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)cc1
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred solution of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (60 mg, 0.128 mmol) in dichloromethane (5.00 ml) were added N,N-DIISOPROPYLETHYLAMINE (100 mg) and 4-((dimethylamino)methyl)aniline (29.8 mg, 0.198 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (90.3 mg, 0.237 mmol, Chem-Impex) and the reaction mixture was stirred for 1 hr. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (2×15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 4% to 50% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-dimethylaminomethyl-phenyl)-amide as white solid (54.1 mg, 70%). MS (ES+) m/z Calcd: [(M+H)+]: 599. found: 599.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][CH3:36])[C:25]=3[CH3:37])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])O2)=[C:6]1[CH3:38])[CH2:2][CH2:3][CH3:4].C(O)C.O.[NH2:43][NH2:44]>O>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]([CH2:33][CH2:34][CH2:35][CH3:36])[C:25]=3[CH3:37])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16](=[O:17])[NH:44][NH:43]2)=[C:6]1[CH3:38])[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCn1c(C)c(C2(c3c(C)n(CCCC)c4ccccc34)OC(=O)c3ccccc32)c2ccccc21
Solvent: O
Solvent: CCO
Product: CCCCn1c(C)c(C2(c3c(C)n(CCCC)c4ccccc34)NNC(=O)c3ccccc32)c2ccccc21
Yield: 92 %

Procedure:
With stirring, a mixture of 25.0 g of 3,3-bis(1-butyl-2-methylindol-3-yl)phthalide, 800.0 ml of ethyl alcohol, 200.0 ml of water and 29.4 g of 85 percent hydrazine hydrate was maintained at reflux temperature for approximately forty-eight hours. The resulting mixture was chilled in an external ice bath to a temperature in the range of 0°-5° C. The solid was collected by filtration, washed with chilled ethyl alcohol and dried in an air oven to obtain 23.65 g of 4,4-bis(1-butyl-2-methylindol-3-yl)-phthalazin-1(2H)-one (Formula V: R=R1 =R8 =R14 =H; R6 =R12 =C4H9 ; R7 =R13 =CH3), a pale orange-colored solid which melted at 205.5°-206.5° C. In the infrared spectrum maxima appeared at 3400 cm-1 (N-H;w) and 1670 cm-1 (C=O;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. Paper treated with an ink formulation of the product produced a purple-colored image when traced with an applied voltage stylus.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.[C:10](=O)([O:19]N1C(=O)CCC1=O)[O:11][N:12]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]1=[O:18]>>[O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([O:11][N:12]2[C:16](=[O:17])[CH2:15][CH2:14][C:13]2=[O:18])=[O:19])[CH2:2]1
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Product: O=C(O[C@H]1CO[C@H]2OCC[C@H]21)ON1C(=O)CCC1=O

Procedure:
In particular, when the (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is processed with disuccinimidyl carbonate, 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione is obtained. Said compound is a preferred (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivate.
Reaction SMILES: N1CCCCC1.C1C2C(COC([N:24]3[CH2:29][CH2:28][S:27][CH2:26][C@H:25]3[C:30](=[O:49])[NH:31][CH2:32][C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)C3C(=CC=CC=3)C=2C=CC=1>C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[NH:41][CH2:40][C:34]1[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:33]=1[CH2:32][NH:31][C:30]([C@@H:25]1[CH2:26][S:27][CH2:28][CH2:29][NH:24]1)=[O:49])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CSCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CSCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Piperidine (0.95 mL, 9.65 mmol) was added dropwise to a stirred solution of (R)-(9H-Fluoren-9-yl)methyl-3-[2-{(tert-butoxycarbonylamino)methyl}-5-chloro benzylcarbamoyl]thiomorpholine-4-carboxylate (1.20 g, 1.93 mmol) in CH2Cl2 (50 mL) and the resulting mixture was stirred at room temperature for 2 h. Volatile solvent was removed under reduced pressure and the residue was purified by reverse phase combiflash column chromatography (C18; eluent: 10-100% acetonitrile:water) to afford the title compound (0.64 g) as a white solid.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O1CCCC1.C(O)C>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:20][CH2:19]1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(C2c3ccccc3-c3[nH]c(=O)c(=O)[nH]c32)CC1
Reaction time: 20 h
Yield: 38.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (1.50 g, 6.39 mmol) was suspended in 15 ml of dry tetrahydrofuran, while cooling in an ice bath. N-Methylpiperazine (1.42 ml, 12.78 mmol) dissolved in 3 ml of dry tetrahydrofuran was added over 20 min, and the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran and dried to give 2.42 g of a remanence, which was dissolved in 100 ml of boiling ethanol, and treated with 300 mg of activated carbon. The mixture was filtered and concentrated to 10 ml. The precipitate was filtered off, washed with ethanol and dried to give 0.65 g of the crude product. From the filtrate another crop of 0.57 g could be isolated. Recrystallization from 6M HCl afforded 0.73 g (30%) of the title compound as a dihydrochloride. M.p. 263°-265° C. 1H-NMR (DMSO-d6, δ): 2.6 (m, 1H), 2.73 (s, 3H), 2.78-3.52 (m, 7H), 4.84 (s, 1H), 5.9-7.0 (broad, 2H), 7.2 (t, 1H), 7.35 (t, 1H), 7.48 (d, 1H), 7.58 (d, 1H), 10.92 (s, 1H), 11.76 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of 3-bromo-5-(trifluoromethyl)aniline (14.00 g, 58 mmol), hexane-2,5-dione (7.05 mL, 60 mmol) and p-toluenesulfonic acid monohydrate (220 mg, 1.2 mmol) in toluene (250 mL) was heated under Dean-Stark conditions. After 1 h, the reaction mixture was concentrated. The residue was purified by column chromatography to give 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (18.15 g, 98%) as orange oil. LCMS: (FA) ES+ 318.1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)O
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CO/C(=C\C=C\c1cc2ccccc2s1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 26.6 %

