Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:20][C:21]([NH2:23])=[S:22].C(O)C>O>[NH2:23][C:21]1[S:22][C:2]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:20]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCc1sc(N)nc1-c1ccc(Cl)cc1
Yield: 89.8 %

Procedure:
A mixture of ethyl 5-bromo-5-(4-chlorobenzoyl)valerate (17.4 g), thiourea (4.57 g) and ethanol (50 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give ethyl 2-amino-4-(4-chlorophenyl)-5-thiazolebutanoate (14.6 g, 85%) as pale yellow prisms. Melting point 114-115° C.
Reaction SMILES: [CH2:1]([CH:8]1[NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[S:37](Cl)(=[O:39])=[O:38])[CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([CH:8]1[N:15]([S:37]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:36]=2[N:27]=[CH:28][CH:29]=[CH:30]3)(=[O:38])=[O:39])[CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC2CCCc3ccccc3CN2)cc1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2CCCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 301 (crude 1.58 mmol), Et3N (0.33 mL, 2.4 mmol) and DMAP (39 mg, 0.32 mmol) in DCM (25 mL), quinoline-8-sulfonyl chloride (538 mg, 2.37 mmol) in DCM (5 mL) was added dropwise at 0° C. After addition was complete, the solution was left to stir at rt overnight. The mixture was washed with water (2×30 mL) and brine. The organic layer was combined, dried over Na2SO4, concentrated in vacuo. MeOH (10 mL) was added to the residue and the precipitation was filtered to give the desired product (60 mg, 81% over three steps). 1H NMR (500 MHz, CDCl3) δ: 9.07 (m, 1H), 8.51 (d, 1H), 8.13 (d, 1H), 7.93 (d, 1H), 7.57 (t, 1H), 7.44 (m, 1H), 7.29 (d, 1H), 7.12 (m, 2H), 6.98 (m, 1H), 6.90 (m, 3H), 6.59 (d, 2H), 5.76 (d, 1H), 5.53 (d, 1H), 4.34 (m, 1H), 3.61 (m, 1H), 2.59 (m, 1H), 2.27 (t, 1H), 2.07 (m, 1H), 1.88 (m, 1H), 1.60 (m, 1H), 1.34 (m, 1H), 1.24 (m, 1H). MS (ESI+) m/z: 443 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:26])[N:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]2[C:17]([C:18]=1O)=[CH:16][CH:15]=[CH:14][N:13]=2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>C(O)(=O)C>[C:2]1([C:1]2[C:9]3[C:10](=[O:26])[N:11]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12]4[N:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:18]=3[NH:29][N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c(-c3ccccc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 52 %

Procedure:
850 mg (2.5 millimoles) of Compound 101 was suspended in 5 ml of glacial acetic acid, and 0.26 ml (5.5 millimoles) of hydrazine monohydrate was added to the suspension. The mixture was heated under reflux for 5 hours and the reaction mixture was cooled to room temperature. The precipitate was collected by filtration, and recrystallized from DMF-water to obtain 440 mg (yield 52.4%) of Compound 1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[SH:18].C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C=O)C>O>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][S:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1])[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: Fc1ccccc1-c1noc2c(Cl)c(S)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1ccc2c(-c3ccccc3F)noc2c1Cl
Temperature: 50 °C

Procedure:
3.2 g of 7-chloro-3-(2-fluorophenyl)-6-mercapto-1,2-benzisoxazole, 3.1 g K2CO3 and 3.67 g of ethyl bromoacetate are added to 60 ml DMF and warmed for two hours at 50° C. with stirring. The solution is poured into 700 ml H2O and extracted with ethyl acetate. The combined organic extracts are dried over K2CO3, and the solvent is removed in vacuo to afford ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]thio}acetate.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Mg]Br.O>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(Cl)c(C(O)c3ccccc3OC)cc2c1
Temperature: -78 °C

