Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([Br:11])=[CH:9][S:8][C:7]=1[CH:12]=O)=O)C.[NH2:14][NH2:15].O>CCO>[Br:11][C:10]1[C:6]2[C:4](=[O:3])[NH:15][N:14]=[CH:12][C:7]=2[S:8][CH:9]=1
Reactant: NN
Reactant: CCOC(=O)c1c(Br)csc1C=O
Solvent: CCO
Solvent: O
Product: O=c1[nH]ncc2scc(Br)c12
Yield: 22.8 %

Procedure:
4-Bromo-2-formyl-thiophene-3-carboxylic acid ethyl ester (1.0 g, 3.8 mmol), NH2NH2.H2O (0.27 g, 4.58 mmol) and 20 mL of EtOH were refluxed under nitrogen for 5 h. The reaction mixture was cooled and precipitate formed, then filtered to give the title compound (0.2 g, yield: 23%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O.CCN(C(C)C)C(C)C>C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:12]=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:8][CH:7]=3)[S:11][CH:16]=2)=[CH:20][CH:21]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=S)Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Nc2nc(-c3ccc(Cl)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
(4-Trifluoromethylphenyl)thiourea (5.00 g; 22.7 mmol) was dissolved in ethanol (45 mL) by gentle heating. Then, α-bromo-p-chloroacetophenone (5.30 g; 22.70 mmol) and DIPEA (3.22 g; 24.9 mmol) was added. The resulting solution was stirred for 16 hours at ambient temperature. The mixture was then concentrated in vacuo, and the residue dissolved in ethyl acetate. The DIPEA hydrobromide, which crystallized out of solution, was removed by filtration. The filtrate was washed with water (2×50 mL) and brine (50 mL), and dried over anhydrous sodium sulphate. The solvent was removed by rotary evaporation to give 7.00 g (93%) of [4-(4-chlorophenyl)thiazol-2-yl]-(4-trifluoromethylphenyl)amine as an oil. The material was pure enough for use in the next step (a crystalline sample can be obtained by re-crystallization in heptane).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[S:6].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.C(OCC)(=O)C>O1CCCC1>[CH2:17]([N:4]1[CH2:3][CH2:2][N:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:5]1=[S:6])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCN(CCc1ccccc1)C(=S)NCCCc1ccncc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: S=C1N(CCCc2ccncc2)CCN1CCc1ccccc1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Anhydrous tetrahydrofuran (2.5 ml) was added to a mixture of 1-(2-hydroxyethyl)-1-phenethyl-3-[3-(4-pyridyl)propyl]thiourea (Compound No. 7-2) (601 mg, 1.75 mmol) and triphenylphosphine (913 mg, 3.49 mmol), and the whole was stirred under ice/methanol-cooling. A solution of diisopropyl azodicarboxylate (710 mg, 3.49 mmol) in anhydrous tetrahydrofuran was added dropwise thereto, and after 10 minutes, ethyl acetate (100 ml) was added to the reaction mixture. The whole was washed with a saturated aqueous sodium bydrogencarbonate solution (40 ml) and saturated brine (40 ml) successively, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained solid was filtered off with hexane to give 107 mg (19%) of the titled compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][CH2:7][C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])=[C:10](OC)[CH:9]=2)=[CH:4][CH:3]=1.C(S)C.[H-].[Na+]>CN(C)C=O>[CH3:20][C:13]1([CH3:19])[C:14](=[O:16])[O:15][C:21]2[CH:22]=[C:8]([CH2:7][NH:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=3)[CH:9]=[CH:10][C:11]=2[O:12]1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2ccc(Cl)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: CC1(C)Oc2ccc(CNc3ccc(Cl)cc3)cc2OC1=O
Temperature: 100 °C
Yield: 59.5 %

