Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].Cl.[CH3:7][N:8]1[CH2:14][C:13]2[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21](O)=O)[CH:17]=[N:18][C:12]=2NC(=O)[CH2:9]1.CNCC1C2C(=CC=CC=2)N(C)C=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[CH3:17][N:18]([CH2:12][C:13]1[C:15]2[C:9](=[CH:21][CH:20]=[CH:19][CH:16]=2)[N:8]([CH3:7])[CH:14]=1)[C:1](=[O:5])[CH:2]=[CH2:3]
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: C=CC(=O)O
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cn(C)c2ccccc12
Agent: Cl
Product: C=CC(=O)N(C)Cc1cn(C)c2ccccc12
Yield: 58 %

Procedure:
According to the procedure of Example 1 (a), except substituting acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-napthalen-2-ylmethyl)amine, the title compound (1.51 g, 58%) was prepared as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.71-7.50 (s, 1H), 7.34-7.21 (m, 2H), 7.15-6.90 (m, 2H), 6.80-6.53 (m, 1H), 6.45-6.35 (s, 1H), 5.72-5.67 (m, 1H), 4.80-4.75 (m, 2H), 3.77 (s, 3H), 3.05-2.99 (m, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C@H:21]([CH2:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C@H:21]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36]2)[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A solution of 3.20 g (6.3 mmol) of 2-(R)-(3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl) propionic acid, benzyl ester (from Step A) in 40 mL of THF at 0° C. was treated with 10 mL of 1.0 M tetrabutylammonium fluoride solution in THF. The resulting mixture was warmed to rt and stirred for 2.5 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of 50% sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4 and concentrated. Flash chromatography on 100 g of silica gel using 2:1 v/v hexanes/ether as the eluant afforded 2.34 g (94%) of the title compound: 1H NMR (500 MHz) δ 1.56-2.07 (8H), 2.15 (br s, 1H), 2.27-2.37 (2H), 2.64 (t, J=11.0, 1H), 2.80 (dd, J=6.5, 11.0), 3.04-3.11 (2H), 3.23-3.30 (2H), 3.56 (dd, J=7.5, 13.0, 1H), 3.68 (dd, J=5.5, 13.0, 1H), 5.15 (ABq, J=20.0, 2H), 7.17-7.40 (10H).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:14])[NH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15](N(C(C)C)C(C)C)C.C[Si](C=[N+]=[N-])(C)C.Cl>O1CCOCC1.CCCCCC.CO>[CH3:15][O:14][C:7]1[C:8]([C:10]([O:12][CH3:13])=[O:11])=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1nc([N+](=O)[O-])c[nH]c1=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COC(=O)c1nc([N+](=O)[O-])cnc1OC
Reaction time: 15 h

Procedure:
In 2.0 L of dioxane was suspended 48.7 g of methyl 6-nitro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate, to which were successively added 42.4 mL of N-ethyldiisopropylamine and 9.9 mL of methanol. Then, 122 mL of a 2.0 mol/L solution of trimethylsilyldiazomethane in hexane was added at room temperature, the mixture thus obtained was stirred at the same temperature as above for 15 hours, and the solvent was removed under reduced pressure. Then, 500 mL of ethyl acetate and 250 mL of water were added to the residue obtained above, pH was adjusted to 1.5 with 6 mol/L hydrochloric acid, and the organic layer was separated. The remaining aqueous layer was extracted with two 200 mL portions of ethyl acetate. All the organic layers were united, washed successively with 200 ml of water and 200 mL of saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel chromatography ]eluent: n-hexane:ethyl acetate=2:1] to obtain 24.3 g of methyl 3-methoxy-6-nitro-2-pyrazinecarboxylate as a solid product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccccc2Cl)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(2-chlorophenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 8, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization from petroleum ether affords the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[O:13][CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:13][CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Yield: 103.9 %

