Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)(=O)C1C=CC=CC=1.Cl[C:11]1[N:12]=[C:13]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:32]=2[C:33]([NH2:35])=[O:34])[C:14]2[CH:19]=[CH:18][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C:15]=2[N:16]=1.[OH-].[NH4+].[CH3:43][O:44][C:45]1[CH:51]=[C:50]([CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][CH3:60])[CH2:54][CH2:53]2)[CH:49]=[CH:48][C:46]=1[NH2:47]>>[F:40][C:36]1[CH:37]=[CH:38][CH:39]=[C:31]([NH:30][C:13]2[N:12]=[C:11]([NH:47][C:46]3[CH:48]=[CH:49][C:50]([CH:52]4[CH2:53][CH2:54][N:55]([CH2:58][CH2:59][CH3:60])[CH2:56][CH2:57]4)=[CH:51][C:45]=3[O:44][CH3:43])[NH:16][C:15]3=[N:17][CH:18]=[CH:19][C:14]=23)[C:32]=1[C:33]([NH2:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Agent: NC(=O)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: CCCN1CCC(c2ccc(Nc3nc(Nc4cccc(F)c4C(N)=O)c4ccnc-4[nH]3)c(OC)c2)CC1
Yield: 34.8 %

Procedure:
According to General Protocol III, 2-fluoro-6-[(2-{[2-methyloxy)-4-(1-propyl-4-piperidinyl)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.30 g, 0.65 mmol), 27% aqueous ammonium hydroxide, and 2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (0.18 g, 0.72 mmol) and isolated as a yellow solid (0.117 g); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=7.5 Hz, 3H), 1.45 (dq, J=14.9, 7.4 Hz, 2 H), 1.64-1.75 (m, 4 H), 1.88-1.98 (m, 2 H), 2.19-2.27 (m, 2 H), 2.42 (dt, J=7.4, 3.8 Hz, 1 H), 2.95 (d, J=11.0 Hz, 2 H), 3.84 (s, 3 H), 6.23 (dd, J=3.5, 2.0 Hz, 1 H), 6.76 (dd, J=8.4, 1.5 Hz, 1 H), 6.87 (d, J=1.5 Hz, 1 H), 6.90-7.00 (m, 2 H), 7.39-7.48 (m, 2 H), 8.01 (s, 1 H), 8.08 (s, 1 H), 8.17 (d, J=8.1 Hz, 1 H), 8.42 (d, J=8.4 Hz, 1 H), 10.42 (s, 1 H), 11.39 (s, 1 H); ESIMS (M+H)+=518.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:18][CH:19]=1
Reactant: Brc1ccc(OC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCC(Oc2ccc(Br)cc2)CC1
Temperature: 50 °C
Yield: 86.9 %

Procedure:
1 N HCl(aq) (45 mL) was added to a solution of 8-(4-bromophenoxy)-1,4-dioxaspiro[4.5]decane (2.8 g, 8.94 mmol) in THF (100 mL). The reaction was heated to 50° C. After 1 hour the reaction was cooled to room temperature and neutralized by addition of solid sodium bicarbonate. The reaction was extracted with ether (1×), the resulting organic layer was washed with water, dried (Na2SO4), filtered and concentrated. Purification on a Biotage SNAP cartridge KP Sil 100 g (hexanes/ethyl acetate=9:1) afforded the title compound as a white solid (2.09 g, 87%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.02-2.13 (m, 2H) 2.21-2.41 (m, 4H) 2.61-2.74 (m, 2H) 4.62-4.71 (m, 1H) 6.81-6.89 (m, 2H) 7.37-7.44 (m, 2H)
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[CH2:19][CH2:18][N:17]=[C:16]1[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C[O-].[Na+].[CH3:29][O:30][CH:31]([O:35][CH3:36])N(C)C>CO>[CH3:29][O:30][CH:31]([O:35][CH3:36])[N:23]1[CH2:24][CH2:25][CH:20]([C:16]2[NH:17][CH2:18][CH2:19][N:15]=2)[CH2:21][CH2:22]1
Reactant: C1CNC(C2CCNCC2)=N1
Reactant: COC(OC)N(C)C
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: COC(OC)N1CCC(C2=NCCN2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of the dihydrochloride salt of 4-(4,5-dihydro-1H-imidazol-2-yl)piperidine (0.99 g, 0.0044M) in methanol (10 ml) which contained sodium methoxide (0.009M) was stirred at room temperature for 10 minutes and dimethylformamide dimethylacetal (10 ml) was added and refluxed at 80° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed to give 4-(4,5-dihydro-1H-imidazol-2-yl)-1-piperidinecarboxaldehyde dimethylacetal. To a mixture of 6-aminopenicillanic acid (0.785 g, 0.0035M) and diisopropyl ethylamine (0.412 ml) in dry chloroform was added the chloroform solution (30 ml) of the above piperidinecarboxaldehyde dimethyl acetal at 0° C. The reaction was stirred at 0° C. for 1 hr and at room temperature for 3 hrs. After this period, the solvent was removed in vacuo and the residue was dissolved in water (40 ml). The aqueous solution washed with ethylacetate was acidified to pH 3 with dil HCl and purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta)]-6-[[[4-(4,5-dihydro-1H-imidazol-2yl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.21 g, 11.5% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([OH:14])[CH:5]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:11])([CH3:12])[CH3:13])=[C:6]([O:14][CH2:20][CH2:19][CH2:18][O:17][CH3:16])[CH:5]=1
Reactant: COCCCBr
Reactant: COC(=O)c1ccc(C(C)(C)C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C(=O)OC)ccc1C(C)(C)C