Procedure:
A mixture of 500 mg of ethyl 2-[4-(4-chloroanilinomethyl)-2-methoxyphenoxy]-2-methylpropionate, 206 mg of ethanethiol, 159 mg of 50% sodium hydride and 10 ml of dimethylformamide is heated at 100° C. for 3 hours. The reaction mixture is poured into ice-water and washed with ether. The aqueous layer is adjusted to pH 2 with 10% hydrochloric acid and extracted with ether. The extract is washed with water, dried and concentrated. The residue is pulverized with a mixture of diisopropyl ether and n-hexane and the crystals are collected by filtration to give 250 mg of 3,3-dimethyl-7-(4-chloroanilinomethyl)-1,4-benzodioxan-2-one, mp 97° to 98° C. From the mother liquor 60 mg of the same compound is further obtained.
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:25])[C:16]3[C:21]([S:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.[Cl-].[NH4+]>O1CCCC1>[F:10][C:11]1[CH:12]=[CH:13][C:14]2[C:15]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:25])[C:16]3[C:21]([S:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: CN1CCC(Cl)CC1
Reactant: O=c1c2ccccc2sc2cc(F)ccc12
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccccc3Sc3cc(F)ccc32)CC1

Procedure:
The Grignard reagent prepared from 0.62 g. of magnesium turnings and 3.5 g. of 4-chloro-N-methylpiperidine in tetrahydrofuran is treated with a solution of 3-fluoro-9-thioxanthone (3.0 g.) in 50 ml. of tetrahydrofuran. The mixture is refluxed for four hours, cooled, treated with saturated ammonium chloride solution and extracted with ether. The ether extract is washed with water, dried and concentrated to give 3-fluoro-9-(1-methyl-4-piperidyl)-thioxanthene-9-ol, m.p. 120°-130° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:14][C:15]1[C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:36]([NH:43][C:44](=[O:52])[NH:45][C@H:46]([CH3:51])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[S:23]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:52])[CH3:51])[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:29][CH:30]=3)=[O:4])[C:20]=2[N:21]=[CH:22]1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2scnc12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCI (1.17 g, 7.32 mmol, 1.2 eq), HOBt (0.93 g, 7.32 mmol, 1.2 eq), DIEA (2.13 mL, 12.2 mmol, 2.4 eq) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 718 (M+H), 740 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:16])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:18]>CO.CCOCC>[CH3:16][C@@:9]1([C:13]([O:15][CH3:18])=[O:14])[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a stirred solution of (S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid 106A in methanol (100 ml) and ether (100 ml) was added TMS-Diazomethane (80 ml) (2.0 M ether solution) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h and the reaction mixture was concentrated. The residue was purified by flash chromatography (10% EtOAc/Hexane) to give (S)-1-tent-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate 106B (28.5 g, 76% overall yield) as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.69 (s, 3H), 3.42-3.56 (m, 2H), 2.13-2.17 (m, 1H), 1.83-1.93 (m, 3H), 1.49 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)C.FC(F)(F)C(O)=O.[NH:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[NH2:35].CS(O)(=O)=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.N1C=CC=CC=1.O>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:34]1[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:13]2)=[CH:5][CH:4]=[N:35]1
Reactant: NNc1ccccn1
Reactant: CCOC(CC(=O)N1CCN(C(=O)OCc2ccccc2)CC1)OCC
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2ccnn2-c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.2 %

Procedure:
Part B: To a solution of benzyl 4-(3,3-diethoxypropanoyl)piperazine-1-carboxylate (3.39 g, 9.30 mmol) in 30 mL of chloroform at 0° C. was added a solution of 10.0 mL of water and 10.0 mL of trifluoroacetic acid, and the resulting biphasic mixture was stirred at 25° C. for 20 h. The mixture then was diluted with additional chloroform, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue then was dissolved in 50 mL of ethanol. To this solution was added 2-hydrazinopyridine (1.015 g, 9.30 mmol) and methanesulfonic acid (0.060 mL, 0.930 mmol), and the resulting mixture was stirred at 25° C. for 18 h. Pyridine (1.00 mL) was added, and then the reaction mixture was concentrated under vacuum. The residue was dissolved in 50 mL of pyridine. To this solution was added phosphorous oxychloride (1.73 mL, 18.6 mmol), and the mixture was stirred at 25° C. for 20 h. The mixture was concentrated under vacuum. The residue was diluted with water and ethyl acetate, and the phases were separated. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 10-50% ethyl acetate/methylene chloride) afforded 0.38 g (11.2%) of benzyl 4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine-1-carboxylate as an oil; Mass Spec.: m/e: 364.20 (M+H)+ [calc'd: 364.18]; 1H NMR (500 MHz, DMSO-D6) δ 8.53 (d, 1H, J=5.0 Hz), 7.97 (t, 1H, J=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 7.58 (s, 1H), 7.40-7.30 (m, 6H), 6.04 (s, 1H), 5.10 (s, 2H), 3.49 (m, 4H), 2.94 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([O:19][CH3:20])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:9]1[CH:10]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]([O:19][CH3:20])=[C:4]2[C:8]=1[N:7]([CH3:12])[CH:6]=[C:5]2[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: OB(O)c1ccccc1
Reactant: COc1c(Br)cc(F)c2c1c(CC(=O)N(C)C)cn2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccccc2)cc(F)c2c1c(CC(=O)N(C)C)cn2C
Yield: 81 %

