Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:19](=O)([O-])[O-].[K+].[K+].IC.O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]([CH3:19])[N:14]=[CH:15][C:16]=2[CH:17]=[O:18])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: CC(C)Oc1ccc(-c2c(C=O)cnn2C)cc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a mixture of 3-(3-chloro-4-isopropoxyphenyl)-1H-pyrazole-4-carbaldehyde (530 mg, 1.76 mmol, 1.00 equiv) and potassium carbonate (828 mg, 5.99 mmol, 3.40 equiv) in acetonitrile (100 mL) was added iodomethane (852 mg, 6.00 mmol, 3.41 equiv) dropwise. The reaction was stirred at 70° C. for 8 h. The resulting mixture was cooled to room temperature then concentrated under vacuum. The residue was dissolved in 20 mL of H2O and then extracted with 3×30 mL ethyl acetate. The combined organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column, XSelect CSH Prep C18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and MeCN (38.0% MeCN up to 45.0% in 15 min); Detector, UV 254/220 nm to afford 100 mg (18%) of 5-[3-chloro-4-(propan-2-yloxy)phenyl]-1-methyl-1H-pyrazole-4-carbaldehyde as colorless oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.03 (s, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.51 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.85-4.77 (m, 1H), 3.78 (s, 3H), 1.33 (d, J=7.5 Hz, 6H) ppm. LCMS (method C, ESI): RT=0.92 min, m/z=279.0 [M+H]+ and 120 mg (22%) of the other regioisomer, 3-(3-chloro-4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde as a colorless oil. 1H-NMR (300 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.51 (s, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.82 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.77-4.69 (m, 1H), 3.94 (s, 3H), 1.32 (d, J=7.5 Hz, 6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15]C)=[O:14])=[CH:10][C:9]=2[S:17][C:18]([F:21])([F:20])[F:19])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[S:17][C:18]([F:20])([F:19])[F:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
A mixture of methyl 5-(p-chlorophenyl)-4-[(trifluoromethyl)thio]pyrrole-2-carboxylate (4.89 g, 0.0146 mol) and sodium hydroxide (1.75 g, 0.0437 mol) in a 2:1 methanol/water solution (150 mL) is warmed to 60° C., stirred for three hours, cooled to room temperature with stirring overnight and concentrated in vacuo to remove most of the methanol. The resulting aqueous solution is treated with 10% hydrochloric acid and a white precipitate forms. Ethyl acetate is added and the organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as an off-white solid (4.98 g, mp 176°-178° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH2:10][C:11]([CH2:13][O:14][CH2:15][CH2:16][Cl:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.N1CCCCC1.[C:34]([CH2:36][CH2:37][O:38][C:39](=[O:44])/[CH:40]=[C:41](\[NH2:43])/[CH3:42])#[N:35]>CC(O)C.C(O)(=O)C>[C:34]([CH2:36][CH2:37][O:38][C:39]([C:40]1[CH:23]([C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([Cl:19])[CH:21]=2)[C:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:18])=[C:11]([CH2:13][O:14][CH2:15][CH2:16][Cl:17])[NH:43][C:41]=1[CH3:42])=[O:44])#[N:35]
Reactant: C/C(N)=C/C(=O)OCCC#N
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C(COCCCl)CC(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCc2ccccc2)=C(COCCCl)N1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
500 mg (1.90 mmol) of 4-(2-chloroethoxy) acetoacetic acid benzyl ester, 260 mg (1.90 mmol) of 3-chlorobenzaldehyde, acetic acid and piperidine were heated and stirred at room temperature for 24 hours in 3 ml of 2-propanol. 280 mg (1.90 mmol) of 3-aminocrotonate 2-cyanoethyl ester was added and further heated and stirred at 50° C. for 48 hours. 2-propanol was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the title compound.
