Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[C:9]([NH:8][C:4]1[CH:5]=[CH:6][C:7]([S:13]([Cl:12])(=[O:15])=[O:14])=[C:2]([F:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1cccc(F)c1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)c(F)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of N-(3-fluorophenyl)acetamide (20.0, 0.13 mol) in chlorosulfonic acid (150 mL) was heated to 75° C. for 1 hr. The solution was allowed to cool to room temperature and was poured over ice. The resulting slurry was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to yield 15.5 g (47%) of 4-acetylamino-2-fluorobenzenesulfonyl chloride as a paste. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:1][CH:2]([CH2:23][N:24]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH3:34])[C:3]([N:5]([CH2:10][C:11]1[CH:21]=[C:20]([Cl:22])[C:14]2[O:15][CH2:16][CH2:17][CH2:18][O:19][C:13]=2[CH:12]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4]
Reactant: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CNCc1ccccc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)C(C)CN(C)Cc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of (±)-2-Methyl-3-(benzylamino)-N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-N-isobutylpropanamide (26 mg), paraformaldehye (16 mg), glacial acetic acid (90 μl) and sodium triacetoxyborohydride (26 mg) was dissolved in tetrahydrofuran (5 ml), and stirred overnight. The mixture was partitioned between aq. potassium carbonate (1N, 10 mL) and ethyl acetate (15 ml). The organic layer was concentrated and the residue was purified by flash chromatography on silica (40% ethyl acetate in hexane) to yield a resin: MS (m+1)=459.2; H NMR (500 MHz, CDCl3) 0.95 (m, 6H), 2.00 (m, 1H), 2.05 (m, 1H), 2.25 (m, 2H), 2.30 (m, 3H), 2.55 (t, 1H), 2.65 (t, 1H), 2.90 (m, 1H), 3.05 (d, 1H), 3.25 (d, 1H), 3.60 (m, 2H), 4.15 (m, 2H), 4.35 (m, 2H), 4.50 (m, 2H), 6.6-7.0 (m, 2H), 7.0-7.5 (m, 5H).
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[O:29]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH:15]([CH:19]([CH3:20])[CH3:21])[C:16]([O:18][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:37]=3)=[O:17])=[CH:12][C:11]=2[CH:22]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1cc2cc(Cl)ccc2s1
Reaction time: 15 h

Procedure:
A mixture of 20 ml DMF, 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (0.5 g), K2CO3 (0.51 g) and 3-phenoxybenzyl bromide (0.44 g) is stirred, under nitrogen, for about 15 hours. The mixture is then taken up in ether, washed with water and brine, dried over Na2SO4 and solvent removed. The crude product is plated developing with 10% ether/hexane to give 3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[Cl:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH:24](OC)OC)[CH:18]=2)=[N:9][N:10]([CH3:16])[C:11]=1[O:12][CH:13]([F:15])[F:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([CH:24]3[S:5][CH2:1][CH2:2][CH2:3][S:4]3)[CH:18]=2)=[N:9][N:10]([CH3:16])[C:11]=1[O:12][CH:13]([F:14])[F:15]
Reactant: SCCCS
Reactant: COC(OC)c1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)c(C3SCCCS3)c2)c(Cl)c1OC(F)F
Temperature: 65 °C

Procedure:
0.5 g (4.6 mmol) of 1,3-propanedithiol was added to a solution of 1.7 g (4.6 mmol) of 4-chloro-3-[4-chloro-3-(dimethoxymethyl)phenyl]-5-difluoromethoxy-1-methyl-1H-pyrazole in 50 ml of toluene. The mixture was heated to 60-70° C. and then a spatula-tipful of p-toluenesulfonic acid was added. The reaction mixture was stirred at reflux temperature for 3 hours and then cooled and diluted with 50 ml of toluene. The organic phase was washed with 10% strength by weight sodium hydrogen carbonate solution and water and then dried over magnesium sulfate and concentrated. The crude product thus obtained was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 1.8 g.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]2=[O:20])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].Cl[CH2:28][N:29]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=2[CH:41]([CH3:43])[CH3:42])[S:30]1(=[O:32])=[O:31]>CN(C)C=O.O>[N:2]1([CH2:8][C:9]2[C:14](=[O:15])[N:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]3=[N:11][C:10]=2[O:20][CH2:28][N:29]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][C:35]([O:44][CH3:45])=[CH:36][C:37]=3[CH:41]([CH3:43])[CH3:42])[S:30]2(=[O:31])=[O:32])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: O=C1N=C2C=CC=CN2C(=O)C1CN1CCOCC1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1nc3ccccn3c(=O)c1CN1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47.1 %

