Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:16]=[C:15]([CH:17]=O)[CH:14]=[C:13]2[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1COCC1.[O:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH:16]=[C:15]([CH2:17][NH:46][C:45]3[CH:47]=[CH:48][C:42]([N:39]4[CH2:38][CH2:37][O:36][CH2:41][CH2:40]4)=[CH:43][CH:44]=3)[CH:14]=[C:13]2[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(CNc3ccc(N4CCOCC4)cc3)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-p-methoxyphenylsulfonyl-2-(3,4,5-trimethoxyphenyl)pyrrole-4-carbaldehyde (50 mg, 0.12 mmol, Example 94a) in THF (1 ml) acetic acid (21 mg, 3 equiv.), 4-morpholinoaniline (21 mg, 1.05 equiv.) and NaBH(OAc)3 (61 mg, 2.5 equiv.) are added. The reaction mixture is stirred at room temperature for 16 h, and diluted with aqueous 1 M Na2CO3 solution and ethyl acetate. The organic layer is dried (MgSO4) and purified by flash chromatography and preparative HPLC. RT (program 2) 3.52. MS: 593.7.
Reaction SMILES: [CH3:1][CH:2]([C:15]1([O:20][CH2:19]1)[C:16](O)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:21]([N:23](CC)[CH2:24]C)C.ClC(OCC)=O.N(CC)(CC)CC.Cl.CNC>O1CCCC1>[CH3:21][N:23]([CH3:24])[C:16](=[O:17])[C:15]1([CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:1])[O:20][CH2:19]1
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCC(C)C1(C(=O)O)CO1
Agent: CCOC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(C)C1(C(=O)N(C)C)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
To a solution of 1.42 g (0.005 mole) of 2-tetradecylglycidic acid in 10 ml of tetrahydrofuran (THF) at 0° C. (ice-water bath) with stirring is added 0.50 g (0.005 mole) of triethylamine in a small amount of THF. The solution is stirred at 0° C. for 30 minutes and 0.51 g (0.005 mole) of ethyl chloroformate is added. The mixture is stirred at about 0° C. (ice-water bath) for 3 hours (ppt. of Et3N.HCl observed). At the end of 3 hours 0.429 g (0.015 mole) of dimethyl amine in THF is added and the mixture stirred overnight (16 hours) at room temperature. The THF solvent is concentrated to about 1/3 its volume, water is added and the mixture extracted with ether. The ether extract is dried over Na2SO4 and the ether solvent removed. A crude oily residue is obtained which is purified by column chromatography on silica gel. A 37.8% yield of pure N,N-dimethyl-2-tetradecylglycidamide is obtained, m.p. 40°-42° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([C@@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: C[C@@H](CCCCC(=O)O)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CCCCC(=O)O)N(C)C(=O)OCc1ccccc1
Yield: 51.9 %

Procedure:
6.5 g (23 mmol) of (S)-6-[1-(benzyloxy)formamido]heptanoic acid are added to a suspension of 3.05 g of 55% sodium hydride (70 mmol) in 200 ml of dimethylformamide and the mixture is left to react at 40° for 30 minutes. Thereafter, 13 g (90 mmol) of methyl iodide are added dropwise and the reaction mixture is heated to 70° for 1 hour. After evaporation of the solvent 120 ml of 1N agueous sodium hydroxide solution and 120 ml of ethanol are added and the reaction mixture is heated to reflux for 30 minutes. Thereafter, the mixture is evaporated to half, 100 ml of saturated aqueous sodium bicarbonate solution are added and the mixture is extracted with ethyl acetate. The aqueous phase is acidified and extracted with methylene chloride. The organic phase is dried over magnesium sulphate and evaporated. The residue (5 g) is chromatographed on silica gel with a 12:1 mixture of methylene chloride and methanol, whereby there are obtained 3.5 g (52.2%) of (S)-6-[1-(benzyloxy)-N-methylformamido]heptanoic acid, MS: M+ 293.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[N+:20]([O-:22])=[O:21])[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)nc2sc3ccccc3n12
Temperature: 0 °C

Procedure:
After cooling 30 ml of fuming nitric acid to -35° to -45° C., 3 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole was gradually added thereto. The reaction mixture was poured into ice water and the crystals which formed were recovered by filtration and recrystallized from acetic acid to provide 2.2 g of 2-(p-chlorophenyl)-3-nitroimidazo[2,1-b]benzothiazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH2:40]([N:44]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][NH2:48])[CH2:41][CH2:42][CH3:43]>C1COCC1>[CH2:40]([N:44]([CH2:49][CH2:50][CH2:51][CH3:52])[CH2:45][CH2:46][CH2:47][NH:48][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:39])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH2:41][CH2:42][CH3:43]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CCCCN(CCCC)CCCN
