Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7](/[CH:10]=[CH:11]/[CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH2:19]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](/C=C/CCC2CCC(O)CC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H](/C=C/CCC2CCC(=O)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(E)-4-(4-(trans-4-Propylcyclohexyl)but-3-en-1-yl)cyclohexanol (s44) (4.7 g) and methylene chloride (100 ml) were placed in a reaction vessel under an atmosphere of nitrogen, and cooled to 0° C. Dess-Martin periodinane (DMP; 9.3 g) was added in the temperature range of 0° C. to 5° C. After 1 hour of stirring at 0° C., the reaction mixture was allowed to come to room temperature, and the stirring was continued for another 8 hours. Celite was added to the reaction mixture, and unnecessary materials were removed. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder to give (E)-4-(4-(trans-4-propylcyclohexyl)but-3-en-1-yl)cyclohexanone (s45) (4.6 g). The yield based on the compound (s44) was 98.6%.
Reaction SMILES: C([N:8]1[CH2:12][C:11](=[O:13])[NH:10][CH:9]1[CH2:14][CH2:15][C:16]([O:18]CC)=O)C1C=CC=CC=1.C([O-])=O.[NH4+].N>[Pd].O.CO>[O:13]=[C:11]1[CH2:12][N:8]2[C:16](=[O:18])[CH2:15][CH2:14][CH:9]2[NH:10]1
Reactant: CCOC(=O)CCC1NC(=O)CN1Cc1ccccc1
Agent: [Pd]
Agent: N
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: O=C1CN2C(=O)CCC2N1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
To a suspension of 10% palladium on charcoal (11.6 g) in water (60 ml), a solution of ethyl 3-benzyl-5-oxo-2-imidazolidinepropanoate (58 g, 0.21 mol) and ammonium formate (52.9 g, 0.84 mol) in methanol (580 ml) were added. The mixture was refluxed under nitrogen for 1 hour. After cooling to 40° C., 32% ammonia (145 ml) was added and the temperature was maintained between 40° and 50° C. for 1.5 hours. After cooling to room temperature, the catalyst was removed by filtration and the solution was evaporated to dryness. The residue was diluted with water (700 ml) and stirred in the presence of ion exchange resins Amberlite IR 120 H (200 ml) and Amberlite IRA 68 (200 ml) for 1.5 hours. The resins were filtered off and washed with water (600 ml). The clear solution was evaporated under vacuum at 60° C. to afford an oil which was dried by azeotropic distillation with ethanol. The resulting residue was triturated with acetone (75 ml) to afford 19.7 g (67%) of the title compound as a white solid, m.p. 154°-157° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]1.ClCCl.ClC1C=CC=C(C(OO)=[O:29])C=1>C(OC)(C)(C)C>[CH3:17][C:2]1([CH2:3][C:4]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:8](=[O:10])[NH:7][CH2:6][CH2:5]2)[CH2:1][O:29]1
Reactant: C=C(C)CC1(c2ccccc2)CCNC(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: CC1(CC2(c3ccccc3)CCNC(=O)O2)CO1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a 1.0 L 2-neck RBF was charged (R)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (135.8 g, 59 wt %, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv). The resulting solution was agitated at rt (Tint=20-25° C.) for 1 h, which HPLC analysis indicates >99 A % (220 nm) conversion. The resulting solution was diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with 1×500 mL of 30 wt % solution of sodium thiosulfate and 1×500 mL of saturated aqueous solution of sodium bicarbonate. The wash sequence was repeated until the peak on an HPLC trace of the organic solution that corresponds to a HPLC sample peak of m-CPBA is <2.5 A % (220 nm), which in this example the wash sequence was repeated 3 times. The resulting organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated to an oil via reduced pressure. The resulting material was diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a thick oil via reduced pressure to provide (6S)-3-(S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one which was used directly in Step 5.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=2)[N:6]1[C:16](=[O:18])[CH3:17])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[C:16]([N:6]1[C:7]2[C:12](=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=2)[CH2:13][CH2:14][CH:5]1[C:3]([OH:4])=[O:2])(=[O:18])[CH3:17]
Reactant: COC(=O)C1CCc2cc(Br)ccc2N1C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(Br)cc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of compound 25b (116 mg, 0.37 mmol) in THF/MeOH/H2O (2/2/2 mL) was added LiOH (62 mg, 1.48 mmol). The reaction mixture was stirred at room temperature for 3 h. The resultant mixture was concentrated under reduced pressure, partitioned between CH2Cl2 and H2O, and the aqueous phase was brought to pH 5 by the addition of 2N HCl (aq). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound 25c, which was used in the next step without further purification. LC/MS m/z 298.0 (M+H+), 300.0 (M+2H+).
Reaction SMILES: CCN(CC)CC.I[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][O:19][CH2:18][CH2:17][N:16]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][O:23][C:21]([C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:20][O:19][CH2:18][CH2:17][N:16]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:11][CH:10]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@@H]2COCCN2C(=O)OC(C)(C)C)cc1
Temperature: 65 °C
Yield: 321.2 %

