Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])(=[O:4])[CH:2]=[O:3].O.[N+:17]([C:20]1[CH:43]=[CH:42][CH:41]=[CH:40][C:21]=1[CH2:22][O:23][C:24]([NH:26][CH:27]([C@H:29]1[C@H:32]([CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[NH:31][C:30]1=[O:39])[CH3:28])=[O:25])([O-:19])=[O:18]>C1C=CC=CC=1>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][O:5][C:1]([CH:2]([OH:3])[N:31]1[C@@H:32]([CH2:33][CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:29]([CH:27]([NH:26][C:24]([O:23][CH2:22][C:21]2[CH:40]=[CH:41][CH:42]=[CH:43][C:20]=2[N+:17]([O-:19])=[O:18])=[O:25])[CH3:28])[C:30]1=[O:39])=[O:4])([O-:15])=[O:14]
Reactant: CC(=O)OCC[C@@H]1NC(=O)[C@H]1C(C)NC(=O)OCc1ccccc1[N+](=O)[O-]
Reactant: O=CC(=O)OCc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)OCC[C@H]1[C@H](C(C)NC(=O)OCc2ccccc2[N+](=O)[O-])C(=O)N1C(O)C(=O)OCc1ccccc1[N+](=O)[O-]
Yield: 87 %

Procedure:
Ortho-nitrobenzyl glyoxalate prepared from (0.650 g, 0.00153 mole) of di-o-nitrobenzyl tartarate, is dissolved in 20 ml benzene and refulxed using a Dean-Stark water separator containing CaH2 for an hour. Trans-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(2-acetoxyethyl)-2-azetidinone (0.580 g, 0.00153 mole) is added and the mixture is refluxed for 8 hrs, cooled, evaporated. The residue is column chromatographed ##STR215## to give 0.775 g (0.00132 mole, 87% yield) of the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CN1CCOCC1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([N:14]([O:15][CH3:16])[CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1cccnc1Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)Cc1cccnc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of (2-chloropyridin-3-yl)acetic acid (Intermediate 3; 2.0 g, 11.6 mmol) in DCM (100 mL) was added N,O-dimethylhydroxylamine hydrochloride (1.19 g, 12.2 mmol), N-methylmorpholine (3.8 mL, 34.8 mmol) and EDC (2.3 g, 12.2 mmol). The mixture was stirred at room temperature for 48 hours, diluted with DCM (100 mL), washed with 10% HCl (aq) solution (200 mL) and brine (200 mL), dried (Na2SO4), filtered and the solvents removed in vacuo. The crude product was purified by column chromatography (SiO2, 1:1 EtOAc:DCM) to give the title compound as a white waxy solid (2.2 g, 88%). δH (DMSO-d6) 8.31 (1H, dd, J 4.7, 1.9 Hz), 7.81 (1H, dd, J 7.5, 1.9 Hz), 7.40 (1H, dd, J 7.5, 4.7 Hz), 3.93 (2H, s), 3.76 (3H, s), 3.15 (3H, s). LCMS (pH 3) RT 2.22 minutes, (ES+) 215 35Cl (M+H)+, 217 37Cl (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=[CH:22][CH:23]=4)[CH2:28]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1cc2c(c(N3CCOCC3)c1)CNCC2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cccc(N3CCOCC3)c2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1](=[O:13])([S:11][CH3:12])[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])C.Cl[C:15](OCCl)=O.C(O)(=O)C(C)(C)C>>[C:1](=[O:13])([S:11][CH3:12])[O:2][CH2:3][O:5][C:6](=[O:10])[C:7]([CH3:15])([CH3:9])[CH3:8]
Reactant: O=C(Cl)OCCl
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Agent: CC(C)(C)C(=O)O
Product: CSC(=O)OCOC(=O)C(C)(C)C

Procedure:
Following the procedures for synthesizing O-(1-isobutanoyloxyethyl) S-methyl thiocarbonate (2) and replacing 1-chloroethyl chloroformate with chloromethyl chloroformate in Step A and replacing isobutyric acid with pivalic acid in Step B affords O-(pivaloyloxymethyl) S-methyl thiocarbonate (9) as an oil.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[CH3:10][S:11]([N:5]1[CH2:6][CH2:7][C:8](=[O:9])[CH:3]([CH3:2])[CH2:4]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CNCCC1=O
Agent: Cl
Product: CC1CN(S(C)(=O)=O)CCC1=O

