Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.O>O1CCCC1>[C:1]1([CH2:7][CH2:8][C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C/c1cccc2sccc12)\c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(CCc2cccc3sccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
To a solution of 4-[(E)-2-phenylvinyl]benzo[b]thiophene (0.56 g) and triethyl amine (2.63 mL) in tetrahydrofuran (25 mL) was added 2,4,6-triisopropylbenzenesulfonylhydrazide (5 g), and the mixture was refluxed overnight under an argon atmosphere. After the reaction mixture was cooled to room temperature, 2 mol/L hydrochloric acid was added to the mixture, and the mixture was stirred for 10 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give a mixture of the starting material and the title compound (0.43 g). This mixture was dissolved in triethylamine (2.04 g) and tetrahydrofuran (18 mL), and 2,4,6-triisopropylbenzenesulfonylhydrazide (3.28 g) was added to the solution, and the mixture was refluxed overnight under an argon atmosphere. The reaction mixture was cooled to room temperature and 2 mol/L hydrochloric acid was added to the mixture, and the mixture was stirred for 10 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.4 g).
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24].C1CCCCC1.ClCCl>C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24]
Reactant: COC(=O)/C=C/c1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Reaction time: 1 h

Procedure:
0.25 g of 5% palladium-on-charcoal is added to a solution of 3.8 g (11.9 mmol) of methyl (E)-3-(2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinol-4-yl)prop-2-enoate in 100 ml of acetic acid and the suspension is subjected to hydrogenation in a Parr apparatus under pressure of approximately 0.3 MPa for 1 h at room temperature and then for 3 h at approximately 50° C. The catalyst is removed by filtering, the filtrate is concentrated under reduced pressure, ice-cold water, 200 ml of dichloromethane and 100 ml of 1N sodium hydroxide are added to the residue, the organic phase is separated, washed with water and dried over sodium sulphate and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 70/30. After recrystallizing from a mixture of cyclohexane and dichloromethane, 2.69 g (8.37 mmol) of white solid are obtained. Melting point: 134°-135° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][CH2:14][C:15]1[N:16]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1>C(OCC)(=O)C>[F:13][CH2:14][C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(CF)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CF)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.26 g), sodium hydrogen carbonate (0.37 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-{[2-(fluoromethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.21 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.08 g, 36%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.COC(C)(C)C>[CH3:18][N:19]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=2)[CH:21]=[N:20]1
Reactant: NC(=O)CCSc1ccc(Br)cc1C(F)(F)F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Cn1cc(-c2ccc(SCCC(N)=O)c(C(F)(F)F)c2)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
3-(4-Bromo-2-trifluoromethyl-phenylsulfanyl)-propionamide (160 g, 488 mmol) was dissolved under Ar in N,N-dimethylformamide (1.5 L) before 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (143 g, 687 mmol), potassium carbonate (160 g, 1.16 mol), and water (130 mL) were added. The solution was degassed and tetrakis-(triphenylphosphine)palladium(0) (24.0 g, 20.8 mmol) was added. The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was poured onto water (5 L) and extracted with ethyl acetate (1×3 L, 2×1 L). The combined organic extracts were washed with brine (1 L), the volume was reduced in vacuo to ca. 2 L and dried over sodium sulfate. The resulting filtrate was further reduced in vacuo until precipitation occurred and a homogeneous slurry was formed. Tert-butyl methyl ether (1 L) was then added in portions to the distillation, keeping the overall volume constant (solvent exchange). The suspension was cooled to 5° C. (ice bath) and filtered. The precipitate was washed with tert-butyl methyl ether (500 mL) and dried in vacuo to provide 141 g of the title compound as brown crystalline solid (88%). MS (ESI & APCI): m/z=330.1 [M+H]. 