Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].C(N(CC)CC)C.[C:13](=[N:18][OH:19])(Cl)[C:14]([CH3:16])=O.Cl>O1CCCC1>[N:18](=[C:13]1[C:14]([CH3:16])=[N:2][CH2:3][CH2:4][S:5]1)[OH:19]
Reactant: NCCS
Reactant: CC(=O)C(Cl)=NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=NCCSC1=NO
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.27 g (0.02 mol) of cysteamine hydrochloride are suspended in 40 ml of absolute tetrahydrofuran and treated with 5.55 ml (0.04 mol) of triethylamine to free the base. The mixture is stirred for 15 minutes at room temperature and then cooled down to about -30° C. At this temperature a solution of 2.42 g (0.02 mol) of pyruvyl chloride 1-oxime in 10 ml of absolute tetrahydrofuran is added dropwise. The reaction mixture is allowed to warm to room temperature while being well stirred. After two hours ice-water and then dilute hydrochloric acid are added until a pH of 5-6 has been attained. The reaction mixture is extracted twice with ethyl acetate and the organic phase is washed with sodium chloride solution, dried over anhydrous sodium sulfate and finally evaporated. The resulting crystalline residue is treated with active charcoal. After recrystallization from hot ethyl acetate and n-hexane there is obtained pure 2-oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine oxime, m.p. 197° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:22]=[CH:21][C:14]([O:15][CH2:16][C@H:17]([OH:20])[CH2:18][OH:19])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:40][C@@H:41]2[O:43][CH2:42]2)(=O)=O)=CC=1>C(#N)C>[O:43]1[CH2:42][C@@H:41]1[CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C@H:17]([OH:20])[CH2:18][OH:19])=[CH:21][CH:22]=2)([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(OC[C@H](O)CO)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H]2CO2)cc1
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a stirred solution of (R)-3-(4-(2-(4-hydroxyphenyl)propan-2-yl)phenoxy)propane-1,2-diol (3.77 g, 12.49 mmol, 1.0 equiv) in anhydrous acetonitrile (35 mL) at rt was added cesium carbonate (6.1 g, 18.73 mmol, 1.5 equiv), and the mixture was stirred for 20 min under argon atmosphere. A solution of (2R)-(−)-glycidyl tosylate 98% (4.3 g, 18.73 mmol, 1.5 equiv) in anhydrous acetonitrile (8 mL) was added slowly via syringe, and the mixture was allowed to react at 30° C. for 120 h. The reaction mixture was quenched at room temperature with a saturated solution of ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with deionized water (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel (eluent: 5% to 10% methanol in dichloromethane) to provide the title compound (4.1 g, 91%) as a transparent foam.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[N:17].N1CCCCC1>CO>[C:16]([C:18](=[CH:10][C:9]1[CH:8]=[C:7]([O:12][CH3:13])[C:6]([O:14][CH3:15])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]([O:21][CH3:22])=[O:20])#[N:17]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: COC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 78.1 %

Procedure:
To a mixture of 7.00 g (33.15 mmol) of 6-nitroveratraldehyde (80%) and 3.4 mL (38.42 mmol) of methyl cyanoacetate in 70 mL of methanol is added 0.7 mL of piperidine. An additional 100 mL of methanol is added and the thick suspension is warmed slightly until the mixture stirred freely. After stirring at room temperature for 1 hour, the solids are collected by filtration washing with methanol followed by diethyl ether to give 7.57 g (78%) of methyl 2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)-2-propenoate as a pale yellow solid, mp 162-164° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24](Br)=[N:23][CH:22]=[C:21]([Cl:26])[N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24]([O:8][CH2:7][C:4]3[CH:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[N:23][CH:22]=[C:21]([Cl:26])[N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1
Reactant: Cc1cc(CO)no1
Reactant: O=S(=O)(Nc1nc(Cl)cnc1Br)c1ccc(Cl)s1
Product: Cc1cc(COc2ncc(Cl)nc2NS(=O)(=O)c2ccc(Cl)s2)no1