Procedure:
Racemic 1-methanesulfonyl-3-methyl-piperidin-4-one was prepared in the same manner from racemic 3-methyl-piperidin-4-one hydrochloride and methanesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[OH:32].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>CCOC(C)=O>[F:1][C:2]1[C:23]([F:24])=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)c(F)cc43)cc2s1
Temperature: 130 °C
Yield: 28.5 %

Procedure:
A stirred mixture of 6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.20 g, 0.55 mmol), (1R,2R)-2-aminocyclohexanol (0.19 g, 1.6 mmol), DIEA (0.71 g, 5.5 mmol) and NMP (2 mL) was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and washed with water (10 mL×2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5,6-difluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (65 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.69-7.78 (m, 3H), 7.30 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 5.44 (s, 2H), 4.74 (d, J=4.8 Hz, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 2.00 (m, 1H), 1.87 (m, 1H), 1.58-1.60 (m, 2H), 1.15-1.25 (m, 4H); LCMS (ESI) m/z 415 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH2:8][C:9]([NH2:11])=[S:10]>O>[ClH:1].[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][S:10][C:9](=[NH:8])[NH2:11])#[N:7]
Reactant: NC(N)=S
Reactant: N#CCCCCCl
Solvent: O
Product: Cl
Product: N#CCCCCSC(=N)N
Reaction time: 1 h

Procedure:
The 5-chloropentanenitrile (5.68 g, 48.3 mmol) and thiourea (4.04 g, 53.1 mmol) are mixed in 40 ml of water. The mixture is heated to reflux for 3 to 4 hours. The reaction mixture is evaporated and 20 ml of ethanol are added and then evaporated as well. This is repeated three times. After that, 10 ml of methanol and 30 ml of acetone are added and the mixture is stirred for one hour. The crystalline material is filtered and the product is dried under high vacuum overnight to yield S-(4-cyanobutyl)isothiourea hydrochloride.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:21][CH:22]1[CH2:26][NH:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23]1.Cl>CCOCC.O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:25]1[CH2:26][CH:22]([OH:21])[CH2:23][C@H:24]1[C:27]([OH:29])=[O:28])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)N1CC(O)C[C@H]1C(=O)O
Reaction time: 0.75 h
Yield: 64.8 %