Procedure:
A solution of (2Z,4E)-5-(benzothiophen-2-yl)-2-methoxy-2,4-pentadienoic acid (53 mg, 0.20 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (34 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole hydrate (27 mg, 0.20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (38 mg, 0.20 mmol) in DMF (1 ml) was stirred at RT for 6 hours. After the same work up as seen in example 3 pure title compound was obtained (22 mg, 0.054 mmol, yield 26.6%) as white crystals, m.p.=240°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[CH3:34][CH:35]([CH3:39])[C:36](Cl)=[O:37].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:36](=[O:37])[CH:35]([CH3:39])[CH3:34])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: CC(C)C(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.16 g, 0.33 mmol) produced in Example C71(iv) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise 2-methylpropanoyl chloride (0.12 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (114 mg, 63%) as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]([C:18]#[N:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH:6]=[C:5]([C:18]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:19]=2)[N:4]=1)#[N:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)CCc1cc(C#N)nc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cc(C#N)nc(-c2nc(=O)c3ccccc3s2)c1
Yield: 36.5 %

Procedure:
tert-Butyl 3-(2,6-dicyano-4-pyridyl)propanoate (1.4 g, 5.5 mmol) and methyl thiosalicylate (1.7 g, 10.1 mmol) were dissolved in toluene (10 ml), and triethylamine (5.0 ml, 35.8 mmol) was added thereto. The mixture was refluxed for 3 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:3, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.79 g, 36%) as white crystals.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[CH:12]1(CC(Cl)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N>C(Cl)Cl.C(C(C)=O)C>[CH:12]1([CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: COC(=O)CC(C)=O
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: COC(=O)CC(=O)CC1CCCCC1
Yield: 98.9 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 176.7 g (1.1 mol) of cyclohexylacetyl chloride. The subsequent reaction time after the ammonia had been metered in was 6 hours at a pH of 9.5. This gave 196 g (GC purity 75.0%) of methyl 4-cyclohexylacetoacetate (yield 74.5%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[CH:14]=[CH:13]2)[CH2:11][CH2:10]1.[I:21]N1C(=O)CCC1=O>CN(C=O)C>[I:21][C:14]1[C:15]2[CH:20]=[N:19][CH:18]=[N:17][C:16]=2[N:12]([C:9]2([CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:11][CH2:10]2)[CH:13]=1
Reactant: c1ncc2ccn(C3(COC4CCCCO4)CC3)c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Ic1cn(C2(COC3CCCCO3)CC2)c2ncncc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a stirred solution of 7-[1-(Tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine (Preparation 248, 390 mg, 1.43 mmol) in DMF (8 mL) was added N-iodosuccinimide (481.5 mg, 2.14 mmol) and stirred at room temperature for 4 hours. The reaction mixture was quenched with water (8 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water (5×15 mL), brine (10 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 99:1) to afford the title compound as a solid in 79% yield, 450 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.S(Cl)([Cl:15])=O>CN(C=O)C>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(F)cc12
Solvent: CN(C)C=O
Product: Fc1ccc2ncnc(Cl)c2c1

Procedure:
6-Fluoro-3,4-dihydroquinazolin-4-one (1.0 g) was suspended in a mixture of thionyl chloride (10 ml) and DMF (1to 2 drops). The mixture was heated to reflux for 2 to 3 hours and allowed to cool. Solvent was removed by evaporation and the residue was dried under vacuum to give 4-chloro-6-fluoroquinazoline which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[N:22][NH:23]2)=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([NH:16][C:2]3[C:11]4[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])[CH:25]=2)[CH:21]=[N:22]1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: Nc1ccc2cn[nH]c2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cccc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 141, 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 219.7 mg (1.65 mmol) of 6-aminoindazole and 105.6 mg (173.3 mmol) of pyridine hydrochloride in 15 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. The work up gave 373.8 mg (79%) of the product as a yellow solid, m.p. 242° C. (dec.), mass (electrospray, m/e): M+H 315.9. HRCIMS: calcd 315.112 for C18H13N5O (M+), obsd 315.1126.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20].C(=O)(O)O>ClCCl>[C:18]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1csc(N)n1
Agent: O=C(O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(NC(=O)C(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold mixture of ethyl 2-amino-1,3-thiazole-4-carboxylate (2 g) prepared in a similar manner according to Step 1 of the following Production Example 7, pyridine (1.3 ml) and dichloromethane (20 ml) was added isobutyryl chloride (0.91 ml) and stirred for 30 minutes. To the mixture was added saturated aqueous hydrogen bicarbonate (30 ml), and the organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crystalline residue was collected and washed with ethyl acetate to give ethyl 2-(isobutyrylamino)-1,3-thiazole-4-carboxylate (1.34 g).