Procedure:
2-Chloro-6-methoxyquinoline-3-carbaldehyde (2.66 g, 12 mmol) was dissolved in THF (40 mL) under nitrogen and cooled to −78° C. At this temperature, a solution of 2-methoxyphenyl magnesium bromide (1M, 12.1 mL, 13.32 mmol) in THF was added by drops. Then the mixture was heated slowly to room temperature. The batch was mixed with water and extracted several times with ethyl acetate. The combined organic phases were washed with water until neutral, dried (sodium sulfate) and concentrated. Yield: 3.9 g (11.8 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][N:17]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:18]3=[O:23])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc(Cl)cc4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
4-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1NHCl (30 mL) for 30 minutes. The mixture was filtered, and the solid was slurried with hot acetone (10 mL) to give 1-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.7 g, 73%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 6.77 (t, J=5.0 Hz, 1H, NH), 7.27 (d, J=10.0 Hz, 2H, Ar), 7.40 (d, J=10 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.77 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 45.19, 51.58, 119.29, 121.56, 124.66, 128.30, 128.44, 130.35, 131.64, 135.46, 139.31, 139.92, 155.08, 168.07, 171.00, 172.84; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.85; H, 4.35; N, 12.97; Cl, 8.19.
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:18]([F:30])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.CCN(C(C)C)C(C)C.[S:40](Cl)(=[O:43])(=[O:42])[NH2:41].[Cl-].[NH4+]>C(Cl)Cl>[F:30][C:18]1[CH:19]=[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:2]([NH:1][S:40](=[O:43])(=[O:42])[NH2:41])=[C:3]([CH:17]=1)[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: NS(=O)(=O)Cl
Reactant: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.7 %

Procedure:
244 mg N-(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-phenyl)ethanesulfonamide (0.448 mmol, 1 eq.) were dissolved in 10 mL DCM, treated with 0.781 mL DIPEA (4.5 mmol, 10 eq.) and 388 mg sulfamoyl chloride (3.36 mmol, 7.5 eq.) and the resulting solution stirred at rt for four days. The reaction mixture was portioned between ammonium chloride solution and DCM, the aqueous layer reextracted with DCM, the combined organic layers dried, filtered and concentrated in vacuo. Flash column chromatography provided 97 mg of the target compound (35% yield). A second product fraction was further purified by thick layer chromatography (hexane/ethyl acetate 1:1 as eluent) yielding additional 67 mg of the target compound (22% yield).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[I-].[K+].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: C1CCNC1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-(trifluoromethyl)-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and pyrrolidine in tetrahydrofuran are reacted to give 8-(trifluoromethyl)-1-(pyrrolidinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.BrCC1C(Cl)=NC(Cl)=CC=1.[CH3:21][C:22]1[N:27]=[C:26]([SH:28])[N:25]=[C:24]([OH:29])[CH:23]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([CH2:8][S:28][C:26]2[N:25]=[C:24]([OH:29])[CH:23]=[C:22]([CH3:21])[N:27]=2)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: OCc1ccc(Cl)nc1Cl
Agent: Clc1ccc(CBr)c(Cl)n1
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccc(Cl)nc2Cl)n1
Yield: 82 %

Procedure:
The crude (2,6-dichloropyridin-3-yl)methanol was converted to 3-(bromomethyl)-2,6-dichloropyridine, which was then reacted with 6-methyl-2-sulfanylpyrimidin-4-ol in the presence of triethylamine to provide 2-{[(2,6-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.822 g, 82% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.36 (s, 2H), 5.95 (bs, 1H), 7.40 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H); M+302.5.
Reaction SMILES: C(#N)C.[CH:4]([C:7]([CH:9]([CH3:11])[CH3:10])=[O:8])([CH3:6])[CH3:5].[I-].[Na+].Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C(N(CC)CC)C>[CH3:5][C:4](=[C:7]([O:8][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]([CH3:11])[CH3:10])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C(=O)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=C(O[Si](C)(C)C)C(C)C
Yield: 96.6 %

