Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1.[C:17](=S)=[S:18]>>[N:6]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1)=[C:17]=[S:18]
Reactant: CCOC(=O)N1CCC(N)C1
Reactant: S=C=S
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(N=C=S)C1
Temperature: -10 °C
Yield: 99.8 %

Procedure:
(a-3) To a stirred and cooled (10° C.) mixture of 37 parts of N,N-methane-tetraylbis[cyclohexanamine] and 594 parts of tetrahydrofuran were added 91.2 parts of carbon disulfide. After cooling to -10° C., 27.5 parts of ethyl 3-aminopyrrolidinecarboxylate were added during a period of 5 minutes (exothermic reaction). The reaction mixture was allowed to reach room temperature and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 32 parts (99.8%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate as a residue (interm. 6).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.C[O-].[Na+].[C:16](O)(=[O:18])C>C(OCC)C>[Cl:12][C:4]1[N:3]=[C:2]([O:18][CH3:16])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH2:11])[CH:5]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1nc(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
2,6-Dichloro-3-nitro-pyridin-4-ylamine (733 mg, 3.52 mmol) was placed in a 48 mL pressure vessel fitted with a magnetic stir bar and treated with NaOMe (7.05 mL, 3.52 mmol, 0.5 M in MeOH). The vessel was sealed and heated to 100° C. for 2 h. The cooled mixture was treated with acetic acid (0.25 mL) in diethyl ether (50 mL). The precipitate was filtered and washed with ether, and the filtrate was concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 35 SPE column (Flow rate=25 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, then 1:19 to 1:4 over 40 min) to yield 6-chloro-2-methoxy-3-nitro-pyridin-4-ylamine as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 6.36 (s, 1H), 6.14 (br. s., 2H), 4.04 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([C:10]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:11]=1[F:27])=[N+:30]=[N-:31]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.64 g, 31.36 mmol) in DMF (30 mL) was added NaN3 (2.45 g, 37.63 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 10.38 g, 78% yield). 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.66 (s, 1H), 7.27-7.12 (m, 3H), 7.10-6.80 (m, 6H), 3.98 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][NH:24][CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:18][CH:19]2[CH2:26][CH:22]3[CH2:23][N:24]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:25][CH:21]3[CH2:20]2)=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([CH:15]3[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CNCC3C2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(C2CC2)cc1Nc1ncc(Cl)c(NC2CC3CN(C(=O)CC#N)CC3C2)n1
Temperature: 45 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of 5-chloro-N2-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (251.7 mg, 0.67 mmol) and 2-cyanoacetic acid (107.2 mg, 1.26 mmol) in a mixture of DCM (20 mL) and DMF (5 mL) were added EDCI (292.5 mg, 1.51 mmol) and HOAT (205.3 mg, 1.51 mmol). After addition, the reaction mixture was stirred at 45° C. for 1 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) to give the title compound as a beige solid (169.4 mg, 57.1%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17](F)[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[NH3:27]>CO>[C:1]([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH2:27])[C:16]=1[N+:23]([O-:25])=[O:24])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(N)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
To the crude 2-(3,5-Difluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester (62 g, 0.42 mol) was added 700 mL of 2M ammonia in methanol in a pressure bottle. The vessel was sealed and heated to 85° C. for 18 hours. The reaction mixture was cooled and the vessel opened carefully and the methanol solution concentrated to provide 140 g of crude material. LCMS [M+Na]−393; 1H NMR (500 MHz, DMSO) δ 6.76 (dd, J=10.8 2.8 Hz, 1H), 6.29 (dd, J=10.8, 2.8 Hz, 1H), 4.99 (brs, 2H), 4.80 (s, 1H), 140 (m, 18H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:24][CH3:25])=[CH:12][C:13]2[O:18][C:17](=[O:19])[C:16]3[CH2:20][CH2:21][CH2:22][C:15]=3[C:14]=2[CH:23]=1)(=O)=O.[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]1[CH2:35][CH2:36][N:37]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[C:11]([O:24][CH3:25])=[CH:12][C:13]3[O:18][C:17](=[O:19])[C:16]4[CH2:20][CH2:21][CH2:22][C:15]=4[C:14]=3[CH:23]=2)[CH2:38][CH2:39]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCOS(C)(=O)=O)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2cccc(C)c2C)CC1)CCC3
Yield: 84 %

