Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Temperature: 80 °C
Yield: 99 %

Procedure:
To a solution of 10-3 (4.36 g, 22 mmol) in dimethylsulfoxide (DMSO; 30 mL) were added morpholine (2.5 g, 1.3 eq) and potassium carbonate (3.98 g, 1.3 eq). The reaction mixture was heated at 80° C. during 1 h, then cooled down to room temperature, poured into 300 mL of water and the resulting yellow solid was filtered off, washed with a bit of water then petroleum ether, to afford 5.8 g (98% yield) of 2-morpholin-4-yl-5-nitro-benzoic acid methyl ester 10-4; m/z=267 (M+H)+.
Reaction SMILES: [NH2:1][C:2](=[O:40])[CH:3]([OH:39])[CH:4]([NH:12][C:13](=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CS(C)=O.ClC(Cl)C(O)=O>ClCCl>[NH2:1][C:2](=[O:40])[C:3](=[O:39])[CH:4]([NH:12][C:13](=[O:38])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(c3ccccc3)CC2)n1
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCC(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
To a solution of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(3-((4-phenylpiperidin-1-yl)methyl)-1H-pyrazol-1-yl)nicotinamide (100 mg, 0.186 mmol) in dichloromethane (3 mL) at room temperature DMSO (300 μL), N,N′-dichyclohexyl-carbodiimide (380 mg, 1.842 mmol) and 2,2-dichloroacetic acid (40 μL, 0.487 mmol) were added, and the mixture stirred for 1.5 h at room temperature. After completion of the reaction the mixture was filtered, the filtrate diluted with 30 mL of water, extracted with ethylacetate, the aqueous layer then adjusted to pH 8 by adding NaHCO3, then extracted again with ethyl acetate (3×30 mL), the combined organic layers washed with brine, dried (MgSO4), filtered and concentrated to give 80 mg of a yellow amorphous solid. Purification by chromatography over silica gel (CH2Cl2/methanol) and concentration afforded 25 mg of the title compound as white amorphous solid; ESI-MS [M+H]+: 537.2.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>CO.O>[CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([OH:5])=[O:4]
Reactant: CC/C=C\C/C=C\C/C=C\CCCCCCC/C=C(\C)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC/C=C\C/C=C\C/C=C\CCCCCCC/C=C(\C)C(=O)O
Temperature: 50 °C

Procedure:
Ethyl (2E,11Z,14Z,17Z)-2-methyl-eicosa-2,11,14,17-tetraenoate (6) (160 mg, 0.46 mmol) was dissolved in methanol (3 ml) and added LiOH (193 mg, 4.6 mmol) in water (3 ml) and the mixture was heated at 50° C. for 2 hrs. The mixture was cooled, and diluted hydrochloric acid was added to pH 2. Extraction with diethylether, drying (MgSO4) and evaporation of solvents under reduced pressure afforded the acid 7. The acid was purified by flash chromatography on silica gel (8:2 hexane-EtOAc); δH(300 MHz) 0.95 (t, J 7.5, 3H, CH3), 1.2-1.5 (m, 10H), 1.81 (s, 3H, CH3), 2.0-2.2 (m, 6H), 2.79 (t, J 5.8, 4H), 5.2-5.4 (m, 6H), 6.90 (dt, J 7.5, J 1.3, 1H); δc(75 MHz) 11.93, 14.25, 20.53, 25.51, 25.60, 27.19, 28.40, 28.87, 29.16, 29.31, 29.58, 126.94, 127.10, 127.71, 128.24, 128.25, 130.25, 131.93, 145.41, 173.76.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+].Cl>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of ethyl 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionate (5.20 g, 18.04 mmol), ethanol (30 mL) and tetrahydrofuran (15 mL) was added 1 M aqueous sodium hydroxide solution (20 mL), and the resulting mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 5 M hydrochloric acid, and extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from methanol/diethyl ether to give the title compound (3.63 g, yield 77%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([C:19]#N)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[N:13]2)=[C:4]([F:25])[CH:3]=1.C(OCC)C.C[Mg]I.Cl>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([C:21]([F:23])([F:22])[F:24])[CH:14]=[N:13]2)=[C:4]([F:25])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2ncc(C(F)(F)F)c(C#N)c2=O)c(F)cc1Cl
Agent: C[Mg]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
After 1.035 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-5) was dissolved in 6.0 mL of tetrahydrofuran, 3.1 mL of a diethyl ether solution of methylmagnesium iodide (0.98M diethyl ether solution) was added to the tetrahydrofuran solution at 0° C. and stirred for 20 min under a nitrogen stream. Afterwards, the reaction solution was poured into 3N-hydrochloric acid and extracted with ethyl acetate. After the organic solvent was washed with aqueous saturated sodium bicarbonate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to afford 0.467 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (compound 2-5).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]2[CH:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][CH:17]([OH:18])[CH:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][CH:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC1CCC2OC2CN1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCC(N=[N+]=[N-])C(O)CN1C(=O)OCc1ccccc1
Yield: 80.1 %