Procedure:
Acetonitrile (300 mL) was mixed with 20.3 g of diisopropyl ketone, 32 g of sodium iodide, and 21.6 g of triethylamine, to which was gradually added 23.1 g of chlorotrimethylsilane. The mixed solution was reacted at 50° C. for 4 hours and then allowed to stand for cooling. The reaction mixture was poured into ice and extracted with hexane. An organic phase was rinsed with a sodium hydrogencarbonate solution, dried, and then concentrated. The resultant was purified by distillation in vacuo to obtain 32 g of 2,4-dimethyl-3-trimethylsilyloxy-2-pentene (silylenol ether of diisopropyl ketone). The resulting silylenol ether (15 g) and 8.8 g of tetramethylene sulfoxide were dissolved in 150 mL of chloroform under a nitrogen gas stream. The solution was cooled to −30° C. or lower, and 17.7 g of trifluoroacetic anhydride was added dropwise thereto over 30 minutes. The mixture was reacted at room temperature for 1 hour, and a solution of potassium nonafluorobutanesulfonate in acetonitrile/water was added to the reaction mixture. The mixture was extracted with chloroform, and an organic phase was subjected to alkali rinsing with a 5% by weight tetramethylammonium hydroxide aqueous solution, followed by rinsing with distilled water until aqueous phases had become neutral. An organic phase was concentrated, and diisopropyl ether was added to the resulting crude product to deposit a powder. The powder was collected by filtration to obtain 17 g of Compound (I-1).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>CN(C)C=O.O>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([C:10]=1[OH:11])[C:7]([NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([F:35])=[CH:37][CH:38]=1)=[O:9]
Reactant: Cc1ncc(C(=O)O)c(O)c1Br
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1Br
Temperature: 25 °C
Reaction time: 9 h
Yield: 77.2 %

Procedure:
The compound 20 (138 g, 0.596 mol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 g, 0.775 mol), and 1-hydroxybenzotriazole (100 g, 0.656 mol) were dissolved in dimethylformamide (970 ml), and 4-fluorobenzylamine (79 ml, 0.715 mol) was added. After the reaction solution was stirred at room temperature for 9 hours, water (2000 ml) was added, and crystals were collected by filtration, followed by washing with ether. 5-Bromo-N-(4-fluorobenzyl)-4-hydroxy-6-methylnicotinamide 21 (156 g, 77%) was obtained as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[C:17]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][O:19][N:20]=1.C(N(CC)CC)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>ClC(Cl)C.CN(C1C=CN=CC=1)C>[C:22]([NH:21][C:17]1[C:16]([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=2[Cl:1])=[N:20][O:19][N:18]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1nonc1N
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nonc1NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
173 mg (0.5 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid and 191 mg (0.505 mmol) of N-(4-amino-1,2,5-oxadiazol-3-yl)acetamide are dissolved in 5 ml of dichloroethane at RT and treated with 0.071 ml (0.5 mmol) of triethylamine, 31 mg (0.25 mmol) of DMAP and 483 mg (0.76 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF). The reaction mixture is stirred for 24 h at RT and subsequently filtered through a glass frit. The residue is washed twice using in each case 1 ml of CH2Cl2. The filtrate is passed over a silica-gel-filled SPE cartridge and eluted twice using in each case 5 ml of a mixture of ethyl acetate/methyl tert-butyl ester (1:1). The organic phase is dried over Na2SO4 and evaporated. The residue is purified by preparative HPLC using acetonitrile/water. Yield 16 mg (9%).
Reaction SMILES: C1(C2ON=C(C3C=CN=CC=3)C=2)CC1.[CH:15]1([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH2:17][CH2:16]1.[H][H]>[Pt]=O.C(O)C>[NH2:19][C:18]([CH:15]1[CH2:17][CH2:16]1)=[CH:22][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: c1cc(-c2cc(C3CC3)no2)ccn1
Reactant: [H][H]
Agent: O=[Pt]
Agent: c1cc(-c2cc(C3CC3)on2)ccn1
Solvent: CCO
Product: NC(=CC(=O)c1ccncc1)C1CC1