Procedure:
Method B (20 h at 60° C.); starting materials: 2,3-dihydro-8-[3-(methanesulfonyloxy)propoxy]-7-methoxy-cyclopenta[c][1]-benzopyran-4(1H)-one (example 82) and 1-(2,3-dimethylphenyl)-piperazine; yield 84%; fusion point 164°-166° C. (from ethanol). Fumarate: method E; yield 94%; fusion point 235°-237° C. (from acetone).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][Si:9](Cl)([CH3:11])[CH3:10].C(N(CC)CC)C>CCOCC>[CH3:8][Si:9]([CH3:11])([CH3:10])[S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CS
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)CS[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of ethyl mercaptoacetate (9.0 mL, 83.2 mmol) in 15 mL of anhydrous ether under nitrogen atmosphere was added trimethylsilyl chloride (12.0 mL, 94.6 mmol) followed by triethyl amine (13.0 mL, 93.3 mmol) slowly. White precipitates were formed upon addition of triethyl amine. The suspension was allowed to stir at room temperature overnight. The white precipitate was removed by filtration. The filtrate was concentrated on a rotavap. The residue oil was distilled at 40° C. (0.5 mm Hg) to give 10.9 g (68%) of ethyl (trimethylsilylthio)acetate as a colorless oil. 1HNMR (300 MHz, CDCl3) δ4.18 (2H, q, J=7.19 Hz), 3.20 (2H, s), 1.29 (3H, t, J=7.12 Hz), 0.35 (9H, s).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: CN1CCOCC1.[C:8]1([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Temperature: -25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
N-Methylmorpholine (3.4 ml) and 4-phenylbutyric acid (5.02 g) were added to L-proline benzyl ester hydrochloride (7.37 g) in dichloromethane (80 ml) under ice-cooling. The mixture was cooled to -25° C., added with DCC (6.31 g) and stirred at room temperature for 16 hours. The resultant dicyclohexylurea was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 9.42 g of N-(4-phenylbutyryl)-L-proline benzyl ester.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=O.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].S(=O)(O)[O-].[Na+]>C(O)C.O>[N:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:21][C:1]=1[C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=Cc1c2cccccc-2[nH]c1=O
Reactant: Nc1ccccc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c2cccccc-2c1-c1nc2ccccc2[nH]1
Yield: 32.9 %

Procedure:
3-Formyl-1-azaazulen-2-one (0.1 mmol) was dissolved in a mixture of 10 mL ethanol and 5 mL water. o-Phenylenediamine (0.15 mmol) and sodium bisulfite (0.2 mmol) were then added and heat to reflux for 1 day. After working up, the residue was then purified by column chromatography to give 8.6 mg of A1, yield 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:27])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([NH2:38])=[O:37]>CC(C)=O>[C:36]([CH2:35][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[CH:8][C:7]=1[C:6]1[N:5]([CH3:27])[N:4]=[CH:3][C:2]=1[Cl:1])(=[O:37])[NH2:38]
Reactant: NC(=O)CBr
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(N)=O
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a mixture of N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (51 mg, 0.13 mmol) and potassium carbonate (27 mg, 0.20 mmol) in acetone (1 mL) was added 2-bromoacetamide (27 mg, 0.20 mmol). The resultant mixture was heated to 65° C. for 1 hour. Cooled to room temperature and partitioned between EtOAc and water. Layers were separated. The organic layer was washed with water (2×) and brine, dried (MgSO4) and reduced to give the title compound as a white solid (49 mg, 83%). LCMS m/z (%)=453 (M+H 35Cl, 100), 455 (M+H 37Cl, 30). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H), 4.46-4.61 (m, 2H), 7.09 (d, J=9.09 Hz, 1H), 7.24 (s, 1H), 7.38 (s, 1H), 7.65 (s, 1H), 7.72 (d, J=2.78 Hz, 1H), 7.73-7.84 (m, 1H), 7.87 (dd, J=8.97, 2.65 Hz, 1H), 7.97 (d, J=6.57 Hz, 1H), 8.21-8.36 (m, 2H), 10.53 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:26])[C@@H:13]3[C@H:16]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:17])[C:10]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:6]=[CH:7][CH:8]=1.C(N(CC)C(C)C)(C)C.[CH3:42][N:43]=[C:44]=[O:45]>ClCCl>[CH3:42][NH:43][C:44]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:26])[C@@H:13]3[C@H:16]([O:18][Si:19]([CH2:20][CH3:21])([CH2:24][CH3:25])[CH2:22][CH3:23])[CH3:17])[C:10]=2[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH:6]=[CH:7][CH:8]=1)=[O:45]
Reactant: C=CCOC(=O)C1=C(c2cccc(CO)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Reactant: CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(c2cccc(COC(=O)NC)c2)C[C@@H]2[C@@H]([C@@H](C)O[Si](CC)(CC)CC)C(=O)N12
Reaction time: 24 h
Yield: 43.4 %