Solvent: C1CCOC1
Product: CCCCN(CCCC)CCCNc1nc(-c2cc(C(=O)Nc3ccc(F)cc3)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 66 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL) was added N,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (16 mg, 66%). LC-MS m/z 674 (M+H)+; 1H-NMR (MeOD) δ 1.00 (t, 6H), 1.30 (m, 4H), 1.40 (m, 4H), 1.50 (m, 2H), 2.34 (s, 3H), 2.43 (m, 6H), 3.10 (m, 2H), 4.13 (s, 2H), 7.15(m, 4H), 7.53 (m, 2H), 7.72 (m, 2H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2=NCCc3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline (4.693 g, 17 mmol) (example 1b) in MeOH (24 mL) was added sodium borohydride (1.94 g, 51.1 mmol) slowly at 0° C. After addition, the mixture was stirred at 0° C. for 15 min and at RT for 2 h. The solvent was then removed and H2O (20 mL) was added to the residue. Then, a saturated NaHCO3 solution (150 mL) was added slowly and the mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was mixed with silica gel (4:1; residue:silica gel). The solid mixture was purified by silica gel flash column chromatography using ISCO instrument (solid loading, 20%-100% EtOAc/hexane) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 278 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH3:33])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1.CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:30])[NH:32][CH3:33])=[CH:25][CH:24]=5)[CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(N)c2)cc1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c2)cc1
Reaction time: 16 h

Procedure:
To a solution of 1-benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl chloride (0.97 mmol) in CH2Cl2 (3 mL) at ambient temperature was added a solution of 3′-amino-N-methylbiphenyl-4-sulfonamide (0.25 g, 0.97 mmol), Et3N (0.68 mL, 4.9 mmol), DMAP (0.050 g, 0.058 mmol), and CH2Cl2 (1 mL) dropwise. The mixture was allowed to stir for 16 h before it was diluted with CH2Cl2 (50 mL). The solution was washed with 1N HCl (2×25 mL), sat. aq. NaHCO3 (2×25 mL), then brine (25 mL). The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (5-25% EtOAc/hexanes) to provide 1-benzo[1,3]dioxol-5-yl-N-[3-[4-(methylsulfamoyl)phenyl]phenyl]-cyclopropane-1-carboxamide as a white solid. ESI-MS m/z calc. 450.5, found 451.3 (M+1)+. Retention time of 3.13 minutes.
Reaction SMILES: C1C2C(COC([N:18]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[N+:58]([C:61]1[CH:62]=[C:63]([CH:69]=[CH:70][CH:71]=1)[CH:64]=[CH:65][C:66]([OH:68])=O)([O-:60])=[O:59]>>[N+:58]([C:61]1[CH:62]=[C:63]([CH:69]=[CH:70][CH:71]=1)[CH:64]=[CH:65][C:66]([N:18]([C:39]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:68])([O-:60])=[O:59]
Reactant: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Product: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)C=Cc1cccc([N+](=O)[O-])c1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
This compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]dopamine (628 mg, 0.8 mmol, example 48, step A) as described for example 48 (step B) using 3-nitrocinnamic acid (240 mg, 1.2 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 15%, 20% and 35% EtOAc/CH2Cl2/1% AcOH as the eluent. The title compound was obtained as a yellow powder (247 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](=[CH:28]/[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])/[C:15]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](=[CH:28]/[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])/[C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCC/C=C(\C(=O)Nc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC/C=C(\C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
700 mg (1.47 mmol) of methyl (Z)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido]benzoate, 25 ml of methanol and 1.2 ml (14.7 mmol) of a 35% sodium hydroxide solution were introduced into a round-bottomed flask. The mixture was stirred at room temperature for 12 hours, the reaction medium was poured into water, acidified to pH 1 with hydrochloric acid (37%), extracted with ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue was triturated in heptane, filtered and dried. 555 mg (82%) of (Z)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-2-nonenamido]benzoic acid of melting point 183°-4° C. were recovered.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=1[NH2:8].O>C(Cl)Cl>[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=1[NH:8][CH2:2][C:3]#[N:4]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: N#CCCl