Procedure:
A mixture of 4-tert-butyl-3-hydroxy-benzoic acid methyl ester (1.56 g, 7.49 mmol), 3-bromopropyl methyl ether (1.72 g, 11.2 mmol) and anhydrous K2CO3 (1.55 g, 11.2 mmol) in MeCN (30 mL) is refluxed overnight. After cooling, the mixture is filtered, the filtrate is diluted with CH2Cl2 and the organics are washed with aqueous 0.5M NaOH, aqueous 0.5M HCl and water, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 97:3) gives the title compound as colorless oil. MS: 281.1 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 6.22 min. 1H-NMR (CDCl3): δ 1.43 (s, 9H), 2.17 (m, 2H), 3.41 (s, 3H), 3.65 (m, 2H), 3.93 (s, 3H), 4.18 (m, 2H), 7.36 (dd, 1H), 7.96 (d, 1H), 7.60 (dd, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][C:6]([CH3:33])=[C:5]([CH3:34])[N:4]=2.[CH:35]([NH2:38])([CH3:37])[CH3:36]>>[CH:35]([NH:38][C:11]([C:10]1[CH:9]=[C:8]2[C:3](=[C:2]([Cl:1])[C:15]=1[NH:14][C:13]([C:16]1[N:17]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[N:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:12])[N:4]=[C:5]([CH3:34])[C:6]([CH3:33])=[N:7]2)=[O:32])([CH3:37])[CH3:36]
Reactant: CC(C)N
Reactant: Cc1nc2cc3c(=O)oc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)nc3c(Cl)c2nc1C
Product: Cc1nc2cc(C(=O)NC(C)C)c(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)c(Cl)c2nc1C
Yield: 42 %

Procedure:
See step f) of example H2 for the reaction conditions starting from 9-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-6,7-dimethyl-3-oxa-1,5,8-triaza-anthracen-4-one and 2 equivalents of isopropylamine. After 18 hours reaction time and purification by flash chromatography on silica gel, a white solid is obtained within 42% yield. m.p.: 243-244° C.
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1.P(Br)(Br)[Br:14]>C(OCC)C>[Br:14][CH2:2][C:3]1[S:4][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCCCSc1ccc(CO)s1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: CCCCSc1ccc(CBr)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of crude 46 (55.4 g, 0.274 mol) in anhydrous ethyl ether (70 mL) was added dropwise to a solution of phosphorus tribromide (12.9 mL, 0.137 mol) in anhydrous ethyl ether (300 mL) at 0° C. After addition was complete, the mixture was allowed to warm slowly to room temperature and stirred for 4 hours under nitrogen. The mixture was then extracted with ethyl ether (3×150 mL). The combined organic solution was washed with brine and dried (MgSO4). MgSO4 was removed by filtration and the crude product was carried to the next step without the removal of solvent to prevent product decomposition.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[NH:12][N:11]=[N:10][CH:9]=2)[CH2:3][CH2:2]1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([C:34](=O)[CH2:35][CH2:36][CH3:37])[C:29](OCC)=[O:30])=[CH:23][CH:22]=1)#[N:14].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C.O1CCCC1>[O:30]=[C:29]1[C:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:22][CH:23]=2)=[C:34]([CH2:35][CH2:36][CH3:37])[N:12]2[N:11]=[N:10][CH:9]=[C:8]2[N:7]1[CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: c1nn[nH]c1NC1CCOCC1
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cnnn12