Procedure:
A mixture of 3-(4-morpholinylmethyl)pyrido[1,2-a]pyrimidine-2,4-dione hydrochloride (0.6 g) and potassium t-butoxide (0.49 g) in dimethylformamide (20 mL) was stirred at room temperature for five minutes. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (0.61 g) was added and stirring was continued at room temperature for one hour. The reaction mixture was diluted with water (50 mL) and extracted with dichlormethane (3×200 mL). The dichloromethane extract was dried over sodium sulfate and stripped of volatiles, finally under high vacuum. The crude product (780 mg) was combined with that (0.65 g) from another run at the same scale using sodium hydride (60% dispersion in mineral oil, 0.19 g) instead of potassium t-butoxide and purified by column chromatography on silica gel with dichloromethane-methanol (95:5) as eluant affording 2-[3-(4-morpholinylmethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl]oxymethyl-4-isopropyl-6-methoxysaccharin (500 mg, 23% yield), part of which was recrystallized from ethanol (m.r. 177°-180 ° C.).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1.[N:18]#[C:19][NH2:20]>CCOCC>[ClH:1].[NH:2]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:5][CH:4]=1)[C:19]([NH2:20])=[NH:18]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=N)N)cc1
Temperature: 25 °C

Procedure:
4-Amino-N-tert-butoxycarbonylbenzylamine hydrochloride (25.77 g, 99.6 mmol.) and cyanamide (55 g, 1.3 mol.) were heated neat at 65° C. over 1.5 hours. The mixture was then cooled to room temperature and ether (250 mL) was added. The insoluble yellow oil was repeatedly washed with additional ethyl ether to remove traces of cyanamide and dried in vacuo to give 4-guanidino-N-tert-butoxycarbonylbenzylamine hydrochloride as an amorphous yellow material which was carried on without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[NH:6][C:7]([C:9]1([NH:14][C:15](=[O:21])[C@@H:16]([SH:20])[CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:2].[CH:31]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:30])[C@H:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[NH:6][C:7]([C:9]1([NH:14][C:15](=[O:21])[C@@H:16]([S:20][C:36]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:37])[CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8])[CH3:2]
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](S)C(C)C)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(=O)C2CCCC2)C(C)C)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[[1-[(2-(S)-mercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine ethyl ester (0.32 g, 0.73 mmole), cyclopentanecarboxylic acid (0.083 g, 0.73 mmole), dicyclohexylcarbodiimide (0.15 g, 0.73 mmole), 1-hydroxy-7-azabenzotriazole (0.10 g, 0.73 mmole), and triethylamine (0.10 ml, 0.73 mmole) in methylene chloride (30 ml) is stirred overnight at room temperature. The resulting mixture is filtered, washed with sodium bicarbonate solution, then with brine, dried over magnesium sulfate and evaporated to dryness. The residue is purified by flash chromatography on silica gel eluting with hexane ethyl acetate. The pure fractions are concentrated and the residue is crystallized from diethyl ether to yield N-[[1-[(2-(S)-cyclopentylcarbonylmercapto-3-methyl- 1-oxobutyl)amino]-1-cyclopentyl]-carbonyl]-L-tyrosine ethyl ester, m.p. 130°-131° C., the compound of formula Ill wherein R4 is 4-hydroxyphenyl, R2 is ethyl, R3 is cyclopentylcarbonyl, and R4 is isopropyl.
Reaction SMILES: [C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:17]=[N:18][CH:19]=[C:20]([NH:22][CH3:23])[CH:21]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][C:32]([OH:34])=O)=[N:29][CH:30]=1>>[C:1]([N:5]1[C:9]2[N:10]=[CH:11][N:12]=[CH:13][C:8]=2[C:7]([C:14]([C:16]2[CH:21]=[C:20]([N:22]([CH3:23])[C:32](=[O:34])[CH2:31][C:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=3)[CH:19]=[N:18][CH:17]=2)=[O:15])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1
Reactant: O=C(O)Cc1ccc(Cl)cn1
Product: CN(C(=O)Cc1ccc(Cl)cn1)c1cncc(C(=O)c2cn(C(C)(C)C)c3ncncc23)c1