Procedure:
To the solution of 8-11 (200 mg, 0.58 mmol) in dioxane (10 mL) was added phenylboronic acid (86 mg, 0.70 mmol), Pd(PPh3)4 (68 mg, 0.06 mmol), and Cs2CO3 (760 mg, 2.3 mmol) under nitrogen atmosphere. The reaction mixture was refluxed overnight, poured into water and extracted with ethyl acetate (20 mL×3). The separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution with petroleum ether:ethyl acetate=1:1) to afford 8-12 (160 mg, 81%) as white solid. LCMS: calc 340.4 and found 341.1 [MH]+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:68]3[N:67]=[C:60]([NH:61][C:62](=[O:66])[CH:63]([CH3:65])[CH3:64])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][O:33][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:68]3[N:67]=[C:60]([NH:61][C:62](=[O:66])[CH:63]([CH3:64])[CH3:65])[NH:59][C:57](=[O:58])[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][OH:33])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 0.90 ml, 0.90 mmol) was added, at room temperature, to a tetrahydrofuran solution (3.0 ml) of Compound 46 (41.3 mg, 0.060 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was distilled under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (AcOH-EtOH, 20:1) to obtain a white powder, Compound 47 (27.1 mg, 0.060 mmol, quant.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl>[C:15]([NH:14][CH2:13][CH:11]1[O:10][C:9](=[O:18])[N:8]([C:6]2[CH:5]=[CH:4][C:3]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:21][CH:20]=3)=[C:2]([F:1])[CH:7]=2)[CH2:12]1)(=[O:17])[CH3:16]
Reactant: CC(=O)NCC1CN(c2ccc(-c3ccc(CO)cc3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2ccc(-c3ccc(COS(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A suspension of 51 (12.49 g, 34.90 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (Et3N, 7.07 g, 9.7 mL, 70 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before being treated dropwise with methanesulfonyl chloride (4.80 g, 3.24 mL, 41.9 mmol, 1.2 equiv) at 0-5° C. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was treated with H2O (100 mL) at 0-5° C. The mixture was then concentrated in vacuo to remove most of the CH2Cl2, and the resulting slurry was treated with H2O (150 mL). The mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 30 min. The solid precipitates were collected by filtration, washed with H2O (2×100 mL) and 20% EtOAc/hexane (2×50 mL), and dried in vacuo. The crude desired methanesulfonic acid 4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl ester 52 (11.84 g, 78% yield) was obtained as off-white solids, which by TLC and HPLC was found to be essentially pure and was directly used in the subsequent reaction without further purification. LCMS (ESI) m/e 437 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:29][N:30]([CH3:40])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])(C(C)(C)C)(C)C>C1COCC1.C(OCC)(=O)C>[OH:26][CH2:27][CH:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:29][N:30]([CH3:40])[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]
Reactant: CN(CC(CO[Si](C)(C)C(C)(C)C)c1ccccc1)S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC(CO)c1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
A THF solution of tetrabutylammonium fluoride (1.0 M, 3.9 mL, 3.9 mmol) was added to dropwise to a solution of N-(3-(tert-butyldimethylsilyloxy)-2-phenylpropyl)-N-methylbenzenesulfonamide (570 mg, 1.31 mmol) in 5.0 mL of THF. After stirring for 30 min at room temperature, the mixture was diluted with 50 mL of ethyl acetate and washed in sucession with 30 mL of 2.0 N aqueous HCl, 30 mL of saturated aqueous sodium bicarbonate, and 30 mL of brine. The organic layer was dried over sodium sulfate, decanted and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 20-30% of ethyl acetate in hexanes to give 393 mg of the title compound as a colorless syrup. 1NMR (400 MHz, CD3OD): δ 7.74 (d, 2H, J=7 Hz), 7.64 (tt, 1H, J=7, 1 Hz), 7.56 (t, 2H, J=7 Hz), 7.33-7.20 (m, 5H), 3.79-3.71 (m, 2H), 3.41 (dd, 1H, J=13, 7 Hz), 3.24 (dd, 1H, J=13, 8 Hz), 3.13-3.04 (m, 1H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([CH3:14])([CH3:13])[C:11]#[N:12].[Br:15]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[Br:15][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([Cl:1])=[C:3]([C:10]([CH3:14])([CH3:13])[C:11]#[N:12])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(C)(C)C#N)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cl)c(C(C)(C)C#N)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (17.5 g, 0.0835 mol) in TFA (100 mL) was cooled to 0° C. N-bromosuccinimide (14.9 g, 0.0835 mol) was added in small portions keeping the temperature below 5° C. The orange solution was stirred for 2 h/25° C. and evaporated to dryness. Water (200 mL) was added and the mixture was stirred vigorously for 1 h. The crude product was filtered off and recrystallized from boiling MeOH. The pure product was isolated as white needles. Yield: 13 g (54%). GCMS: >99%
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:51])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3F)[CH:26](S(C3C=CC=CC=3)(=O)=O)[CH2:25][CH:24]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[CH2:9]([C@H:26]1[C@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:23]([C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:51])[NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:9]([OH:8])=[O:10])[C@H:24]([C:44]([O:46][C:47]([CH3:48])([CH3:49])[CH3:50])=[O:45])[CH2:25]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1CC(S(=O)(=O)c2ccccc2)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](Cc2ccccc2)[C@H](c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 126.1 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2A, but from 5.8 g of tert-butyl (2RS,4SR,5RS)-1-{2-[3-(3-(benzyloxycarbonyl)phenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(phenylsulphonyl)pyrrolidine-2-carboxylate and 0.6 g of 10% palladium-on-charcoal in 200 cm3 of ethanol. After treatment, there are obtained 2.85 g of (2RS,4SR,5RS)-3-{3-[2-(2-tert-butoxycarbonyl-5-(2-fluorophenyl)-4-phenylsulphonyl-1-pyrrolidinyl)2-oxoethyl]ureido}benzoic acid [Rf =0.25; eluent: methylene chloride/methanol (90/10)].
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:15]([C:3]2[CH:4]=[N:5][N:6]([CH2:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:2]=2[CH3:1])=[O:17])[CH:20]=[CH:21][C:22]=1[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[CH2:29][CH2:28]1)#[N:25]
Reactant: Cc1c(C(=O)O)cnn1CCc1ccccc1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1CCc1ccccc1
Yield: 30.8 %