Procedure:
A solution of N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-amine (260 mg), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (1.08 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (236 mg) in N,N-diethylaniline (20 mL) was stirred at 180° C. for 16 hr. The reaction mixture was diluted with ethyl acetate-tetrahydrofuran (1:1), and the mixture was washed with 1 N hydrochloric acid 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 chromatography [eluent: hexane/ethyl acetate=50/50→10/90 (volume ratio)] to give the title compound as a brown amorphous compound (207 mg, 29%).
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=O.O.[NH2:33][NH2:34]>C(O)(=O)C>[C:25]1(=[O:26])[N:21]([CH2:20][CH2:19][CH2:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([C:2]3[CH2:3][CH2:4][C:5](=[O:7])[NH:33][N:34]=3)=[CH:10][CH:11]=2)(=[O:16])=[O:17])[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]12
Reactant: COC(=O)CCC(=O)c1ccc(S(=O)(=O)CCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(c2ccc(S(=O)(=O)CCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Temperature: 0 °C

Procedure:
34 g (78.2 mmol) of methyl 4-oxo-4-[4-(3-phthalimidopropylsulphonyl)phenyl]butyrate are refluxed for two hours in a solution of 6 ml (120 mmol) of hydrazine hydrate (99%) in 350 ml of glacial acetic acid. Then the mixture is poured onto 2.5 liters of ice water, the product precipitated is suction filtered and dried in a circulating air dryer at 80° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH2:24][C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3.Cl.C(OCC)C>ClCCl>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH2:24][C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3
Reactant: CC(C)CC(COc1cc2c(cc1Br)-c1ccncc1CO2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CC(N)COc1cc2c(cc1Br)-c1ccncc1CO2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
To a solution of tert-butyl (1-((9-bromo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.045 g, 0.094 mmol) in dichloromethane (4 mL) cooled to 0° C. was added hydrogen chloride, 2M in diethyl ether (6 mL, 0.094 mmol) slowly over a period of 5 min. The reaction mixture was stirred at 0° C. for 5 min, then at room temperature for 2 h. The solvents were removed by concentration under reduced pressure. The crude product was taken up in water (10 mL) and washed with diethyl ether (3×10 mL). The aqueous layer was concentrated and purified by reverse phase HPLC (0.1% TFA in water and acetonitrile) to yield 1-((9-bromo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (0.016 g, 0.042 mmol, 45% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.68 (bs, 2H), 8.35 (s, 1H), 8.26 (s, 1H), 6.90 (s, 1H), 5.39 (s, 2H), 4.41 (m, 1H), 4.27 (m, 1H), 3.76 (m, 1H), 1.82 (m, 2H), 1.69 (m, 1H), 1.05 (m, 6H). LCMS (ESI) m/e 377.0 [(M+H)+, calcd for C18H22BrN2O2 377.1]; LC/MS retention time (Method D): tR=1.25 min; HPLC retention time (method A): tR=8.59 min; HPLC retention time (method B): tR=10.33 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:13]=O)[N:9]1[CH2:15][CH2:16][N:17]=[C:8]1[CH2:7][CH2:6]2.[NH2:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(N1CCC[C@H](NCC2C=C3C(CCC4N3N=NN=4)=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][CH2:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8]4[N:9]3[CH2:15][CH2:16][N:17]=4)=[CH:4][C:3]=2[O:2][CH3:1])[C@@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1cc2c(cc1C=O)N1CCN=C1CC2
Agent: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)-n1nnnc1CC2
Product: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)N1CCN=C1CC2