Procedure:
Carbon monoxide gas was bubbled through a reaction mixture containing Et3N (4.742 g, 6.532 ml, 48.86 mmol), tert-butyl (3R)-3-(4-iodophenyl)morpholine-4-carboxylate 8 (5.21 g, 13.39 mmol) and Pd(dppf)Cl2—CH2Cl2 (1.093 g, 1.339 mmol) in methanol (157 mL) cooled in an ice bath for 10 mins. The reaction vessel was quickly sealed and the reaction mixture heated at 65° C. for 18 h. The reaction mixture cooled to rt and filtered through celite, washing through with methanol. The filtrate was concentrated in vacuo and crude product purified by ISCO companion (330 g SiO2 0 to 20% EtOAc/petroleum ether) and the product fractions combined and concentrated in vacuo to leave the product as a colourless oil (6.91 g, 81% yield); 1H NMR (400.0 MHz, DMSO) d 1.39 (9H, s), 3.01 (1H, m), 3.51 (1H, m), 3.71-3.85 (6H, m), 4.29 (1H, m), 5.04 (1H, s), 7.48 (2H, m) and 7.97 (2H, m) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=1[NH2:23].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17](=[O:18])[NH:23][C:22]1[C:21]([F:20])=[CH:27][CH:26]=[CH:25][C:24]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)isoindoline-1-carboxylic acid (500 mg, 1.9 mmol, Eq: 1.00) and 2,6-difluoroaniline (294 mg, 2.28 mmol, Eq: 1.2) in pyridine (10 mL) at 0° C. was added POCl3 (437 mg, 266 μL, 2.85 mmol, Eq: 1.5). The reaction was warmed to RT and stirred for 2 h. The mixture was evaporated and water was added and the resulting mixture was extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give 1-(2,6-difluoro-phenylcarbamoyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (462 mg) as a light yellow foam.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][NH2:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CCN)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)CCl)cc1OC

Procedure:
4.5 ml of triethylamine were added to a solution of 5.11 g of 2-(3,4-dimethoxyphenyl)ethylamine dissolved in 35 ml of methylene chloride, and the mixture was stirred, whilst ice-cooling. 2.4 ml of chloroacetyl chloride were then added dropwise to the mixture over a period of 5 minutes, after which the mixture was stirred for 15 minutes, whilst ice-cooling. The reaction mixture was then concentrated by evaporation under reduced pressure, and ethyl acetate was added to the resulting residue. The ethyl acetate solution was washed, in turn, with water, with a 5% w/v aqueous solution of sodium bicarbonate, with 10% w/v aqueous hydrochloric acid and with a saturated aqueous solution of sodium chloride. It was then dried, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate and hexane, to give 5.77 g of the title compound as pale yellow-brown, feather-like crystals melting at 92-94° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3)cccc2c1N
Yield: 70.2 %

Procedure:
Using method F, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.50 mmol) and 4-methoxyphenylboronic acid (303 mg, 2.00 mmol) were reacted (reflux 14 hours) to afford the title compound (118 mg, 70% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ8.58 (bm, 1H), 7.69-7.83 (m, 3H), 7.62 (d, J=8.9 Hz, 2H), 7.05 (d, J=8.9 Hz, 2H), 3.87 (s, 3 H), 3.45 (apparent q, J=6.6 Hz, 2H), 1.65 (apparent sextet, J=7.4 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). MS APCI, m/z=337 (M+H) HPLC 1.71 min.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([N+:23]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl.Cl.[Sn].[OH-].[Na+]>CO>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]([F:13])[F:12])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[CH3:22])[C:6]=2[CH:5]=[C:4]([NH2:23])[CH:3]=1
Reactant: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C(F)F)nc2c(Br)cc(N)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
To a 250 mL rb flask containing MeOH (50 mL) was added 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-6-nitro-1H-benzo[d]imidazole (4.0 g, 9.29 mmol), tin(II) chloride dihydrate (12.58 g, 55.7 mmol) and concentrated hydrochloric acid (6.97 ml, 84 mmol). The resultant suspension was heated to 50° C. and monitored by LC/MS. By LC/MS the reaction was complete in 45 minutes. After the reaction had cooled to room temperature and was filtered to remove insoluble tin salts, 6N NaOH (0.8 ml, 4.00 mmol) was added to adjust the pH to about 11 and the mixture was concentrated to remove any MeOH. The sticky mixture was extracted with EtOAC; however, because it was difficult to extract from the tin-salt containing aqueous the entire mixture of two phases was filtered then the layers were separated. The organic was dried over MgSO4 and concentrated in vacuo to provide and the organic was washed with H2O and brine and dried over MgSO4 and filtered. The solvent was removed in-vacuo leaving light brown solid 4-bromo-1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-1H-benzo[d]imidazol-6-amine (2.25 g, 5.62 mmol, 60.5% yield) as crude material. LC/MS: MS (ES+) m/e 402.4 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.33 (d, J=7.83 Hz, 1H), 6.80-7.13 (m, 3H), 6.33 (d, J=7.83 Hz, 1H), 6.25 (d, J=2.02 Hz, 1H), 5.46 (s, 2H), 3.81 (s, 2H), 2.49 (s, 3H)
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15].CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O>>[C:1]([OH:19])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[CH:15]
Reactant: C#CCCCCC#CCCCCCCCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C#CCCCCC#CCCCCCCC(=O)O
Yield: 87 %