Reaction SMILES: C(S([C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[N:11][C:9]=2[N:10]=1)=O)C.[CH3:29][N:30]([CH3:39])[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCOCC1>[CH3:29][N:30]([CH3:39])[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:5]2[N:6]=[CH:7][C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:12]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=4)=[N:11][C:9]=3[N:10]=2)[CH2:35][CH2:34]1
Reactant: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: CN(C)CCN1CCNCC1
Solvent: C1COCCO1
Product: CN(C)CCN1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-(ethylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (6-4; 900 mg, 2.33 mmoles) in dioxane (1 mL) was added 1-(2-dimethylaminoethyl)-piperazine (66 mg, 2.33 mmoles) and heated to 150° C. in a microwave reactor for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% Hex. to 100% EtOAc) to give the title compound. LRMS m/z (M+H) Calcd: 467.2, found 467.6.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:31])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C2CCC2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCN(C2CCC2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-cyclobutylpiperazin-1-yl)quinolin-7-yl]ethanone (0.0692 g, 0.201 mmol) and ammonium acetate (0.155 g, 2.01 mmol) in methanol (0.8 mL) and acetonitrile (0.8 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.50 mL, 0.50 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C19H26ClN4 (M+H)+: m/z=345.2; Found: 345.1.
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[Cl:50]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:50][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[C:24]=3[N:23]=[CH:12]2)=[CH:2][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COC(=O)c1scc(-c2ccc(Cl)cc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccc(Cl)cc3)c2ncn1-c1ccc(Cl)cc1
Yield: 11 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(4-chlorophenyl)thiophene-2-carboxylate (100 mg, 0.373 mmol), triethyl orthoformate (2 ml), 4-chloroaniline (88.5 mg, 0.70 mmol), and acetic acid (0.1 ml) were used to give 15 mg (0.04 mmol, 11% yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:28])[O:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[CH:7][C:6]=1[CH3:29])C.[BH4-].[Na+].CO.Cl>O1CCCC1.C(OCC)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]([CH3:28])[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[C:6]([CH3:29])[CH:7]=3)=[CH:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)cc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CO
Temperature: 60 °C
Yield: 98 %

Procedure:
414 mg of 4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid ethyl ester (VIIIa) and 152 mg of sodium borohydride were suspended in 10 ml tetrahydrofurane. The mixture was heated to 60° C. and 0.85 ml of methanol was the added dropwise under vigorous stirring. The mixture was stirred at 60° C. until the gas evolution subsided. The mixture was then cooled and ice water followed by diethylether were added. Then a solution of hydrochloric acid (1N) was slowly added to acidify the solution. The organic phase was washed with water and dried. Evaporation of the solvent afforded {4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-methanol as a solidified foam in 98% yield. 1H-NMR (CDCl3, δ in ppm): 7.28-7.45 (m, 6H), 5.34 (s, 1H), 4.72 (s, 2H), 2.99 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:35])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([CH2:21][O:19][C:6]3[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]4[CH:18]=[CH:17][N:16]=[N:15]4)=[C:4]([CH3:3])[CH:5]=3)=[CH:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
36 mg (0.89 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 197 mg (0.85 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-fluoro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. 325 mg (89%) of the title compound were obtained as pale beige powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2C1CCCCO1)=[CH2:5])C.O.[Br:22]N1C(=O)CCC1=O>O1CCCC1>[Br:22][CH2:3][C:4]([C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][NH:10]2)=[O:5]
Reactant: C=C(OCC)c1ncnc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ncnc2[nH]cnc12