1H NMR (CDCl3, 600 MHz): δ 2.54 (t, J=7.4 Hz, 2H), 3.27 (t, J=7.4 Hz, 2H), 5.39 (bs, 1H), 5.52 (bs, 1H), 7.56 (s, 1H), 7.57 (s, 1H), 7.66 (s, 1H), 7.73 (bs, 1H), 7.77 (d, J=0.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:4][C@@H:3]1[C:5]([N:7]1[CH2:12]C[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=2)[C@H:9](C)[CH2:8]1)=[O:6].[CH2:24](Cl)[CH2:25]Cl.C1C=NC2N(O)N=NC=2C=1.CC(N(C)C)=O.[CH3:44][O:45][C:46](=[O:79])[NH:47][C@H:48]([C:52]([N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[C:59]1[NH:60][CH:61]=[C:62]([C:64]2[CH:69]=[CH:68][C:67]([C:70]3[CH:75]=[CH:74][C:73]([NH2:76])=[CH:72][C:71]=3[F:77])=[C:66]([F:78])[CH:65]=2)[N:63]=1)=[O:53])[CH:49]([CH3:51])[CH3:50].C(N(CC)C(C)C)(C)C>>[CH3:44][O:45][C:46](=[O:79])[NH:47][C@H:48]([C:52]([N:54]1[CH2:58][CH2:57][CH2:56][C@H:55]1[C:59]1[NH:60][CH:61]=[C:62]([C:64]2[CH:69]=[CH:68][C:67]([C:70]3[CH:75]=[CH:74][C:73]([NH:76][C:17]([C:16]4[CH:15]=[N:14][C:13]([N:10]5[CH2:9][CH2:8][N:7]([C:5]([C@H:3]6[CH2:4][C:2]6([CH3:1])[CH3:23])=[O:6])[CH2:12][C@H:24]5[CH3:25])=[CH:21][CH:20]=4)=[O:19])=[CH:72][C:71]=3[F:77])=[C:66]([F:78])[CH:65]=2)[N:63]=1)=[O:53])[CH:49]([CH3:51])[CH3:50]
Reactant: C[C@@H]1CN(C(=O)[C@H]2CC2(C)C)CCN1c1ccc(C(=O)O)cn1
Reactant: ClCCCl
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(N)cc3F)c(F)c2)c[nH]1)C(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(NC(=O)c4ccc(N5CCN(C(=O)[C@H]6CC6(C)C)C[C@H]5C)nc4)cc3F)c(F)c2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution of 6-[(R)-4-((S)-2,2-dimethyl-cyclopropanecarbonyl)-2-methyl-piperazin-1-yl]-nicotinic acid (6.4 mg, 0.020 mmol; Preparation 36) was added EDC (5.8 mg, 0.030 mmol) and HOAt (4.2 mg, 0.030 mmol) in DMA (0.5 mL, 5 mmol). The reaction mixture was stirred at RT for 30 min and then ((S)-1-{(S)-2-[4-(4′-amino-2,2′-difluoro-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (10 mg, 0.02 mmol; Preparation 38-B) and N,N-diisopropylethylamine (18 uL, 0.10 mmol) were added and the reaction mixture was stirred at RT overnight. The reaction mixture was concentrated by rotary evaporation, dissolved in 1:1 acetic acid:water (1.5 mL) and purified by reverse phase HPLC to provide the di-TFA salt of the title compound (6.8 mg). (m/z): [M+H]+ calcd for C43H50F2N8O5 797.39 found 797.4.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(N1C2C(=CC=C(OCCCNC(N)=N)C=2)C=C(CC(O)=O)C1=O)C.FC(F)(F)C(O)=O.[CH2:40]([N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([O:52][CH2:53][CH2:54][NH:55][C:56]([NH2:58])=[NH:57])[CH:50]=2)[CH:45]=[C:44]([CH2:59][C:60]([OH:62])=[O:61])[C:43]1=[O:63])[CH3:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:40]([N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([O:52][CH2:53][CH2:54][NH:55][C:56]([NH2:58])=[NH:57])[CH:50]=2)[CH2:45][CH:44]([CH2:59][C:60]([OH:62])=[O:61])[C:43]1=[O:63])[CH3:41]
Reactant: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCNC(=N)N)cc21
Agent: CCn1c(=O)c(CC(=O)O)cc2ccc(OCCCNC(=N)N)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(CC(=O)O)Cc2ccc(OCCNC(=N)N)cc21

Procedure:
The title compound is prepared using the procedure of Example 158 except that [1-ethyl-7-(3-guanidino-propoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid trifluoroacetate is replaced with [1-ethyl-7-(2-guanidino-ethoxy)-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid trifluoroacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16].[CH2:19]([O:21][C:22]([N:24]=[C:25]=[S:26])=[O:23])[CH3:20].[ClH:27]>C1C=CC=CC=1.C(O)C.C(OCC)C>[ClH:27].[CH2:19]([O:21][C:22]([NH:24][C:25]([NH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:18])[CH2:14][N:15]([CH3:17])[CH3:16])=[S:26])=[O:23])[CH3:20]