Procedure:
Oxidation of pentadeca-8,14-diyn-1-ol (3.0 g, 13.69 mmol) using Jones reagent as described above and purification by SiO2 column chromatography using 15% EtOAc/hexanes as eluent gave pentadeca-8,14-diynoic acid (2.80 g, 87%) as a colorless oil. TLC: 30% EtOAc/hexanes, Rf≈0.33; 1H NMR (400 MHz, CDCl3) δ 2.34 (t, J=7.0 Hz, 2H), 2.10-2.18 (m, 6H), 1.93 (t, J=2.6 Hz, 1H), 1.55-1.67 (m, 6H), 1.33-1.49 (m, 6H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]([NH2:14])=[S:13]>CO>[C:5]1([C:3]2[N:11]=[C:12]([NH2:14])[S:13][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Product: Nc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
2-Bromo-1-phenyl-ethanone (19.9 g, 0.100 mol) and thiourea (7.9 g, 0.10 mol) were mixed in a 150 mL of methanol. The reaction mixture was warmed to dissolve the reagents and then allowed to stir overnight at room temperature. The methanol was evaporated to dryness and the crude product was dissolved in a minimum of ethyl acetate. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (16.8 g, 0.0953 mol, 95.3%) of product. ESI-MS m/z calc. 176.0. found 177.2 (M+1)+ Retention time 1.41 minutes. 1H NMR (400 MHz, CD3CN) δ 5.73 (s, 2H), 6.87 (s, 1H), 7.28-7.34 (m, 1H), 7.36-7.43 (m, 2H), 7.79-7.85 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([C@@H:9]2[O:31][C@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@@H:20]([O:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:10]2[O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5](=[O:42])[NH:4][C:3]=1[NH2:43].[CH3:44]C1C=CC(S(O)(=O)=O)=CC=1>C(OC(OCC)OCC)C>[C:12]([O:11][C@@H:10]1[C@H:20]([O:21][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:30]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:31][C@H:9]1[N:6]1[C:7](=[O:8])[C:2]2[NH:1][CH:44]=[N:43][C:3]=2[NH:4][C:5]1=[O:42])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1[nH]c(=O)n([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)c1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Product: O=C(OC[C@H]1O[C@@H](n2c(=O)[nH]c3nc[nH]c3c2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
A mixture of 50 (4.30 g, 7.33 mmol), TsOH (catalytic amount), and triethylorthoformate (90 mL) was stirred at room temperature for 24 hr, concentrated, and the residue purified on a silica gel column (CHCl3:MeOH=30:1 v/v) to give compound 51 (2.20 g, 50%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C@H:30](N)[CH3:31])[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8][NH:9][C@@H:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)[CH3:31])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=CC#N)cc1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC=Cc2ccc(C)cc2)c1

Procedure:
In a similar fashion, 4-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(4-methylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12B, as a clear, colorless oil; m/z (rel. int.) 281 (M+, 6), 266 (5), 176 (27), 146 (75), 135 (63), 131 (100), 115 (25), 105 (21), 91 (21), 77 (21).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[CH3:13]/[C:14](/[C:17]([CH3:19])=O)=[N:15]\[OH:16].[ClH:20].C(OCC)C>C(O)(=O)C>[ClH:20].[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([C:7]2[O:8][C:17]([CH3:19])=[C:14]([CH3:13])[N+:15]=2[O-:16])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 25 °C
Yield: 86 %