Procedure:
4-Methylbenzenesulfonyl chloride (22.7 g) was added portionwise to a stirred, cooled solution of tert-butyl (S)-2-hydroxyoxymethylpyrrolidine-1-carboxylate (20.0 g) in pyridine (70 mL) while maintaining the temperature at 0° C. The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was dissolved in DCM and washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give tert-butyl (S)-2-(4-methylbenzenesulfonyl-oxymethyl)pyrrolidine-1-carboxylate (34 g) as a yellow oil which was used without further characterisation.
Reaction SMILES: [C:1]12([PH:11][C:12]34[CH2:21][CH:16]5[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]5)[CH2:13]3)[CH2:19]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC=CC=1.C(Br)CCC>C(OCCCC)CCC>[C:1]12([P:11]([C:12]34[CH2:19][CH:18]5[CH2:20][CH:14]([CH2:15][CH:16]([CH2:17]5)[CH2:21]3)[CH2:13]4)[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C1C2CC3CC1CC(PC14CC5CC(CC(C5)C1)C4)(C2)C3
Reactant: [Li]CCCC
Solvent: CCCCBr
Solvent: Cc1ccccc1
Solvent: CCCCOCCCC
Product: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2

Procedure:
4.6 g (15 mmol) of di(1-adamantyl)phosphine were placed in 50 ml of di-n-butyl ether, and 20 ml of a 2.5 M solution of n-BuLi in toluene (50 mmol) were added. The mixture was refluxed for 1 h and cooled and 4.1 g (30 mmol) of 1-butyl bromide were added dropwise. The mixture was refluxed for 30 min, cooled and washed with saturated ammonium chloride solution (3×), the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]([CH2:46][CH2:47][O:48][CH3:49])[CH3:45])[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: COCCN(C)C(=O)CCl
Product: COCCN(C)CCOc1ccc(CN(c2cc(OC)ccc2C2CCc3cc(O)ccc3C2)C(C)C)cc1F
Yield: 5.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.4 mg) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:27](=O)[O:26][CH2:25]2.Cl.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:27](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:26][CH2:25]2
Reactant: O=C1Cc2ccccc2N1
Reactant: Nc1ccc2c(c1)COC2=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
To a solution containing oxindole (0.5 g, 3.76 mmol) in 7.5 mL DMF was added 7.51 mL of sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring 10 min at room temperature, a solution of 5-aminophthalide (0.672 g, 4.51 mmol) in 4.0 mL DMF was added over 3 min. The reaction was stirred for 30 min at room temperature and then poured into 4% aqueous HCl solution to give a yellow cloudy solution. After stirring the mixture 3 min, the solution was made basic by adding saturated NaHCO3. The yellow solid was filtered, washed with H2O, and then dissolved in CHCl3/MeOH. The solvent was removed in vacuo and the solid purified by chromatography (silica gel, CHCl3/MeOH, 95:5) to give the title compound (345 mg, 35%) as a yellow solid.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.Cl.NC1[N:18]=[CH:19][NH:20][C:21]=1[C:22]([NH2:24])=[O:23].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:18]3[CH:19]=[N:20][C:21]([C:22]([NH2:24])=[O:23])=[C:14]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(C(=O)C=CN(C)C)cc1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccnc3c(C(N)=O)ncn23)cc1
Yield: 69 %

Procedure:
A mixture of 15.0 g of 3-dimethylamino-4'-methylacrylophenone (prepared as described in Example 11) and 10.0 g of 4-amino-5-imidazolecarboxamide hydrochloride in 150 ml of glacial acetic acid was stirred and heated at reflux for 4 hours. The mixture was evaporated in vacuo to give a yellow crystalline solid. The solid was treated with saturated sodium bicarbonate solution and was collected by filtration, and then it was recrystallized from acetonitrile to give 10.7 g of the desired product as yellow crystals, mp 263°-266° C.
Reaction SMILES: [CH2:1](N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)[CH3:2].[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]3[C:76]([C:77]([F:80])([F:79])[F:78])=[CH:75][N:74]=[C:73]([NH:81][C:82]4[CH:92]=[CH:91][C:85]([CH2:86][P:87](=[O:90])([O-:89])[O-:88])=[CH:84][CH:83]=4)[N:72]=3)=[CH:62][CH:61]=2)[CH:57]=[N:56]1>>[OH:50][CH2:51][CH2:52][CH2:53][CH2:54][N:55]1[CH:59]=[C:58]([C:60]2[N:65]=[C:64]([C:66](=[O:69])[NH:67][CH3:68])[C:63]([NH:70][C:71]3[C:76]([C:77]([F:79])([F:80])[F:78])=[CH:75][N:74]=[C:73]([NH:81][C:82]4[CH:83]=[CH:84][C:85]([CH2:86][P:87](=[O:89])([OH:88])[O:90][CH2:1][CH3:2])=[CH:91][CH:92]=4)[N:72]=3)=[CH:62][CH:61]=2)[CH:57]=[N:56]1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Reactant: CNC(=O)c1nc(-c2cnn(CCCCO)c2)ccc1Nc1nc(Nc2ccc(CP(=O)([O-])[O-])cc2)ncc1C(F)(F)F
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)nc3C(=O)NC)n2)cc1
Yield: 90 %