Procedure:
A 1.0 g. sample of the mixture of 4-(5-cyclopropyl-3-isoxazolyl)pyridine and 4-(3-cyclopropyl-5-isoxazolyl)pyridine, obtained as described in Examples 2 and 3, is mixed with 0.125 g. of platinum oxide and 75 ml. of ethanol. This mixture is treated with hydrogen on a Parr apparatus at 40 psi for 2 hours at room temperature. The mixture is filtered and the filtrate concentrated to yield a solid. Recrystallization from ethyl acetate-petroleum ether (30°-60°C.) provides 3-amino-3-cyclopropyl-1-(4-pyridyl)-2-propen-1-one as white crystals, melting point 124°-125°C. The ethyl acetate-petroleum ether (30°-60°C.) filtrate is concentrated to a solid which is recrystallized from aqueous ethanol to give 4-(5-cyclopropyl-3-isoxazolyl)pyridine as white crystals, melting point 78°-79.5°C., mmr spectrum δ6.85 (DMSO-d6, s, 4-isoxazolyl H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1.C([O-])(O)=O.[Na+].[I:16]I.OS([O-])(=O)=O.[Na+]>O>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:16])[CH:5]=[C:4]([CH2:9][OH:10])[N:3]=1
Reactant: II
Reactant: OCc1ccc(O)c(Cl)n1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: OCc1cc(I)c(O)c(Cl)n1
Yield: 62 %

Procedure:
C1 (11.6 g, 72.7 mmol) and NaHCO3 (18.3 g, 218 mmol) are added to 200 mL H2O. The mixture is stirred until homogeneous, the flask is placed in an ice bath, iodine (19.4 g, 76.3 mmol) is added, and the reaction is stirred over the weekend at rt. The pH of the mixture is adjusted to 3 with 2N NaHSO4, and the mixture is extracted with 4×50 mL EtOAc. The combined organic layer is dried over MgSO4, is filtered, and the filtrate is concentrated in vacuo to a yellow solid. The crude solid is washed with EtOAc to provide 2-chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) as an off-white solid (62% yield), and the filtrate is concentrated to a small volume and is chromatographed over 250 g silica gel (230-400 mesh) eluting with 2.5:4.5:4:0.1 EtOAc/CH2Cl2/hexane/acetic acid to afford additional pure C2 (12% yield). MS (EI) for C6H5Cl/NO2, m/z: 285(M)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:4]([C:8]#[N:9])=[CH:5][N:6]([CH3:7])[C:2]=2[Cl:1])=[CH:11][CH:12]=1
Reactant: Cn1cc(C#N)c(-c2ccc(CO)cc2)c1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1cc(C#N)c(-c2ccc(CBr)cc2)c1Cl
Yield: 39 %

Procedure:
To a stirred solution of 5-chloro-4-(4-hydroxymethylphenyl)-1-methylpyrrole-3-carbonitrile (450 mg) in methylene chloride (20 ml) was added triphenylphosphine (1.44 g) and carbon tetrabromide (1.21 g) successively at 0° C. and the resulting yellow solution was stirred at the same temperature for a while. The mixture was washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and filtered. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography eluted with a mixture of ethyl acetate and n-hexane 1:4 (V/V) then with 1:3 (V/V) to give 4-(4-bromomethylphenyl)-5-chloro-1-methylpyrrole-3-carbonitrile (220 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14](OC)=[O:15].[H-].C([Al+]CC(C)C)C(C)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][OH:15]
Reactant: COC(=O)Cc1nc(-c2ccccc2)oc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCO
Yield: 118.4 %