Procedure:
The reaction and treatment in the same manner as in Example 64 were conducted using 5-methyl-1-(2-phenylethyl)pyrazole-4-carboxylic acid (0.6 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (0.75 g) and the resulting product was recrystallized from ethyl acetate to give the title compound (0.4 g), melting point: 195° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.F[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:3]3[C:4]([NH2:9])=[N:5][C:6]([NH2:8])=[N:7][C:2]=3[CH3:1])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(F)cc1
Reactant: Cc1nc(N)nc(N)c1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 0 °C
Yield: 83.8 %

Procedure:
A mixture of 12.5 g (0.060 mole of 6-methyl-5-(1-piperazinyl)-2,4-pyrimidinediamine, 7.27 g (0.060 mole) of 4-fluorobenzonitrile, and 8.28 g (0.060 mole) of potassium carbonate was heated at 100° C. for two hours in 100 ml of dimethylsulfoxide. The mixture was then cooled and poured into 500 ml of ice water. The solid which separated was triturated with hot dimethylsulfoxide and then dried in vacuo overnight at 67° C. to give 15.56 g of the product as a white solid, mp>310° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(OCC)C>[CH:21]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(C)OB(c2cnn(C3C=CCCC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250 mg, 1.29 mmol), 3-bromocyclohexene (0.17 mL, 1.42 mmol), and cesium carbonate (462 mg, 1.42 mmol) were added to an oven-dried flask, followed by DMF (4.3 mL). The reaction mixture was stirred at 90° C. overnight then cooled to room temperature, diluted with diethyl ether, washed with water (3×50 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(cyclohex-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (500 MHz, CD3OD) δ 7.82 (s, 1H), 7.69 (s, 1H), 5.81-5.62 (m, 2H), 4.15-4.09 (m, 1H), 2.24-1.41 (m, 6H), 1.31 (s, 12H).