Procedure:
The title compound was prepared according to the method described for Example 1 using (7-tert-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(5-methylamino-pyridin-3-yl)-methanone (Preparation 187) and (5-chloro-pyridin-2-yl)-acetic acid (see Preparation 90) to afford the title compound as off white solid in 21% yield, 25 mg. 1H NMR (400 MHz, DMSO-D6) δ: 1.78 (s, 9H), 3.32 (s, 3H), 3.77 (brs, 2H), 7.26 (br, 1H), 7.83 (br, 1H), 8.21 (s, 1H), 8.32 (s, 1H), 8.48 (s, 1H), 8.85 (s, 1H), 8.97 (s, 1H), 9.02 (s, 1H), 9.51 (s, 1H); LCMS (system 10): Rt=3.29 min; m/z 463.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[C:22](=[O:31])[NH:23][C:24]4[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15]3)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[B-](F)(F)(F)[F:33].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:33][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH2:11][N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH2:7]3)[CH:13]=2)[NH:17][C:16]=1[C:21]1[C:22](=[O:31])[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: F[B-](F)(F)F
Reactant: CS(=O)(=O)N1CCN(Cc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)cc3c2)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(Cc2ccc3[nH]c(-c4cc5ccccc5[nH]c4=O)c(F)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-(5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}-1H-indol-2-yl)quinolin-2(1H)-one (3-1, 60 mg, 1.37 mmol) was dissolved in 5 mL of anhydrous dimethylsolfoxide and diluted with 5 mL of anhydrous acetonitrile. The solution was cooled to 0° C., and the fluorinating reagent, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate, 3-2 (0.25 equiv., 12 mg, 0.03 mmol) was added. After addition, the ice bath was removed, and the reaction stirred at room temperature for 30 minutes. 3-2 was continually added in this fashion until half of the starting material was consumed. At which point, the reaction was diluted with ethyl acetate (150 mL) and partitioned with water (25 mL). The two layers were separated, and the organic layer was washed several times with water. The organic layer was condensed under vacuum. The crude residue was purified by reverse phase HPLC (5-95% ACN/H2O-40 minutes). The pure fractions were combined and volatiles were removed under reduced pressure. The resulting solution was partitioned with ethyl acetate (200 mL) and washed with 1 N NaOH (15 mL) and brine. The organic layer was dried with Na2SO4, filtered and condensed under vacuum. The resulting pure product was isolated as yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 12.3 (s, 1H), 11.3 (s, 1H), 8.47 (s, 1H), 7.83 (d, 1H, J=7.8 Hz), 7.58-7.52 (m, 2H), 7.46 (s, 1H), 7.39 (d, 1H, J=8.3 Hz), 7.26 (t, 1H, J=7.8 Hz), 7.13 (d, 1H, J=8.5 Hz), 3.60 (s, H), 3.11 (m, 4H), 2.87 (s, 3H), 2.48 (m, 4H).
Reaction SMILES: C([O:5][C:6](=[O:24])[CH2:7][N:8]([C:15](=[O:23])[CH:16]([CH3:22])[CH2:17][S:18][C:19](=[O:21])[CH3:20])[CH2:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:19]([S:18][CH2:17][CH:16]([CH3:22])[C:15]([N:8]([CH2:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([OH:24])=[O:5])=[O:23])(=[O:21])[CH3:20]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)Cc1ccco1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)Cc1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
Crude N-(3-acetylthio-2-methylpropanoyl)-N-furfurylglycine tert-butyl ester (14.6 g, 0.0407 mol) was dissolved in a mixture of anisole (20 ml) and trifluoroacetic acid (65 ml). The resulting solution was stirred at room temperature for two hours. The solvent was evaporated in vacuo and the residue was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous bicarbonate extract was washed twice with ethyl acetate and then acidifed cautiously with concentrated hydrochloric acid to pH 4-5. The product was extracted several times into chloroform and the chloroform was washed twice with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give crude product as a pale yellow oil which was purified by HPLC using the following solvent system: ethyl acetate/n-hexane/acetic acid (40:60:1) to give pure product as a colorless oil (5.5 g, 44.7%). The product was purified by its DCHA salt which was prepared in ether, m.p. 140°-141° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]=[O:33])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1.[CH3:43][Mg]Br>C1COCC1.C(Cl)Cl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]([OH:33])[CH3:43])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1
Reactant: O=Cc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Reactant: C[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)c1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 4-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehyde (75 mg, 0.12 mmol) in THF (0.6 mL) at −78° C. under N2, add methylmagnesium bromide (120 μL, 3.0 M in Et2O). Allow the reaction to warm to 0° C. and stir for two h., then quench the reaction with a saturated solution of NH4Cl (1 mL). Dilute the mixture with CH2Cl2 (1 mL), wash with H2O (1 mL) and brine (1 mL). Pass the organic layer through a Varian ChemElute® drying cartridge and concentrate. Purify the residue by chromatography on silica gel using a gradient of 10:1 Hex/EtOAc to 2:1 Hex/EtOAc to afford the title compound (4.3 mg, 6%). MS/ES (M+1)=620.9.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[NH:16])=[CH:5][CH:4]=1.[Cl:17][CH2:18][C:19](O)=[O:20].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[Cl:17][CH2:18][C:19]([N:16]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][N:10]1[CH2:9][C:6]1[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=1)=[O:20]
Reactant: O=C(O)CCl
Reactant: N=c1ccccn1Cc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CCl)N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
70 mg (0.27 mmol) of the 1-[(6-chloropyridin-3-yl)methyl]pyridin-2(1H)-imine hydrochloride obtained by the method described in another method of Synthetic Example P1 was dissolved in 4 ml of anhydrous dichloromethane, 82 mg (0.67 mmol) of DMAP, 25 mg (0.27 mmol) of chloroacetic acid and 62 mg (0.32 mmol) of EDC-HCl were added thereto in sequence, and the resulting mixture was stirred at room temperature overnight. After the reaction was completed, dichloromethane was added thereto to dilute the mixture, and the mixture was washed with water and a 1% HCl aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the subject material. Amount obtained 4 mg (yield 5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10]([C:14]1[N:15]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:16]=[C:17]([Sn](CCCC)(CCCC)CCCC)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[N:15]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:16]=[C:17]([C:2]2[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=2)[C:8]#[N:9])[N:18]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CC2CCOCC2)c(C(C)(C)C)n1
Product: CC(C)(C)c1nc(-c2cc(C#N)ccn2)cn1CC1CCOCC1