Procedure:
Prepared by the method of Example 20b using (5-methyl-3-isoxazolyl)methanol and 5-chloro-N-(3-bromo-6-chloro-2-pyrazinyl)-2-thiophenesulphonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: CCC(NC(=O)Cc1ccc(Cl)c(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3,4-dichlorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure BJ above) the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:33]=1[C:34](Cl)=[O:35]>C1COCC1>[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:33]=1[C:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:35]
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: C1CCOC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine (92 mg, 0.23 mmol) in 2 mL of THF, added 2-chloro-6-fluorobenzoyl chloride (48 mg, 0.27 mmol). The reaction was stirred for 30 min at rt and quenched by addition of polystyrene-trisamine resin (20 mg). The reaction was allowed to stir overnight. The reaction was treated with excess Et3N, filtered, and washed with THF. The filtrate was collected, reduced in vacuo, and upon treatment with DCM, a white solid formed. Filtration and washing with the solid with Et2O yielded the desired product as a white solid, 96 mg, 65% yield. 1H NMR (400 MHz, d6-DMSO): δ 10.89 (s, 1H); 9.78 (s, 1H); 8.84 (d, J=6 Hz, 1H); 8.30 (d, J=5 Hz, 1H); 8.00 (s, 1H); 7.77-7.23 (m, 2H); 7.55-7.33 (m, 7H); 7.22 (q, J=8 Hz, 1H); 7.11 (t, J=7 Hz, 1H); 6.69 (td, J=2, 8 Hz, 1H); 6.60 (d, J=5 Hz, 1H). HRMS calculated C30H20ClF2N6O [M+H]+ 553.1355, found 553.1360.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])=O.[NH3:26]>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[N:26]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2Cl)c1C
Reactant: N
Solvent: CCO
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3Cl)nc2c1C
Reaction time: 8 h
Yield: 30 %

Procedure:
504 mg of ethyl 4-formyl-2,6-dimethyl-3-(o-chlorobenzoylamino)benzoate was dissolved in 50 ml of ethanol saturated with ammonia and the solution was left to stand overnight at room temperature. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography. Fractions eluted with diethyl ether/n-hexane (volume ratio 2:8) were collected and the solvent was evaporated. The residue was recrystallized from methanol/n-hexane to give 150 mg (yield 30%) of 2-(o-chlorophenyl)-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 69.5° to 70.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C@H:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COC(OC1C=CC(C2C=CC(C(OCCCCCCCC)=O)=CC=2)=CC=1)=O>>[CH3:10][C@@H:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N#Cc1ccccc1O
Reactant: CCCCCC[C@H](C)O
Agent: CCCCCCCCOC(=O)c1ccc(-c2ccc(OC(=O)OC)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCC[C@@H](C)Oc1ccccc1C#N