Procedure:
This compound was prepared from Compound 15 and Compound 5 in the same manner of Compound 7.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([CH2:10][OH:11])=[CH:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)C.[OH-].[Na+]>ClCCl>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: OCc1csc2c1CCCC2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1csc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
A solution of 4,5,6,7-tetrahydro-1-benzothien-3-ylmethanol (Step 1, 320 mg, 1.9 mmol) in dichloromethane (10 mL) was added to a stirred solution of 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (0.92 g, 2.1 mmol) in dichloromethane (10 mL) under nitrogen and stirred at room temperature for 20 minutes. Diethyl ether (50 mL) and 1N sodium hydroxide solution (25 mL) were added and the mixture stirred vigorously for 15 minutes. The organic layer was washed with sodium hydroxide, water and brine, dried over MgSO4 and evaporated in vacuo to give 4,5,6,7-tetrahydro-1-benzothiophene-3-carbaldehyde (280 mg, 88%). 1H NMR (360 MHz, CDCl3) δ 9.88 (1H, s), 7.85 (1H, s), 2.92–2.88 (2H, m), 2.76 (2H, t, J=6.0 Hz), 1.88–1.76 (4H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([S:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([S:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(CCc1ccccc1)SCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CCc1ccccc1)SCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.3 %

Procedure:
5.6 g (16.5 mmol) of 2-tert-butyloxycarbonylmethylthio-4-phenyl-butyric acid ethyl ester are placed at room temperature in 60 ml of dichloromethane. 3.8 ml (49.6 mmol) of trifluoro-acetic acid are added and the mixture is stirred for 16 hours at room temperature, then a further 3.8 ml of trifluoroacetic acid is added and the mixture is stirred for 24 hours at room temperature and then washed in succession with 25 ml of water and 25 ml of saturated sodium chloride solution. The aqueous phases are then washed with 2550 ml of dichloro-methane. The combined organic phases are dried over sodium sulfate, filtered and concentrated by evaporation. 4.86 g (100% of theory) of crude 2-carboxymethylthio-4-phenyl-butyric acid ethyl ester are obtained in the form of a brown oil.
Reaction SMILES: [CH:1]1([CH2:4][S:5][C:6]2[N:10]=[CH:9][NH:8][N:7]=2)[CH2:3][CH2:2]1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12].O>N1C=CC=CC=1>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([N:8]1[CH:9]=[N:10][C:6]([S:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:7]1)=[O:15])[CH3:12]
Reactant: c1nc(SCC2CC2)n[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)C(=O)n1cnc(SCC2CC2)n1
Reaction time: 10 h
Yield: 83.5 %

Procedure:
To a solution of 3-cyclopropylmethylthio-1,2,4-triazole (3.8 g) in pyridine (30 ml), diethylcarbamoyl chloride (3.4 g) was added, and the resultant mixture was allowed to stand at room temperature for 10 hours. Water 250 ml) was added to the reaction mixture, which was then extracted with chloroform (150 ml) two times. The chloroform extract was washed with 1N hydrochloric acid (150 ml) two times and water (200 ml) one time, dried over magnesium sulfate, and concentrated under reduced pressure to give 5.2 g of 1-diethylcarbamoyl-3-cyclopropylmethylthio-1,2,4triazole (Compound No. 1). Yield, 84 %. M.P. 51°- 52° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:51])[CH2:7][C@H:8]([NH:24][C:25](=[O:50])[CH2:26][N:27]([C:35](=[O:49])[C@@H:36]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:37]([CH3:39])[CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:9]([C:11]1[O:12][CH:13]=[C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[N:15]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:51])[CH2:7][C@H:8]([NH:24][C:25](=[O:50])[CH2:26][N:27]([C:35](=[O:49])[C@@H:36]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:37]([CH3:39])[CH3:38])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:9]([C:11]1[O:12][CH:13]=[C:14]([C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])[N:15]=1)=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a suspension of Dessmarten (259 mg, 0.61 mmol) in CH2Cl2 (4.0 mL) was added dropwise a solution of compound 708 (150 mg, 0.20 mmol) in CH2Cl2 (2.0 mL). After stirring at rt for 1 hr. the reaction was concentrated in vacuo. The residue was dissolved into EtOAc and washed with 1:1 sat. aq. Na2S2O3 :sat. aq. NaHCO3, sat. aq. NaHCO3, brine, dried over MgSO4, filtered and concentrated in vacuo. Chromatography on silica gel (elution with 2-5% MeOH:CH2 Cl2) provided 74 mg of compound 709. ##STR88##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:34]5[CH2:35][CH2:36][C@@H:32]([OH:31])[CH2:33]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O[C@@H]1CCNC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CC[C@@H](O)C5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), (R)-3-hydroxylpyrrolidine (0.113 g, 1.3 mmol), DIEA(0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and the solution was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to obtain a crude yellow solid, which was washed with methanol to obtain a purified product (0.301 g) in 61.4% yield.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:19](=[O:20])[N:18]([CH2:21][CH2:22][CH3:23])[C:17](=[O:24])[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=4)[C:15]=3[N:34]=CN(C)C)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].Cl>C(O)C>[NH2:34][C:15]1[N:16]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:17](=[O:24])[N:18]([CH2:21][CH2:22][CH3:23])[C:19](=[O:20])[C:14]=1[C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:10]=[CH:11][CH:12]=1
Reactant: CCCn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(N=CN(C)C)n(-c2cccc([N+](=O)[O-])c2)c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(N)n(-c2cccc([N+](=O)[O-])c2)c1=O
Yield: 71.3 %