Procedure:
The title compound 124 (70 mg, 0.22 mmol, yield: 68%) was obtained in the same manner as in step 3 of Example 101, using 2-chloro-4-cyanopyridine and 2-tert-butyl-1-(tetrahydropyran-4-yl)methyl-4-tributylstannyl-1H-imidazole obtained in step 1 of Example 108.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[C:11]1([NH:17][C:18]([NH2:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C1CCCCC1>O>[C:11]1([NH:17][C:18]([NH:20][C:2]2[CH2:3][S:4][CH2:5][C:6]=2[C:7]([O:9][CH3:10])=[O:8])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)Nc1ccccc1
Reactant: COC(=O)C1CSCC1=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: C1CCCCC1
Product: COC(=O)C1=C(NC(=O)Nc2ccccc2)CSC1

Procedure:
14.4 parts by weight of methyl 3-keto-3,4-dihydrothiophene-4-carboxylate, 16.1 parts by weight of phenylurea and 0.5 part by weight of toluenesulfonic acid in 90 parts by weight of cyclohexane were refluxed for 3 hours, while stirring, in an apparatus equipped with a water separator. The mixture was cooled, and the residue was then filtered off under suction and recrystallized from ethanol. 16.1 parts by weight of N-phenyl-N'-(3-methoxycarbonyl-2,5-dihydrothien-4-yl)-urea of melting point 182°-184° C. were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][O:31]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][O:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 223 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(3-bromopropyl)tetrahydrofuran but conducting the alkylation over 1 hour at 60° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=[O:2].C1(C)C=CC(S([CH2:22][N:23]=[C:24]=O)(=O)=O)=CC=1>>[O:2]1[C:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:24][N:23]=[CH:22]1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(-c2cnco2)cc1
Yield: 86.7 %

Procedure:
The procedure of Example 1 was repeated, except that methyl 4-formylbenzoate (4.92 g) and p-toluenesulfonylmethylisocyanate (7.03 g) were used, to thereby yield the title compound (5.28 g).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[CH:31]2)([O-:27])=[O:26]>CN(C)C=O.C(OCC)(=O)C>[N+:25]([C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[N:32]=[CH:31]2)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc([N+](=O)[O-])ccc32)CC1
Yield: 22.2 %

Procedure:
tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (30.6 mmol, 8.56 g), potassium carbonate (61.3 mmol, 8.47 g) and 5-nitro-1H-indazole (30.6 mmol, 5 g) were combined and heated to 100° C. in N,N-dimethylformamide (30 mL) for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate and concentrated at reduced pressure. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 30% ethyl acetate/heptane to 50% ethyl acetate/heptane) to afford the title compound (2.35 g). MS (ESI) m/z 291.0 [M+H]+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.