Reactant: CCOC(=O)N=C=S
Reactant: CCCCc1ccc(NC(=O)CN(C)C)c(N)c1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCO
Product: CCCCc1ccc(NC(=O)CN(C)C)c(NC(=S)NC(=O)OCC)c1

Procedure:
Petroleum spirit (b.p. 60°-80° C; 50 ml) was added to a solution of N-(2-amino-4-n-butylphenyl)-2-dimethylaminoacetamide (4.98 g) in benzene (50 ml) and the solution stirred vigorously while ethoxycarbonyl isothiocyanate (2.65 g) was added dropwise, with external cooling, to maintain the temperature between 15° C. and 20° C. After ten minutes, the precipitated solid was filtered off and recrystallised from benzene to give crude 1-ethoxycarbonyl-3-(5-n-butyl-2-dimethylaminoacetamidophenyl)thiourea, m.p.152°-155° C. (with decomposition), which was then dissolved in the minimum of ethanol. Diethyl ether (200 ml) was added, followed by an excess of a saturated solution of hydrogen chloride in diethyl ether. The precipitated solid was filtered off and recrystallised from ethanol/ethyl acetate to give 1-ethoxycarbonyl-3-(5-n-butyl-2-dimethylaminoacetamidophenyl)thiourea hydrochloride (1.9 g), m.p. 174°-176° C. (with decomposition).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>O1CCCC1>[C:7]([CH:9]=[CH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (45.8 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (7.77 mL, 0.0480 mol) in tetrahydrofuran (58.39 mL). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (9.91 g, 0.0436 mol) in tetrahydrofuran (11.7 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexanes, to give the desired product (8.22 g, 75% in 2 steps). LCMS (M+Na) 273.0.
Reaction SMILES: [C:1](/[C:3](=[CH:9]\[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)/[C:4]([O:6]CC)=O)#[N:2].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCC>[OH:6][C:4]1[C:12]2[C:11](=[CH:16][CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[CH:13]=2)[N:10]=[CH:9][C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)/C(C#N)=C/Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1O
Temperature: 50 °C
Yield: 60.7 %

Procedure:
A mixture of (E)-ethyl 2-cyano-3-((4-nitrophenyl)amino)acrylate (24.0 g) and Dowtherm A (500 mL) was added to a 1 L flask, the mixture was heated to reflux under nitrogen for 10 hours. After cooling to 50° C., the mixture was diluted with hexane (1 L). The product was filtered, washed with ethanol (100×2 mL), and dried to give 4-hydroxy-6-nitroquinoline-3-carbonitrile (Compound 16) as a brown solid (12.0 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:23])([F:22])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCOC(C)=O>[F:22][C:11]([F:23])([C:8]1[N:6]2[N:7]=[C:2]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cn1cc(-c2ccc3ncc(C(F)(F)c4ccc5ncccc5c4)n3n2)cn1
Temperature: 150 °C

Procedure:
A microwave tube was charged with 6-[(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-difluoro-methyl]-quinoline (Stage 6.1, 10 mg, 0.03 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.045 mmol), tetrakis-(triphenylphosphine)palladium (1.7 mg), 2M Na2CO3 (0.054 mL) and DME (1 mL). It was heated at 150° C. under microwave irradiation for 20 min. The RM was taken up with EtOAc (2 mL) and washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a brown solid (tR 1.379 min (conditions 1), MH+=376.8, 1H-NMR in DMSO-d6: 9.00 (m, 1H); 8.65 (d, 1H); 8.52 (s, 1H); 8.30 (s, 1H); 8.21 (d, 1H); 8.14 (d, 1H); 7.99 (m, 2H); 7.87 (s, 1H); 7.66 (m, 2H); 3.86 (s, 3H)).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCCC1.O.CCOCC>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[Cl:1]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1ccc2ncnc(Cl)c2c1
Reaction time: 2 h

Procedure:
A mixture consisting of 3.25 g of 4-chloro-6-nitroquinazoline, 10.8 g of sodium hydrosulfite, and 0.3 g of the phase transfer catalyst (C8 H17)3NCH3 +Cl- in 97 ml of tetrahydrofuran and 32 ml of water was stirred rapidly for 2 hours. The mixture was diluted with ether and the organic layer was separated. The organic solution was washed with brine and then dried over magnesium sulfate. The solution was passed through a small column of silica gel. The solvent was removed at 30° C. at reduced pressure giving 6-amino-4-chloroquinazoline which is used in the next step without additional purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]1[C:31]2C(=CC=CC=2)[CH2:25][CH:24]1N>>[CH2:5]1[C:4]2[C:3](=[CH:31][CH:23]=[CH:24][CH:25]=2)[CH2:2][CH:1]1[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2Cc3ccccc3C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2,3-dihydro-1H-inden-2-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.86 (s, 3H), 2.11 (s, 3H), 2.76 (bs, 2H), 2.99 (bs, 2H), 4.49 (bs, 2H), 4.61 (bs, 1H), 6.23 (bs, 1H), 6.72-6.79 (m, 1H), 7.12 (bs, 4H), 7.216-7.23 (m, 1H), 7.21-7.29 (m, 1H), 7.65-7.73 (m, 1H), 8.41 (bs, 1H); MS (ESI) m/z 346.8 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:20]CC2C=CC=CC=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[C].[Pd].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([OH:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cn(Cc2ccccc2)nc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
A mixture of ethyl(E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.30 g), 5% palladium-carbon (28.00 g), ethanol (150 ml), and tetrahydrofuran (150 ml) was stirred at room temperature for 3 hours under a hydrogen atmosphere. After the palladium-carbon was removed by filtration, the filtrate was concentrated. The crystals obtained were collected by filtration to yield ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazol-4-yl)propionate (9.01 g, yield: 83%). This was recrystallized from ethyl acetate-hexane. Melting point: 75–76° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][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.C(#N)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cccc(F)c1
Temperature: 4 °C
Yield: 75.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-fluorobenzoic acid (20 g), N,N'-carbonyldiimidazole (23 g) and 2-amino-7-chloro-1,8-naphthyridine (16.9 g). The product produced by precipitation in water (25 g; m.p. 201° C.) is dissolved in boiling acetonitrile (230 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3-fluorobenzamide (21.4 g) is produced, m.p. 202° C. EXAMPLE 15
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:36])[C:7]=2[CH:37]=1)#[N:2].O1CCCC1.[OH-].[Li+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:36])[C:7]=2[CH:37]=1)#[N:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(C#N)cc3c2C)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (193 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N lithium hydroxide aqueous solution (770 μL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (770 μL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (163 mg, 90%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]=[CH:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>ClCCl>[CH3:20][C:21]([Si:24]([CH3:26])([CH3:25])[O:14][CH2:13][CH:12]=[CH:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(SC=CCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC=CSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
A solution of a 1.5 to 1 mixture of (E) and (Z) 3-(4-nitrophenylthio)-2-propenol (3.53 g, 16.71 mmol) (JCS, Perkin Trans. I, 1974, 25) in dichloromethane (40 mL) was treated with imidazole (2.28 g, 33.4 mmol) and TBDMSCl (2.77 g, 18.4 mmol), stirred at room temperature for 24 hours, and then partioned between dichloromethane and water. The organic phase was dried, concentrated, and purified on silica gel by flash column chromatography eluting with 8 to 1 hexanes/ethyl acetate to give 5.1 g (94%) of the desired product. Rf: 0.8 (2:1 hexane:ethyl acetate)