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
A solution of 6-(1-ethoxyvinyl)-9-tetrahydro-2H-pyran-2-yl-9H-purine (430 mg, 1.57 mmols), being prepared as described in Tetrahedron, 53 (6), 2291-2302, (1997), in tetrahydrofuran (24 ml) and water (1.5 ml) was treated with N-bromo-succinimide (NBS, 280 mg, 1.57 mmols) and kept at room temperature for 15 minutes. The solution was evaporated under reduced pressure, taken up with water and filtered to obtain the title compound (312 mg, Y=82%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[F:50][C:51]([F:63])([F:62])[C:52]([N:54]1[CH2:61][CH2:60][CH2:59][C@H:55]1[C:56](Cl)=[O:57])=[O:53]>ClCCl>[CH3:7][N:6]([CH3:8])[C:4]([C:3]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20]([S:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)(=[O:32])=[O:33])[C:17]3=[N:18][CH:19]=2)[CH:11]=[C:12]([F:13])[C:2]=1[NH:1][C:56]([CH:55]1[CH2:59][CH2:60][CH2:61][N:54]1[C:52](=[O:53])[C:51]([F:63])([F:50])[F:62])=[O:57])=[O:5]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)N(C)C)c3)cc12
Reactant: O=C(Cl)[C@@H]1CCCN1C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)C4CCCN4C(=O)C(F)(F)F)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a scintillation vial was combined 32 mg (0.06 mmol) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide and 15 uL (0.09 mmol) of N,N-diisopropylethylamine. To the vial was added 745 μL of a 0.1M solution of (S)-(−)-N-(trifluoroacetyl)prolylchloride in dichloromethane. The reaction was stirred at room temperature for 30 minutes, quenched with a few drops of methanol, and concentrated down. MS: m/z 752.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[S:12][C:13]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:14]=3[C:15]=2[CH2:16][CH2:17][CH3:18])[CH:5]=[CH:4][C:3]=1[CH2:28][CH2:29][C:30]([O:32]C)=[O:31].C(C1C2C=CC(C(F)(F)F)=CC=2SC=1CO)CC>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[S:12][C:13]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:14]=3[C:15]=2[CH2:16][CH2:17][CH3:18])[CH:5]=[CH:4][C:3]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCCc1c(CCC(=O)c2ccc(CCC(=O)OC)c(C)c2)sc2cc(C(F)(F)F)ccc12
Agent: CCCc1c(CO)sc2cc(C(F)(F)F)ccc12
Product: CCCc1c(CCC(=O)c2ccc(CCC(=O)O)c(C)c2)sc2cc(C(F)(F)F)ccc12

Procedure:
The titled compound was prepared from the above-mentioned methyl 3-[2-methyl-4-[3-[3-propyl-6-(trifluoromethyl)benzothiophen-2-yl]propionyl]phenyl]propionate (38 mg, 0.08 mmol) in a procedure similar to that of Example (3) as a white crystal (14 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.O[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:14][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:3]=[C:2]([Cl:1])[Cl:15])[CH:11]=[C:10]([Cl:12])[C:9]=1[O:13][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC(Cl)=CCOc1cc(Cl)c(OCc2ccncc2)c(Cl)c1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
To a solution of 0.43 g of 4-(3,3-dichloro-2-propenyloxy)-2,6-dichlorophenol, 0.16 g of 4-(hydroxymethyl)pyridine and 0.39 g of triphenylphosphine dissolved in 10 ml of tetrahydrofuran was added dropwise a solution of 0.30 g of diisopropyl azodicarboxylate dissolved in 5 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was concentrated, to which 20 ml of diethyl ether was added, and the precipitate was filtered. The filtrate was concentrated, and the residue was subjected to silica gel chromatography, which afforded 0.29 g of 3,5-dichloro-4-(4-pyridylmethyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (51% yield), m.p. 74.0° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].C(N(CC)CC)C.Br[CH2:46][C:47]([O:49][CH3:50])=[O:48].C(OCC)(=O)C>CN(C=O)C>[CH3:50][O:49][C:47](=[O:48])[CH2:46][NH:1][C@H:2]([C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CBr