Procedure:
Allyl (5R,6S)-3-[3-(hydroxymethyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (250 mg) prepared in the above step, was dissolved in dichloromethane (10 ml), and thereto were added N,N-diisopropylethylamine (14 mg) and methyl isocyanate (276 mg). The mixture was stirred for 1 day, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform) to give allyl (5R,6S)-3-[3-({[(methylamino)carbonyl]oxy}methyl)phenyl]-7-oxo-6-{(1R)-1-[(triethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (122 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25](O)=[O:26])=[N:10]2)=[CH:5][CH:4]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].O>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[O:26])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)NCCN(C)C)nc2n1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
N,N'-Carbonyldiimidazole (1.8 g) is added at a temperature in the region of 25° C. to a solution of [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (4 g) in anhydrous dimethylformamide (85 cc), and the mixture is stirred for 2 hours at this temperature. 2-Dimethylaminoethylamine (0.7 g) is then added and the mixture is stirred for 18 hours at this same temperature. The reaction mixture is then poured into water (200 cc) and extracted with methylene chloride (3×200 cc). The organic extracts are washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is crystallized by stirring in ethyl ether. [2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-(2-dimethylamino ethyl)acetamide (3.5 g), m.p. 146° C., is thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([F:23])([F:22])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][N:27]([CH3:32])[C:28](=[O:31])[CH2:29]Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]([F:22])([F:23])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=1)[CH2:29][C:28]([N:27]([CH3:32])[CH3:26])=[O:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)CCl
Reactant: CCCCOc1cccc(C(F)(F)CNC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C(F)(F)CN(CC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
150 mg (0.46 mmol) of N-(tert-butoxycarbonyl)-2,2-difluoro-2-(3-butoxyphenyl)ethylamine are dissolved in dry DMF (2.5 mL) and the solution was cooled to 0° C. NaH (60% in mineral oil; 22 mg; 0.55 mmol) is added and the reaction mixture stirred for 10 minutes at 0° C. and for further 10 minutes at room temperature. The reaction mixture is cooled again at 0° C., then N,N-dimethylchloroacetamide (73 mg; 0.60 mmol) is added and stirring is continued for 24 hours at room temperature. The reaction is quenched with water, extracted three times with EtAc, washed with brine. The organic phases are dried over anhydrous Na2SO4, filtered and evaporated. The residue is flash-chromatographed on silica gel (eluant: DCM/EtAc, from 98/2 to 95/5). 2-[N′-(tert-butoxycarbonyl)-2,2-difluoro-2-(3-butoxyphenyl)-ethylamino]-N,N-dimethyl-acetamide (165 mg; 87%) is obtained as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([OH:6])[CH3:5].[Br:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[C:10]([Br:15])[CH:9]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:7][C:8]1[CH:13]=[C:12]([O:6][CH:4]([CH3:5])[CH3:3])[CH:11]=[C:10]([Br:15])[CH:9]=1
Reactant: CC(C)O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(Br)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of NaH 60% dispersion in mineral oil (1.89 g, 47.25 mmol) in dry DMF (20 mL) under inert atmosphere was added dropwise at 0° C. i-PrOH (3.62 mL, 47.25 mmol). The mixture was stirred at 0° C. for 15 min. Then, a solution of 1,3-dibromo-5-fluoro-benzene (1.98 mL, 15.75 mmol) in dry DMF (20 mL) was added dropwise at 0° C. The reaction mixture was stirred for 16 h at room temperature. A saturated solution of NaHCO3 was added dropwise and the crude product was extracted with Et2O (2 times), the organic layer was washed with a saturated solution of NaHCO3 (3 times), then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give I-a as yellow oil in quantitative yield. 1H RMN (300 MHz, CDCl3) δ 7.21 (t, J=1.4 Hz, 1H), 6.97 (d, J=1.5 Hz, 2H), 4.61-4.40 (m, 1H), 1.32 (d, J=6.0 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[CH3:39])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CN
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: Cc1ccccc1CNC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and o-methylbenzylamine.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[CH:18][N:19]=[C:4]2[N:3]=1.C(N(CC)CC)C.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([C:28]([F:27])([F:36])[F:37])[CH:30]=4)=[N:3][C:4]4[N:5]([N:17]=[CH:18][N:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: CCn1ncc2c1ncc1c(Cl)nc3ncnn3c12
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CCn1ncc2c1ncc1c(Nc3cccc(C(F)(F)F)c3)nc3ncnn3c12