Procedure:
24.05 g (0.121 mol) of o-acetoxybenzoyl chloride in 50 ml of anhydrous ether, and 17 ml (0.121 mol) of pure triethylamine in 18 ml of iced water, were added simultaneously over the course of 0.5 hr, at -2° C. ± 1° C., whilst stirring so as to produce emulsification, to a solution of 15.9 g (0.121 mol) of 4-hydroxy-L-proline in 42 ml of water and 17 ml (0.121 mol) of pure triethylamine. Stirring was continued for 0.75 hr at the same temperature and then for 25 minutes at ambient temperature. The pH was reduced from 7 to 3 by adding 9.8 ml of 12.35 N HCl (0.121 mol). The milky cloudiness was extracted with a total of 900 ml of pure ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4 and then concentrated in vacuo to give, in 2 to 3 successive crops, 23 g of the desired product (65% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][CH2:24][Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-(phenyl)propylmagnesium bromide. After the reaction the material was submitted to chiral preparatory HPLC (Chiralcel AS Column, 2% EtOH in hexanes, 60 minute run). The first enantiomer off of the column is Enantiomer A.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[Cl:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O[C@H](CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
2-Chloroacetophenone (154.0 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, purification by silica gel column chromatography furnished a desired compound, (S)-(+)-2-chloro-1-phenylethanol (145.1 mg; yield: 93.0%; optical purity: 96.6% ee).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:25]=[C:6]2[N:7]=[C:8]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:5]2[N:4]=1.[NH:26]1[CH2:29][CH:28]([C:30]2[NH:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[N:36]=3)[N:31]=2)[CH2:27]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.CC(O)=O>[CH3:41][C:37]1[N:36]=[C:35]([C:32]2[NH:33][N:34]=[C:30]([CH:28]3[CH2:27][N:26]([CH2:21][C:20]4[CH:23]=[CH:24][C:17]([C:8]5[C:9]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=6)=[CH:10][N:5]6[N:4]=[C:3]([S:2][CH3:1])[N:25]=[C:6]6[N:7]=5)=[CH:18][CH:19]=4)[CH2:29]3)[N:31]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CSc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CSc1nc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6cccc(C)n6)n5)C4)cc3)c(-c3ccccc3)cn2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-methylsulfanyl-6-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (200 mg, 0.548 mmol), 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (174 mg, 60% pure), triethylamine (0.168 mL), AcOH (0.075 mL) and NMP (4.6 mL) were stirred overnight at room temperature. Sodium triacetoxyborohydride (279 mg) and the mixture stirred for 3 h. The reaction was partitioned between CH2Cl2 and water, the organic phase separated, dried and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (78 mg) as a white solid.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:11]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1>[O:22]=[C:21]1[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:19][CH2:20]1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1=NN(c2ccccc2)C(=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In a three neck flask equipped with a Dean-Stark trap, phenylhydrazine hydrochloride and diethyl 4-oxoheptanedioate (1 equiv.) were combined in Toluene (1.15 M). The suspension was stirred 48 h at reflux. The reaction mixture was cooled to rt and concentrated under vacuum to afford the desired material as a brown oil which was used as such in the next step.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29].O>C1COCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:22][C:21]=1[N+:28]([O-:30])=[O:29]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. and with cooling, 156.32 g (620 mmol) of tert-butyl diethylphosphonoacetate were added dropwise to a suspension of 23.71 g (593 mmol) of sodium hydride (60% in mineral oil) in 1.0 liters of THF. After the addition had ended, the mixture was stirred at 0° C. for 30 min and a solution of 100.0 g (539 mmol) of 4-chloro-3-nitrobenzaldehyde in 200 ml of THF was then added. The reaction mixture was heated at RT overnight, and water and ethyl acetate were then added. The organic phase was removed, dried with magnesium sulphate and concentrated under reduced pressure. The residue was recrystallized from isopropanol. Drying under high vacuum gave 144.0 g (94.2% of theory) of the target product.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[N:8]=[C:7]([C:9]#N)[CH:6]=[C:5]([C:11]2[O:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:4]=1.Cl.C1C[O:22]CC1.[Li+:24].[OH-:25]>O.CO>[Li+:24].[CH3:1][N:2]([CH3:17])[C:3]1[N:8]=[C:7]([C:9]([O-:22])=[O:25])[CH:6]=[C:5]([C:11]2[O:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[N:4]=1
Reactant: [OH-]
Reactant: Cc1ccc(-c2cc(C#N)nc(N(C)C)n2)o1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)[O-])nc(N(C)C)n2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of 2-dimethylamino-6-(5-methylfuran-2-yl)pyrimidine-4-carbonitrile (0.68 g, 2.98 mmol) in 6-M HCl (40 mL) and THF (10 mL) was refluxed for 6 h, cooled, concentrated in vacuo and the residue subjected to ion-exchange column chromatography (Isolute® Flash SCX-2; DCM; MeOH then 1-M NH3:MeOH). The resulting mixture of methyl ester and carboxylic acid (0.42 g) was treated with MeOH (15 mL), water (15 mL) and LiOH (72 mg, 1.81 mmol), stirred at room temperature for 1 h and concentrated in vacuo to give the title compound (0.48 g, 98%) as a white solid: NMR δH (400 MHz, CD3OD) 2.38 (3H, s), 3.23 (6H, s), 6.19-6.20 (1H, m), 7.08-7.09 (1H, m) and 7.31 (1H, s); M/Z 248 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:19])[N:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[CH3:20][I:21]>>[I-:21].[C:15]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[N:3][N+:2]([CH3:20])([CH3:1])[CH3:19])=[CH:18][CH:17]=1)#[N:16]
Reactant: CN(C)N=C1CCCCC1Cc1ccc(C#N)cc1
Reactant: CI
Product: C[N+](C)(C)N=C1CCCCC1Cc1ccc(C#N)cc1
Product: [I-]

Procedure:
4-[[2-(dimethylhydrazono)cyclohexyl]methyl]-benzonitrile (6.1 g) (0.024 mol) and methyl iodide (35 ml) were stirred overnight at RT. The precipitate was filtered, washed twice with ethyl ether, then with EtOH, and finally with pentane. After drying, 2-[2-[(4-cyanophenyl)methyl]-cyclohexylidene]-1,1,1-trimethyl-hydrazinium iodide was obtained as a white solid (7.8 g, mp=175° C.). 1H NMR (CDCl3): 7.55 (2H, d), 7.25 (2H, d), 3.7 (9H, s), 3.3 (1H, m), 3.15 (1H, dd), 2.8-2.5 (3H, m), 2.2-1.4 (6H, m).
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[N+:12]([O-:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:16])(=[O:3])[CH3:2].[Br:17]Br>CO>[C:1]([C:4]1[C:13]([CH2:14][Br:17])=[N+:12]([O-:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Product: CC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred suspension of 2-acetyl-3-methylquinoxaline-1,4-dioxide (1.57 moles) in 3 liters of methanol was added bromine (1.74 moles) over a period of 2 hours. The reaction mixture was then stirred for 5 days at room temperature. The resulting yellow solid was collected by filtration, washed with methanol and ether. Yield, 331 grams (71%); m.p. 164-6° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH3:18])[C:11]2[O:15][C:14](S)=[N:13][C:12]=2[CH:17]=1.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH3:18])[C:11]2[O:15][C:14]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[N:13][C:12]=2[CH:17]=1
Reactant: Cc1cc(Cl)cc2nc(S)oc12
Reactant: C1CNCCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc2nc(N3CCNCC3)oc12
Yield: 34.2 %