Procedure:
Sodium azide (0.56 g, 8.62 mmol) was added to a solution of racemic (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.75 g, 2.87 mmol) and ammonium chloride (0.46 g, 8.62 mmol) in MeOH (5 ml) and H2O (0.5 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.7 g, 80%): 7.39–7.30 (m, 5H), 5.15 (2H, s), 4.10–3.67 (m, 2H), 3.10 (1H, d), 1.85–1.53 (m, 4H), 1.09 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: [CH3:1]SCCC(Cl)=O.[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24]N=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([F:39])[CH:33]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:8][S:9][CH2:10][CH2:11][C:12]([N:14]=[C:15]=[S:16])=[O:13].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[O:29][CH3:30])[N:25]=[CH:24][CH:1]=[C:22]2[O:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][S:9][CH3:8])=[S:16])=[C:34]([F:39])[CH:33]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: CSCCC(=O)Cl
Agent: CSCCC(=O)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCSC)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
3-(Methylsulfanyl)propanoyl isothiocyanate was prepared using commercially available 3-(methylsulfanyl)propanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-(Methylsulfanyl)propanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (43 mg, yield 57%).
Reaction SMILES: ClC1C=CC(C2[C:9]([CH:14]=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=CC=1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.N1(C(OC(C)(C)C)=O)CCNC[CH2:30]1>>[CH3:30][C:12]1([CH3:13])[CH2:11][CH:10]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:17]2)[CH2:9][CH2:14][O:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C2CCOC(C)(C)C2)C1

Procedure:
The title compound was prepared by substituting 2,2-dimethyldihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (R)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5][C@H:4]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1.C(N(CC)CC)C.[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C.O>C1COCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C@H:4]2[C@H:3]([CH2:2][NH:1][C:37](=[O:38])[CH2:36][O:35][CH3:32])[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)NC[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (140 mg) and triethylamine (0.156 mL) in THF (3.0 mL) was added acetoxyacetyl chloride (81 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (168 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Cl)=CC=1.[Cl:9][CH2:10][SiH2:11][CH:12](Cl)Cl.[CH2:15]([Li])[CH2:16][CH2:17][CH3:18]>O1CCCC1.C(=O)=O.CC(C)=O.CCCCCC.[Cl-].[Li+]>[Cl:9][CH2:10][Si:11]([CH2:2][CH2:7][CH2:6][CH3:5])([CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: Clc1ccc(Br)cc1
Reactant: ClC[SiH2]C(Cl)Cl
Reactant: [Li]CCCC
Agent: O=C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Si](C)(CCl)CCCC
Temperature: 25 °C
Yield: 11.6 %

Procedure:
A solution of 14.4 g (0.075 mol) of 4-bromochlorobenzene and 9.5 ml (12.3 g, 0.075 mol) of chloromethyl(dichloro)methylsilane in 150 ml of tetrahydrofuran was stirred under nitrogen and cooled in dry ice-acetone while 94 ml (0.15 mol) of 1.6 molar n-butyllithium in hexane was added dropwise at a rate that held the mixture between -65° and -55°. The resulting slurry was allowed to warm to room temperature, giving a solution that was diluted with hexanes until no more lithium chloride precipitated. Filtration, evaporation of the filtrate, dissolution of the residue in hexanes, refiltration, and evaporation left 19.8 g of a pale orange liquid. Distillation gave first 1.8 g (12%) of chloromethyl(dibutyl)methylsilane, bp 45° (0.05 mm), followed by 6.8 g (35%) of the title compound as a colorless liquid: bp 90° (0.05 mm); nD21 1.5246; ir (neat) 2925, 1580, 1380, 1260, 1090, 1015, 820, 740 cm -1 ; nmr (CDCl3) 0.4 (3H, s), 0.6-1.5 (9H, m), 2.9 (2H, s), 7.0-7.4 (4H, q).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:25])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH2:14][CH2:15][C:10]=3[CH:9]=2)=[CH:6][C:5]([Br:25])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1-c1cc2c(s1)C(=O)NCC2
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1-c1cc2c(s1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 2-(2-aminopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (250 mg, 1.02 mmol) in DMF (3 ml) was added NBS (199 mg, 1.12 mmol). The reaction was stirred at room temperature for 1 h, then concentrated and taken up in DCM (10 mL). The organic solution was washed with a sat. aq. Na2S2O3, then dried over Na2SO4, and concentrated to give 2-(2-amino-5-bromopyridin-3-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (320 mg, 97% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, J=2.0 Hz, 1H), 7.73 (br. s., 1H), 7.66 (d, J=1.8 Hz, 1H), 7.29 (s, 1H), 6.23 (br. s., 2H), 3.40-3.50 (m, 2H), 2.83 (t, J=6.9 Hz, 2H); MS (EI) m/z=325.2 [M+1]+.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:22])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C>C(O)C>[NH3:9].[C:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:22])=[O:5])[CH2:14][CH2:13]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CCC(=O)O)CC1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 132.2 %
Yield: 10 %