Procedure:
A 750-ml 4-necked flask equipped with a mechanical stirrer, a thermometer, a dropping funnel and an argon inlet, cooled with a CO2/acetone bath, was charged with a solution of 49.15 g of crude methyl 2-(5-methyl-2-phenyl-4-oxazolyl)acetate (ca. 0.16 mol) and 90 ml of toluene and stirred. 400 ml of diisobutyl aluminiumhydride 1.2 M in toluene were added under argon at ca. −20 to −25° C. during 60 min. After additional 15 min a solution of 191 g of citric acid monohydrate in 400 ml of deionized water was added with cooling during 30 min, so that the temperature did not exceed 5-10° C. The aqueous phase of the clear biphasic mixture was extracted with 200 ml of toluene. The combined organic phases were washed twice with 40 ml, a total of 80 ml of deionized water, twice with 40 ml, a total of 80 ml of brine and dried (Na2SO4). Rotary evaporation (50° C., 8 mbar, 1 h) afforded 38.5 g of crude 2-(5-Methyl-2-phenyl-4-oxazolyl)ethanol (theor. amount 32.4 g) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8](C)[CH2:9][C:10](O)=[O:11])=S)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[NH:8][CH2:9][C:10](=[O:11])[NH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: CN(CC(=O)O)C(=S)c1ccc(Cl)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: O=C1CNC(c2ccc(Cl)cc2)=NN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorothiobenzoyl methyl glycine (4.87 g, 20 mmol), 2.2 g of hydrazine hydrate (44 mmol) and 20 mL of methanol were combined and stirred at room temperature overnight, then heated to reflux. The reaction mixture was cooled and filtered. The solids were washed, then dried, giving 3-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3](O)=[O:4].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Cl-].[Li+].[C:25]1([C@H:31]2[C@@H:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33](=[O:42])[NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:1]/[C:2](=[CH:6]\[CH2:7][CH3:8])/[C:3]([N:32]1[C@@H:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:34][C:33]1=[O:42])=[O:4]
Reactant: O=C1N[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Reactant: CC/C=C(\C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC/C=C(\C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of (E)-2-methyl-2-pentenoic acid (5.3 g, 47 mmol) in 250 mL of THF at 0° C. was added 16.3 mL (117 mmol) of triethylamine, then 5.8 mL (47 mmol) of pivaloyl chloride resulting in a thick suspension. The mixture was stirred for 1 hour at 0° C. at which time 2.0 g (47 mmol) of lithium chloride was added in one portion, followed by 10 g (42 mmol) of (4S,5R)-4,5-diphenyl-2-oxazolidinone in four batches. Stirring was maintained throughout the solid additions. The reaction mixture was stirred for 1 hour at 0° C., and for 1 hour at ambient temperature, and was vacuum filtered through a coarse frit and concentrated. The residue was partitioned between EtOAc/water, and the organics were dried over MgSO4 and concentrated. To the residue was added 200 mL of MTBE and the mixture was warmed cautiously with swirling. The warm slurry was filtered to provide 13.0 g (83% yield) of the titled compound as a colorless solid: 1H NMR (CDCl3) δ 7.12 (m, 3H), 7.08 (m, 3H), 6.93 (m, 2H), 6.86 (m, 2H), 6.14 (m, 1H), 5.90 (d, J=7.8 Hz, 1H), 5.69 (d, J=7.8 Hz, 1H), 2.23 (pent, J=7.6 Hz, 2H), 1.92 (s, 3H), 1.07 (t, J=7.6 Hz, 3H). The titled acylated oxazolidinone may be used in the next step instead of (S)-3-((E)-2-Methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[SH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(S)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3-Aminothiophenol (1.0 g, 7.99 mmol), acetic anhydride (0.83 mL) and triethyl amine (1.7 mL) were dissolved in methylene chloride, and the solution was stirred at room temperature for 2 hours. It was then purified by silica gel chromatography (hexane:ethyl acetate=3:1) to yield the title compound (1.16 g, 87%).