Procedure:
Prepared analogously to Compound 3A using (4-{[4-({6-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 16B, 127 mg, 188 μmol) to afford 109 mg of the title compound (90%). 1H NMR (400 MHz, CD3OD) δ 9.16 (br. s., 1H), 8.44 (br. s., 1H), 8.28 (s, 1H), 8.15-8.19 (m, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.44 (dd, J=2.6, 7.9 Hz, 2H), 7.33 (dd, J=1.9, 8.5 Hz, 2H), 4.22 (t, J=7.1 Hz, 2H), 3.86 (quin, J=7.0 Hz, 2H), 3.57-3.63 (m, 2H), 3.03 (s, 1H), 2.94-3.00 (m, 4H), 1.92-2.05 (m, 2H), 1.50-1.64 (m, 2H), 1.16 (t, J=7.1 Hz, 3H). MS (ESI): m/z 649.75 [M+H]+. UPLC: tR=1.10 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[C:4]([Cl:10])[N:3]=1.C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[N:3]=[C:4]([Cl:10])[C:5]([F:9])=[CH:6][N:7]=1
Reactant: Fc1nc(Cl)c(F)c(Cl)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ncc(F)c(Cl)n1
Yield: 70.4 %

Procedure:
185 g (1 mol) of 2,5-difluoro-4,6-dichloropyrimidine in 1800 ml of ethyl acetate were hydrogenated in a stirred stainless steel autoclave for 95 minutes at 30° C. and under a hydrogen pressure of 3.5 bar, with the addition of 110 g of triethylamine and 15 g of palladium on carbon (5% strength by weight). Thereafter, the solid components of the reaction mixture were filtered off, the residue was washed with ethyl acetate, and the wash liquid together with the filtrate was distilled under atmospheric pressure over a 30 cm packed column. After the solvent had been distilled off, 106 g of 2,5-difluoro-4-chloropyrimidine having a boiling point of 145° to 146° C. were obtained. The yield was accordingly 70.5% of theory. According to analysis by gas chromatography, the reaction product isolated had a purity of 94.7%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][OH:13])[CH2:7][CH2:6]2)OCC1.C1COCC1.Cl.C([O-])(O)=O.[Na+]>CC(C)=O>[OH:13][CH2:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5](=[O:1])[CH2:6][CH2:7]1
Reactant: OCCC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(1,4-Dioxaspiro[4.5]dec-8-yl)ethanol (2.70 g, 0.0145 mol) was dissolved in acetone (10.00 mL) and THF (10.00 mL) and 6.00 M HCl (6.00 mL) was added. The reaction was stirred at 25° C. for 16 hours, neutralized with NaHCO3 solution and was then extracted with ethyl acetate. The organic extracts were washed with water, and with saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The crude product was used in the next reaction without further purification. 1H NMR (CDCl3): 3.75 (m, 2H), 2.36 (m, 4H), 1.20-2.13 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29][C:30]([F:33])([F:31])[F:32])=[CH:25][CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Solvent: CO
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(SC(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 64 %