Procedure:
Quantities: 2-(hydroxybenzonitrile (38) (9.17 g, 0.077 mol), (S)-(+)-octan-2-ol (10.00 g, 0.077 mol), DEAD (13.41 g, 0.077 mol), triphenylphosphine (20.20 g, 0.077 mol). The experimental procedure was as described for the preparation of compound 5. The crude product was purified by column chromatography (20% petrol/dichloromethane) to give a colourless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(F)c1F
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1F
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
40% Methanolic Triton B (0.51 mL, 1.12 mM) was added to a solution of the 9-[(2,3-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (303 mg, 0.86 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (270 mg, 1.72 mM) was added and the resultant mixture stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 295 mg (80%) of the {9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.5-7.3 (m, 5H), 7.05 (d, 1H, J=8 Hz), 6.8 (m, 1H), 6.6 (d, 1H, J=8 Hz), 6.4 (t, 1H, J=8 Hz), 6.2 (br s, 1H), 6.0 (br s, 1H), 5.6 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3432, 3180, 1774, 1766, and 1674. MS (ES) m/e 425.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:12]([OH:15])([CH3:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)[CH3:4].I[CH3:17]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:15][CH3:17])([CH3:14])[CH3:13])[CH:7]=1)[CH3:4]
Reactant: CCOc1cccc(C(C)(C)O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1cccc(C(C)(C)OC)c1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Sodium hydride (3.261 g, 81.54 mmol, 60% in mineral oil, Aldrich) was washed twice with hexane, and tetrahydrofuran (60 mL) was added. To this suspension was added 2-(3-ethoxy-phenyl)-propan-2-ol (4.9 g, 27.18 mmol). The mixture was stirred at 45° C. for 1.5 h until the bubbling subsided. It was cooled down to 0° C. and iodomethane (5.08 mL, 81.54 mmol, Aldrich) was added. After 4 h of stirring at room temperature, another portion of iodomethane (5.08 mL, 81.54 mmol) was added. The mixture was stirred at room temperature for 4 d then quenched at 0° C. with cold 20% solution of ammonium chloride. The product was extracted with ethyl acetate (2×1 L). The organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give 1-ethoxy-3-(1-methoxy-1-methyl-ethyl)-benzene (5.15 g, 97%).
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=C[C:4]=1[CH2:18][S:19](N)(=[O:21])=[O:20].[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.C(S(Cl)(=O)=O)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([S:19]([N:51]1[CH2:52][CH2:53][N:48]([C:45]2[N:44]=[CH:43][C:42]([C:39]3[CH:40]=[C:41]4[C:33]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]6[CH:64]=[CH:65][CH:66]=[C:24]([F:23])[CH:25]=6)[CH:32]=5)=[CH:34][N:35]([S:54]([C:57]5[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=5)(=[O:56])=[O:55])[C:36]4=[N:37][CH:38]=3)=[CH:47][CH:46]=2)[CH2:49][CH2:50]1)(=[O:21])=[O:20])[CH3:4]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CCS(=O)(=O)Cl
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(Cc5cccc(F)c5)c3)cn4S(=O)(=O)c3ccc(C)cc3)cn2)CC1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was alkylated with ethanesulfonyl chloride (25 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=700.2 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:12])[CH3:11])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.F[C:23]1[CH:24]=[C:25]([CH2:32][OH:33])[CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30]>C(#N)C>[OH:33][CH2:32][C:25]1[CH:26]=[CH:27][C:28]([N+:29]([O-:31])=[O:30])=[C:23]([NH:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:12])[CH3:11])[CH2:7][CH2:8]2)[CH:24]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1F
Reactant: CC(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N[C@H]1CC[C@H](Nc2cc(CO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(trans-4-aminocyclohexyl)acetamide hydrochloride (200 mg, 1.038 mmol) and DIPEA (0.494 mL, 2.83 mmol) in ACN (2 mL) was added (3-fluoro-4-nitrophenyl)methanol (161 mg, 0.944 mmol). The resulting mixture was stirred overnight at 80° C. After 16 hours, the reaction was concentrated and the residue purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide N-(trans-4-(5-(hydroxymethyl)-2-nitrophenylamino)cyclohexyl)acetamide as a yellow powder (50 mg, 17.24% yield). MS, m/z (C15H21N3O4): calcd, 307.2. found, 308.1 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1)[CH:5]=O.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:7]=[C:8]([Cl:20])[C:9]=1[C:10]1[N:14]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: O=Cc1cc(Cl)c(-c2nnc3ccc(F)cn23)c(Cl)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(F)cn34)c(Cl)c2)CC1
Reaction time: 5 h
Yield: 57.8 %

Procedure:
A cloudy solution of Intermediate 13c (0.66 g, 1.80 mmol) in DCE (18 mL) was treated with 1-methylpiperazine (0.22 mL, 2.00 mmol) then sodium triacetoxyborohydride (0.58 g, 2.70 mmol), and the solution was stirred at ambient temperature overnight. The mixture was treated with another portion of 1-methylpiperazine (0.22 mL, 2.00 mmol) and sodium triacetoxyborohydride (0.58 g, 2.70 mmol), and stirred for 5 h. The mixture was cautiously diluted with a saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM and purified by FCC, using 0-8% [2M NH3 in MeOH] in DCM, to give the title compound (0.41 g, 57%). LCMS (Method 3): Rt 2.11 min, m/z 394, 396 [MH+].
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:18])([CH2:14][CH2:15][CH2:16][CH3:17])[C:5](=[O:13])[CH2:6]P(=O)(OC)OC.[CH:19]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[CH2:27][CH2:28][S:29][C:30]1[S:31][CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=1)=O.Cl>O1CCCC1>[CH3:18][C:4]([CH3:3])([CH2:14][CH2:15][CH2:16][CH3:17])[C:5](=[O:13])/[CH:6]=[CH:19]/[C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[CH2:27][CH2:28][S:29][C:30]1[S:31][CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=1
Reactant: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Reactant: CCOC(=O)c1csc(SCCN2C(=O)OC[C@@H]2C=O)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To sodium hydride (60.0% in oil) (49.0 mg) was added slowly a solution of dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate (332 mg) in anhydrous tetrahydrofuran (7.30 mL) at 0° C. and the solution was stirred at room temperature for 1 hour. To the reaction solution was added slowly a solution of the compound 5 (336 mg) in anhydrous tetrahydrofuran (2.90 mL) at room temperature and the solution was stirred for 2 hours. To the reaction solution was added 1N hydrochloric acid at 0° C. and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2), to give the title compound (211 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:19]O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:17][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(Cl)c2)on1
Yield: 73.5 %