Procedure:
To a solution of N′-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-3-(3-nitrophenyl)-2,6-dioxo-1-propyl-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformimidamide (prepared in Example 29) (11.0 mg) in ethanol (1.0 ml) was added 1N hydrochloric acid (2.0 ml) and the resulting mixture was stirred with heating under reflux for six hours. The reaction mixture was concentrated under reduced pressure, and weakly basified with aqueous sodium hydroxide solution, and thereto was added water and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 4-[5-[6-amino-1-(3-nitrophenyl)-2,4-dioxo-3-propyl-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (7.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([NH2:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C[O:16][C:17](=O)[C:18]([C:20]1[C:30]2=[C:31]3[C:26](=[CH:27][CH:28]=[CH:29]2)[C:25]([CH3:33])([CH3:32])[CH2:24][CH2:23][N:22]3[CH:21]=1)=O>>[CH3:32][C:25]1([CH3:33])[C:26]2[C:31]3=[C:30]([C:20]([C:18]4[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=4[C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][CH:7]=4)=[CH:21][N:22]3[CH2:23][CH2:24]1)[CH:29]=[CH:28][CH:27]=2
Reactant: NC(=O)Cc1c[nH]c2cc(F)ccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)C(C)(C)CC2
Product: CC1(C)CCn2cc(C3=C(c4c[nH]c5cc(F)ccc45)C(=O)NC3=O)c3cccc1c32

Procedure:
Beginning with (6-fluoroindol-3-yl)acetamide and (6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH:7]2[CH2:10][CH2:9]C2)[CH:3]=1.ClC(Cl)(Cl)[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14].C(N(CC)CC)C>C(#N)C>[CH:7]1([C:4]2[CH:3]=[C:2]([NH:1][C:13]([C:15]3[NH:16][CH:17]=[CH:18][CH:19]=3)=[O:14])[NH:6][N:5]=2)[CH2:10][CH2:9]1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: Nc1cc(C2CCC2)n[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1cc(C2CC2)n[nH]1)c1ccc[nH]1
Yield: 45.8 %

Procedure:
To 260 mg (1.9 mmol) of 5-amino-3-cyclobutylpyrazole in 7 mL of acetonitrile was added 407 mg (1.9 mmol) of 2-trichloroacetylpyrrole and 220 μL of triethylamine. The mixture was stirred and heated at reflux, under nitrogen, for 12 hours. TLC analysis showed some starting material still remained. The mixture was concentrated and chromatographed over silica gel, eluting with 5% methanol in chloroform. The fractions containing the product were concentrated to an oil, which crystallized upon concentration from ether and methanol, to afford 200 mg (0.87 mmol, 46%) of a beige solid, m.p. 207–209° C., 1H NMR (DMSO-d6) δ 12.1 (s, 1H), 11.5 (s, 1H), 10.2 (s, 1H), 7.08 (s, 1H), 6.89 (s, 1H), 6.41 (s, 1H), 6.09 (s, 1H), 3.46 (m, 1H), 2.24 (m, 2H), 2.11 (m, 2H), 2.0–1.8 (m, 2H); IR (drift) 3329, 3294, 3257, 3225 (b), 2460 (w), 2351 (w), 2318 (w), 2257 (w), 1643 (s), 1588 (s), 1541, 1487 (s), 1416, 757, 747, cm−1 Anal. Calcd for C12H14N4O: C, 62.59; H, 6.13; N, 24.33. Found: C, 62.37; H, 6.22; N, 24.13.