Procedure:
34.8 g (0.20 mol) of 4-trifluoromethylbenzaldehyde and 20.2 g (0.20 mol) of 2,3-butanedione monoxime were dissolved in 100 ml of glacial acetic acid and the mixture was stirred at room temperature while passing gaseous hydrogen chloride through the mixture until a saturated solution was obtained. The mixture was stirred at room temperature overnight and then treated with an excess of anhydrous diethyl ether. The colourless crystalline precipitate was filtered off, washed free of mother liquors using fresh anhydrous diethyl ether and dried in vacuo to give 50 g (86%) of 2-(4-trifluoromethylphenyl)-4,5-dimethyloxazole N-oxide hydrochloride of melting point 175°-177° C. (decomposition).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][P:8]([CH2:28][NH2:29])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6].[C:30]1([C:36]2=[C:37]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:38]([O:40][C:41]2=O)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:5]([O:7][P:8]([CH2:28][N:29]1[C:41](=[O:40])[C:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:38]1=[O:39])([CH2:10][CH:11]([C:16](=[O:27])[NH:17][C@H:18]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])[CH3:6]
Reactant: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Reactant: O=C1OC(=O)C(c2ccccc2)=C1c1ccccc1
Solvent: CC(=O)O
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)C(c2ccccc2)=C(c2ccccc2)C1=O
Yield: 80.2 %

Procedure:
In a manner analogous to that described in Example 3(A), from 0.52 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate and 0.34 g of diphenylmaleic anhydride, there was obtained 0.581 g of [(2,3-diphenylmaleimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester in the form of a yellow-green foam.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14])(=[O:5])=[O:4].CCCCN=[C:23]=[O:24].C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:1][N:2]([CH3:17])[S:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:23]=[O:24])(=[O:15])=[O:14])(=[O:4])=[O:5]
Reactant: CCCCN=C=O
Reactant: CN(C)S(=O)(=O)Oc1ccccc1S(N)(=O)=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: CN(C)S(=O)(=O)Oc1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C

Procedure:
To 6.0 g (0.021 mole) 2-(dimethylaminosulfonyloxy)benzenesulfonamide suspended in 75 ml dry xylenes was added 2.1 g (0.021 mole) N-butyl isocyanate and a catalytic amount of 1,4-diazobicyclo[2.2.2]octane (~0.05 g). This mixture was rapidly heated to reflux temperature (~135° C.) and 3.0 ml of phosgene was slowly added (at such a rate as to keep the reaction temperature greater than 128° C.). The phosgene addition required ~3 hours. The reaction was cooled to room temperature, filtered under N2, and the solvent evaporated under reduced pressure. The infrared spectrum of the resultant oil was consistent for 2-(dimethylaminosulfonyloxy)benzenesulfonyl isocyanate, (2240 cm-1).
Reaction SMILES: C(O)C.Cl[C:5]1[C:10]([Cl:11])=[N:9][CH:8]=[CH:7][N:6]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14]>C(N(CC)CC)C>[Cl:11][C:10]1[C:5]([NH:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:19])=[N:6][CH:7]=[CH:8][N:9]=1
Reactant: Clc1nccnc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1nccnc1Cl
Yield: 14.6 %

Procedure:
To an ethanol solution (10 mL) of 2,3-dichloropyrazine (1.0 g), glycine ethyl ester hydrochloride (940 mg) and triethylamine (1.9 mL) were added and the mixture was irradiated with microwave (150° C., 10 min). The reaction mixture was concentrated under reduced pressure. To the resulting residue, a saturated aqueous sodium bicarbonate solution was added and the product was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd.; NH-©M1020) column chromatography (hexane:ethyl acetate=10:1) to give 212 mg (15% yield) of the desired product.
Reaction SMILES: [Cl:1][C:2]1([S:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[S:29][C:30]([CH3:40])=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:23]=23)(=[O:20])=[O:19])[CH2:7][CH2:6][N:5](C(OCC2C=CC=CC=2)=O)[CH2:4][CH2:3]1.CO.C(O)(=O)C.[H][H]>CCO.[Pd]>[Cl:1][C:2]1([S:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]3[S:29][C:30]([CH3:40])=[C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:23]=23)(=[O:20])=[O:19])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)C4(Cl)CCN(C(=O)OCc5ccccc5)CC4)c23)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)C4(Cl)CCNCC4)c23)c1
Yield: 11.3 %

Procedure:
Phenylmethyl 4-chloro-4-[({2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}amino)sulfonyl]-1-piperidinecarboxylate (Example 10) (80 mg, 0.133 mmol) was taken-up in EtOH (5 mL), MeOH (5 mL) and acetic acid (1 mL). 10% Palladium on carbon (14.19 mg, 0.013 mmol) was then added and the reaction mixture was stirred at RT under 2 Bar of hydrogen for 48 h. The reaction mixture was then filtered through celite and the celite was washed with 50 mL of MeOH. The solvent was concentrated to give a residue which was purified by normal phase chromatography, eluting with a gradient from 0-10% 2N NH3 in MeOH in DCM and then further purified by MDAP (basic conditions), to afford the title compound (7 mg). LCMS (A) m/z: 466 [M+1]+, Rt 0.81 min (basic).