Procedure:
A solution of crude ethyl 4-(3-chlorophenyl)-2,4-dioxobutanoate (max 294 g, 1.16 mol) and hydroxylamine hydrochloride (120.4 g, 1.73 mol) in ethanol (4 L) was heated at 80° C. for 4 h. After cooling (over night) to ca 5-10° C., the mixture was filtered, washed with cold ethanol and dried in vacuo to afford the title compound (214.5 g, 74%). 1H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H). MS (M++1)=252.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7](O)[CH3:8])[CH2:3][CH2:2]1.C[O-].[Na+].COC1C=CC(O)=CC=1.[C:22]([O:27]C)(=[O:26])[C:23]([CH3:25])=[CH2:24]>>[C:22]([O:27][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: CC(O)N1CCOCC1
Reactant: C=C(C)C(=O)OC
Agent: COc1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Product: C=C(C)C(=O)OCCN1CCOCC1

Procedure:
A 1000 ml resin kettle was equipped with a still head, air bubbler, and thermometer. The kettle was placed in a regulated water bath, set at 80°. 750 ml methyl methacrylate was added to the kettle followed by a solution containing 250 g morpholinoethanol, 5.0 g sodium methoxide and 0.5 g p-methoxyphenol. During the 120 minute reaction time, air was bubbled slowly through the vigorously stirred solution. After 30 and 60 minutes, 5.0 g sodium methoxide was added. At the end of the reaction time, the mixture was cooled and neutralized with 17.0 g glacial acetic acid.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)[N:6]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([S:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:29])=[CH:12][CH:13]=2)[N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1nc(Cc2ccc(Sc3ccccc3)cc2)cs1
Solvent: ClC(Cl)Cl
Product: O=S(c1ccccc1)c1ccc(Cc2csc(Br)n2)cc1

Procedure:
The starting 2-bromo-4-(4-phenylsulfinylbenzyl)thiazole was prepared by mild oxydation of 2-bromo-4-(4-phenylthiobenzyl)thiazole, M.P. 82° C., by the means of meta-chloroperbenzoic acid in chloroform.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9](N(OC)C)=[O:10]>C1COCC1.C(OCC)C>[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9]([CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: CON(C)C(=O)c1ccc(C)cc1Cl
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C(=O)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added to 1.09 g (5.10 mmol) of the compound from Example 121A in 19 ml of diethyl ether, and the mixture was stirred at RT overnight. A further 7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water and extracted with dichloromethane, the organic phase was dried over magnesium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 326 mg (33% of theory) of the title compound.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[C:8]([OH:14])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].[C:15](O)(=O)[CH2:16][C:17]([CH3:19])=O.[C:22](O)(=O)CC(C)=O.C(C(CO)(CO)CC)O.[OH-].[K+]>>[C:1]([O:7][CH2:19][CH2:17][CH2:16][CH2:15][CH2:22][O:13][C:8](=[O:14])[CH2:9][C:10]([CH3:12])=[O:11])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)O
Reactant: CC(=O)CC(=O)[O-]
Agent: CCC(CO)(CO)CO
Agent: [K+]
Agent: [OH-]
Product: CC(=O)CC(=O)OCCCCCOC(=O)CC(C)=O

Procedure:
Acetoacetate-functional compound B5 1,1,1-Trimethylol propane tri-acetoacetate, Lonzamon MTMP ex Lonza AG. Functionality: 3, acetoacetate equivalent weight: 128.7 (435 mg KOH/g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:21]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:27]([N:28]1[CH2:33][CH2:32][N:31]([CH2:19][CH2:18][CH2:17][CH2:16][CH:14]2[O:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:15]2)[CH2:30][CH2:29]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)cc1OC
Yield: 68.8 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (31.0 mg, 0.111 mmol), 1-(diphenylmethyl)piperazine (25.6 mg, 0.101 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (64.6 mg, 0.308 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 35.7 mg (68.4%) of the target compound was obtained.