Procedure:
Piperazine (4.3 g, 0.05 mol) was added to a suspension of 5-chloro-2-mercapto-7-methylbenzoxazole (5.0 g, 0.25 mol) in toluene (100 mL) with stirring. The reaction mixture was stirred for 7 hours under reflux, then cooled, and the mixture was added to a mixture of ethyl acetate (45 mL) and water (80 mL). The mixture was adjusted to pH 7.5 by gradually adding 5 N hydrochloric acid. The separated organic layer was washed with water (80 mL), added with water (80 mL) again, and adjusted to pH 1–1.5 with 5 N hydrochloric acid. The organic layer was removed by phase separation. The remaining aqueous layer was added with ethyl acetate, adjusted to pH 8.0 with 5 N aqueous sodium hydroxide, and then extracted. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (4.3 g). This compound may be converted into 5-chloro-7-methyl-2-(1-piperazinyl) benzoxazole hydrochloride by treatment with 4 N hydrochloric acid/ethyl acetate in ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:20]([C:17]2[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:23])[CH:16]=2)=[O:22])[CH2:26][CH2:27]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC2CCOCC2)[nH]n1
Yield: 28 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using 4-aminotetrahydropyran instead of 2-hydroxy-2-methylpropylamine, to the title compound (9.1 mg, 28%) which was obtained as an off white solid. MS: m/e=400.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[N:3]=[C:2]1[C:11]1[C:12]([CH3:22])=[CH:13][C:14]([CH3:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17].[CH:23]1(C2C(I)=CC(C(O)=O)=C(C)C=2)C[CH2:24]1.IC1C(C)=CC(C)=C(C=1)C(O)=O>>[CH:22]1([C:12]2[C:11]([C:2]3[NH:3][C:4]4[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=4[N:1]=3)=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:21])[CH:13]=2)[CH2:24][CH2:23]1
Reactant: Cc1cc(C2CC2)c(I)cc1C(=O)O
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C)cc1C
Agent: Cc1cc(C)c(C(=O)O)cc1I
Product: COC(=O)c1cc(-c2nc3c([nH]2)CCNCC3)c(C2CC2)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 83.4, except 4-cyclopropyl-5-iodo-2-methylbenzoic acid (compound 86.3) was used in place of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3).
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCCC1>[F:35][C:20]([F:19])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]([Cl:1])=[O:4])[CH2:27][CH2:26]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cl)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A magnetically stirred mixture of triphosgene (365 mg, 1.23 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere was treated slowly with pyridine (485 mg, 6.15 mmol) via syringe. The resulting white suspension was then treated with a solution of 1-(3-Trifluoromethyl-benzyl) piperazine (1.0 g, 4.10 mmol) in tetrahydrofuran (10 mL) via addition funnel over 10 min. The reaction mixture was stirred at 25° C. overnight. At this time, the reaction was filtered to remove solids. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60:40 hexanes/ethyl acetate afforded 4-(3-Trifluoromethyl-benzyl)-piperazine-1-carbonyl chloride (350 mg, 28%) as a clear oil. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][CH:13]=[CH:12][CH2:11][N:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:14][CH:13]=[CH:12][CH2:11][N:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CC=CCN(OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4.14 g (12.45 mmoles) of (1-benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-carbamic acid tert-butyl ester from Step C in 30 mL of dichloromethane was added 20 mL of trifluoroacetic acid. The reaction mixture was stirred for two hours at room temperature, and the solvent was removed under vacuum. Next, the reaction mixture was diluted in dichloromethane, and neutralized with NaHCO3(s). The reaction mixture was then extracted with NaHCO3(aq.) and NaCl (aq.) solutions. The aqueous layers were re-extracted with dichloromethane twice, and the organic layers combined and dried over Na2SO4(s). Filtration and solvent removal gave 3.685 g of a purple, viscous oil. MS: 465 (2M+H), 233 (M+H).