Procedure:
1N Aqueous lithium hydroxide (15.6 ml) was added to a solution of tert-butyl 4-(3-ethoxy-3-oxopropyl)-1-piperazinecarboxylate (2.23 g) [see Preparation 89] in ethanol (95 ml). The reaction mixture was stirred for 18 hrs at room temperature, after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on reverse phase MCI gel eluting with 1:1, acetonitrile:water and further purified on Dowex 50W-X8-100 ion-exchange resin eluting with water and then 10% ammonia to afford 3-[4-(tert-butoxycarbonyl)piperazino]propanoic acid (1.33 g) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH:10]2[CH2:12][CH2:11]2)=[C:8]([C:13]([OH:15])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][CH:51]=1)[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:9]([CH:10]2[CH2:11][CH2:12]2)=[C:8]([C:13]([NH:27][C:28]2[CH:51]=[CH:50][CH:49]=[C:30]([O:31][C:32]3[CH:46]=[CH:45][C:35]4[N:36]=[C:37]([NH:39][C:40]([CH:42]5[CH2:44][CH2:43]5)=[O:41])[S:38][C:34]=4[C:33]=3[C:47]#[N:48])[CH:29]=2)=[O:15])[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: CC(C)(C)n1ncc(C(=O)O)c1C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
To a solution of 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid (71 mg, 0.342 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (36 μL, 0.420 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.29 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. 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/n-hexane=50/50→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (111 mg, 72%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(O)(=O)C>O>[OH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([N:1]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:3][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(CCO)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccc(CCO)cc1
Temperature: 100 °C
Yield: 61.6 %

Procedure:
A flask containing 4-aminophenethyl alcohol (1 g, 7.29 mmol), phthalic anhydride (1.13 g, 7.65 mmol) and acetic acid (6 mL) was heated at 100° C. for 1 h. The reaction mixture was poured into water (50 mL) and the solid was filtered off and washed with water. The crude was purified by flash column chromatography to afford the desired product as white solid (1.2 g, 62%). 1H NMR: 2.92 (t, 2H, J=6.6 Hz), 3.89 (t, 2H, J=6.6 Hz), 7.38 (s, 3H), 7.77-7.82 (m, 2H), 7.92-7.97 (m, 21-1).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)[CH3:3].[N:12]#[C:13]Br>C(O)C.O>[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:13]([NH2:12])=[N:11][N:10]=2)[N:9]=1)[CH3:3]
Reactant: N#CBr
Reactant: CCc1ccc(NN)nn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1ccc2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Ethylpyridazin-3-yl)hydrazine hydrochloride (2 g) was initially charged in a mixture of ethanol (30 ml) and water (6 ml) while stirring at RT. Thereafter, cyanogen bromide was cautiously added dropwise (2.4 g dissolved in 7.5 ml of ethanol and 1.5 ml of water). After stirring at RT for one hour, the mixture was left to stand overnight and, the next day, stirred for 4 further hours. The solvent was then drawn off and the residue was purified by means of preparative HPLC (met. C). The clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 830 mg of the title compound were obtained.
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]([CH:27]([F:29])[F:28])[CH:24]=[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][C@@H:4]1[F:36].[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]([CH:27]([F:29])[F:28])=[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:40](=[O:41])[CH2:39][O:38][CH3:37])[C@@H:4]([F:36])[CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](F)C1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f62) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[NH3:14]>>[CH3:1][O:2][C:3]1[C:4]([C:10]([NH2:14])=[O:12])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COC(=O)c1ncc(C)nc1OC
Reactant: N
Product: COc1nc(C)cnc1C(N)=O
Yield: 87 %

Procedure:
1 g (5.5 mmol) of methyl 3-methoxy-5-methylpyrazine-carboxylate was initially charged in 15 ml (198 mmol) of NH3 (25%) and the mixture was stied at 50° C. After concentration, 0.8 g of 3-methoxy-5-methylpyrazine-2carboxamide was obtained. The yield was 86 percent. Other data concerning the title product was:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[C:23]([Cl:24])=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([C:25]2[NH:26][C:27](=[O:34])[C:28]3[S:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH:15]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[C:23]([Cl:24])=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([C:25]2[N:26]=[C:27]([O:34][S:9]([CH3:8])(=[O:11])=[O:10])[C:28]3[S:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH:15]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Cl)c(Cl)cc1-c1nc(OS(C)(=O)=O)c2sccc2n1
Reaction time: 0.5 h

Procedure:
Triethylamine and methanesulfonyl chloride were added to a chloroform solution of methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate under ice cooling and stirred under ice cooling for 30 minutes to give methyl 4,5-dichloro-2-{4-[(methanesulfonyl)oxy]thieno[3,2-d]pyrimidine-2-yl}benzoate.