Procedure:
5.8 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine (0.02 mol.), 3 g. of triethylamine and 3.3. g. of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml. of water and filtered off. Recrystallization from alcohol yields 8-ethyl-N-[3-(trifluoromethyl)phenyl]-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5-amine.
Reaction SMILES: C(O[C:6]([C:8]1[CH:18]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[C:11]2[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:23][C:24]1[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=1>>[CH3:29][N:26]1[CH:27]=[CH:28][C:24]([NH:23][C:6]([C:8]2[CH:18]=[C:17]([O:19][CH:20]([CH3:21])[CH3:22])[C:11]3[CH2:12][CH:13]([CH2:15][OH:16])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:25]1
Reactant: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(CO)O2
Reactant: Cn1ccc(N)n1
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(CO)O2

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 2-hydroxymethyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (215a) and 3-amino-1-methyl-pyrazole. 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1 H) 7.26-7.35 (m, 1 H) 6.95-7.05 (m, 1 H) 6.76-6.86 (m, 2 H) 4.93-5.08 (m, 1 H) 4.59-4.71 (m, 1 H) 3.84-3.91 (m, 1 H) 3.83 (s, 3 H) 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.89-3.02 (m, 1 H) 1.98 (t, J=6.44 Hz, 1 H) 1.35 (d, J=6.06 Hz, 6 H); LCMS for C17H21N3O4 m/z 332.20 (M+H+).
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=O)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4].[OH-].[Na+]>C(O)C.O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:1]=[N:2][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=4[CH:19]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([O:5][CH3:6])=[O:4]
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)nn2)cc1

Procedure:
0.3 g (10 millimoles) of 100% pure hydrazine were added dropwise at room temperature to a solution of 4.0 g (10 millimoles) of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione (for preparation see Example 9) in 50 ml of ethanol. The reaction mixture was then refluxed for 20 minutes, cooled and then stirred into water, and the yellow crystals were filtered off under suction and dried in a stream of nitrogen. For aromatization of unoxidized dihydropyridazine, the crude product was stirred with periodic acid in ethanol until checking by thin layer chromatography showed that mainly a pure product was obtained. The product was then diluted with water, rendered basic with 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and evaporated down. 3.1 g of the title compound remained as an oil; H-NMR (CF3COOH) : =8.82 and 8.88 ppm (in each case d, 2H, pyridazine-H).