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) (0.023 g, 0.044 mmol) in DMF (0.7 mL) was added triethylamine (12.0 μL, 0.087 mmol) and methyl bromoacetate (4.0 μL, 0.054 mmol). The mixture was stirred to room temperature for 1 h. Ethyl acetate was added and the organic layer was washed with a saturated solution of NaHCO3, then dried with MgSO4 and concentrated. The residue was purified by flash chromatography eluting with a mixture of hexane/EtOAc. The yield obtained was 47%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:36]OC1C=CC(C)=CC=1S(Cl)(=O)=O>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:25])=[O:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 515.29 (M+H+.), was prepared in analogy to example 40, steps 1 to 5. Step 4 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride, yielding 2-Chloro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][CH:28]=2)=[CH:20][CH:19]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:27][CH:28]=3)=[CH:35][CH:36]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (318 mg), 4-(4-chloromethylphenoxymethyl)-2-phenyloxazole (450 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 60.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration, and ethyl 3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (616 mg, yield: 86%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 80–81° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:19])[CH:16]=3)[NH:11][C:10]=2[CH:9]=[N:8][CH:7]=1)=[O:5])[CH3:2].N1(C2CCCCCCCCCC2)CCCCCC[CH2:24][CH2:23][CH2:22]N1.[CH2:42](Br)[CH:43]=[CH2:44]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N:19]([CH2:44][CH:43]=[CH2:42])[CH2:24][CH:23]=[CH2:22])[CH:16]=3)[NH:11][C:10]=2[CH:9]=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2[nH]c3ccc(N)cc3c12
Reactant: C=CCBr
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: CCO
Product: C=CCN(CC=C)c1ccc2[nH]c3cncc(C(=O)OCC)c3c2c1

Procedure:
A solution of 0.28 g of 6-amino-β-carboline-4-carboxylic acid ethyl ester, 0.18 g of diazabicycloundecane and 0.26 g of allylbromide in 5 ml of ethanol is heated for 3 hours to 70° C. Then the solution is evaporated. The evaporation residue is extracted with ethyl acetate and water, the combined extracts are evaporated and chromatographed on silica gel with methylene chloride/methanol=5:1. Yield: 0.05 g.
Reaction SMILES: [OH-].[K+].[CH:3]([O:6][C:7]1[C:8]([CH3:17])=[N:9][CH:10]=[C:11]([CH:16]=1)[C:12]([O:14]C)=[S:13])([CH3:5])[CH3:4]>O.CO>[CH:3]([O:6][C:7]1[C:8]([CH3:17])=[N:9][CH:10]=[C:11]([CH:16]=1)[C:12]([OH:14])=[S:13])([CH3:5])[CH3:4]
Reactant: COC(=S)c1cnc(C)c(OC(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ncc(C(O)=S)cc1OC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Potassium hydroxide (770 mg) in water (8 mL) is added to a solution of methyl 5-isopropyloxy-6-methylthionicotinoate (1.1 g) in methanol (15 mL) and the mixture stirred at room temperature for 6 hours. After concentrating in vacuo the residue is dissolved in water and acidified to pH 1 with concentrated aqueous hydrochloric acid. The mixture is extracted with ethyl acetate, the extracts washed with water and dried (MgSO4). The solvent is removed in vacuo to give 5-isopropyloxy-6-methylthionicotinic acid as a white solid, m.p. 154–5° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: Cc1ccc(Br)c2c1NCC2
Reactant: COc1ccc2c(Cl)ncnc2c1
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4c(Br)ccc(C)c43)ncnc2c1
Yield: 69 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 69% yield from 4-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 134°-135° C.; LC-MS: 370, 372 (MH+); anal. RP18-HPLC RT: 5.60 min.).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:13])[O:8][N:7]=1)([CH3:5])[CH:3]=O.Cl.[NH2:26][OH:27].N1C=CC=CC=1>CO>[OH:27][N:26]=[CH:3][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:13])[O:8][N:7]=1)([CH3:1])[CH3:5]
Reactant: CC(C)(C=O)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C=NO)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To 90.0 mg (0.27 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(1,1-dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-amide in MeOH (3.00 mL) are added 22.4 mg (0.32 mmol) hydroxylamine hydrochloride and 58.5 μL (0.72 mmol) pyridine. The reaction is stirred at 60° C. for 3 h. The solvent is removed under reduced pressure and the residue is purified by HPLC-MS to afford 79.0 mg of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(2-hydroxyimino-1,1-dimethyl-ethyl)-isoxazol-5-yl]-amide. Yield: 84%; ESI-MS: 351 [M+H]+; HPLC (Rt): 1.04 min (method E)