Procedure:
The titled compound was prepared in 64% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (100 mg, 0.316 mmol) and 1-bromomethyl-4-trifluoromethylsulfanyl-benzene (90 mg, 0.332 mmol) according to the procedure described in Example 3: 1H NMR (400 Mz, DMSO-d6) δ 7.79 (d, 2 H, J=8.8), 7.61 (d, 2 H, J=8.8), 7.59 (d, 2 H), J=8.1), 7.43 (d, 2 H, J=8.1), 7.32 (br s, 1 H), 6.65 (br s, 1 H), 4.62 (ABq, 2 H, Δv=73.1, Jab=17.3), 3.88 (dt, 1 H, Jd=12.7, Jt=3.9), 2.79 (m, 1 H), 2.43 (m, 1 H), 1.79 (m, 1 H), 1.65 (m, 2 H), 1.42–1.19 (m, 3 H), 0.94 (m, 1 H); MS m/e 529.1 (M+Na)+. Optical rotation: [α]D=−28.6 (c=5.87 mg/mL, MeOH).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14]([C:21]([CH2:23][CH2:24][CH2:25]Cl)=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:25][CH2:24][CH2:23][C:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:22])=[N:5][N:4]=[N:3]1
Reactant: O=C(CCCCl)Cc1ccccc1
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g), potassium carbonate (2.1 g) and 3-chloropropyl benzyl ketone (2.9 g) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography [Kieselgel 60, eluant: benzene-ether (10:1)] to obtain 1-methyl-5-[3-(benzylcabonyl)propyl]thio-1,2,3,4-tetrazole (yield 50%) as colorless liquid, nD25 =1.5610.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]([CH3:32])([CH3:31])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C:23]([O:22][CH3:21])([CH3:31])[CH3:32])[N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 56.8 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 0.1 g, 0.37 mmol) and 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 94, 0.065 g, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.19 g, 0.44 mmol) in methylene chloride (10 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.10 mmol) and the resulting solution stirred at room temperature for 19 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution, and dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF15-40 g column, 50%-70% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (0.063 g, 0.21 mmol, 41%) as an off white solid; [α]29D=−47.5° (c=0.28, chloroform); HR-ES(+) m/e calcd for C24H32N4O3 [M+Na]+ 447.2366, observed 447.2368; 1H NMR (300 MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.62 (m, 2H), 7.48 (d, J=2.3 Hz, 1H), 7.45-7.54 (m, 1H), 6.43 (d, J=2.3 Hz, 1H), 5.05 (dd, J=10.7, 5.0 Hz, 1H), 4.87 (d, J=17.8 Hz, 1H), 4.53 (d, J=17.8 Hz, 1H), 3.99 (s, 2H), 3.15 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 0.98-2.10 (m, 11H).
Reaction SMILES: [CH3:1]N(C)C=O.[C:6]([C:8]1[CH:9]=[C:10]([NH:20][C:21]([C:23]2[C:24]([CH3:35])=[N:25][N:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:27]=2)=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:7].[H-].[Na+].CI>O>[C:6]([C:8]1[CH:9]=[C:10]([N:20]([CH3:1])[C:21]([C:23]2[C:24]([CH3:35])=[N:25][N:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:27]=2)=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:7]
Reactant: CN(C)C=O
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)N(C)c1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dimethylformamide (5 ml) solution containing N-(3-cyano-4-neopentyloxyphenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide (1.5 g) was added sodium hydride (60% content, 0.2 g) under ice-cooling and the mixture was stirred for 1 h. A solution of dimethylformamide (1 ml) containing methyl iodide (0.6 g) was added and the mixture was stirred under ice-cooling for 1 h. The mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate:n-hexane=5:1) to give the title compound (0.5 g), melting point: 65–69° C.
Reaction SMILES: C(N(CC)CC)C.[NH:8]([CH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11]1)[NH2:9].[O:21]([C:28](Cl)=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[O:21]([C:28]([NH:9][NH:8][CH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11]1)=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC1NS(=O)(=O)c2ccccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NNC1NS(=O)(=O)c2ccccc21)Oc1ccccc1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
5 g (0.05 mol) of triethylamine are added to 9.8 g (0.05 mol) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide in 100 ml of dioxane, and 8.6 g (0.55 mol) of phenoxycarbonyl chloride, dissolved in 25 ml of dioxane, are then added dropwise to the stirred mixture. After about 2 hours, the precipitated salt is filtered off under suction and washed with 15 ml of cold dioxane, and the combined mother liquors are evaporated down. Crystallization from ethanol gives 12.8 g (81% of theory) of 3-phenoxycarbonylhydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide of melting point 216° C.