Solvent: O
Solvent: ClCCl
Product: N#CCNc1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
Chloroacetonitrile (40 ml) and 2,4-dichloroaniline (81.0 g) were heated with stirring in a 250 ml round-bottomed three-necked flask at 120°-125° C. for 1.0 hour and then for approximately 1 hour at 140°-145° C. The reaction mixture was cooled, diluted with CH2Cl2, and then placed in a separatory funnel and water added. Shaking the mixture resulted in crystal formation. The mixture was filtered and 39.2 g of 2,4-dichloroaniline hydrochloride removed. The CH2Cl2 layer was then separated from the filtrate and the CH2Cl2 layer treated with diatomaceous earth and activated charcoal and then filtered. The CH2Cl2 was then evaporated off, leaving a black viscous gum which on cooling with stirring solidified. Recrystallization from carbon tetrachloride gave 21.5 g of 2,4-dichloroanilinoacetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([O:34][CH3:35])=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:30]([C:28]3[CH:29]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=3[O:34][CH3:35])(=[O:31])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: COc1ccc(F)cc1S(=O)(=O)Cl
Product: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 79 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (309 mg, 0.934 mmol) and 5-fluoro-2-(methyloxy)benzenesulfonyl chloride (210 mg, 0.934 mmol) the title compound of Step A was obtained as a white solid. (381 mg, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.34 (s, 1H), 8.42 (d, J=5.3 Hz, 1H), 7.39-7.54 (m, 2H), 7.23-7.37 (m, 1H), 7.09-7.23 (m, 4H), 6.87 (d, J=5.3 Hz, 1H), 3.79 (s, 3H), 3.29-3.38 (m, 1H), 1.33 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24](N(OC)C)=[O:25])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:37]1.C[Mg]Br.O>O1CCCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[N:10]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:11](=[O:30])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24](=[O:25])[CH3:37])=[CH:14][CH:13]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)N(C)OC)cc12
Agent: C[Mg]Br
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(C)=O)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl(4-butoxy-2-isobutyl-6{[methoxy(methyl)amino]carbonyl}-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.49 g, 1 mmol) in tetrahydrofuran (10 ml) was added 1N methylmagnesium bromide tetrahydrofuran solution (5 ml) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(6-acetyl-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.37 g, 84.1%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[O:12][CH2:11][CH2:10][N:9]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1>C(OC(C)C)(=O)C.C(#N)C>[CH2:15]([N:9]1[CH:10]=[CH:11][O:12][C:13](=[O:14])[C@@H:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1OCCN(Cc2ccccc2)C1c1ccc(F)cc1
Solvent: CC#N
Solvent: CC(=O)OC(C)C
Product: O=C1OC=CN(Cc2ccccc2)[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of 3-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-4-fluorophenyl-1,4-oxazin-2-one) (10 g) in isopropyl acetate (110 ml) at room temperature was added a solution of (−)-3-bromocamphor-8-sulphonic acid ((−)-3BCS) (12 g) in acetonitrile (24 ml). Crystallisation began after 2-3 min. The slurry was stirred for 1 h at room temperature. Trifluoroacetic acid (7 ml) was added and the mixture stirred at 65° C. for 3 days. The mixture was cooled to 0-5° C., aged for 1 h. and the solid collected, washed with isopropyl acetate and dried in vacuo at 40° C., to give the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 17.24 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 79%(R), 21%(S). The liquors were stirred at 65° C. for 3 days, then cooled to 0-5° C. The solid was collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 0.84 g, ee 98.6% (S) isomer. The chiral composition of the remaining liquors was determined as 64%(R), 36%(S). The liquors were stripped in vacuo and the residue was dissolved in isopropyl acetate (20 ml) containing trifluoroacetic acid (1 ml) and stirred at 65° C. for 20 h. The mixture was cooled to 0-5° C. for 1 h and the solid collected, washed with isopropyl acetate and dried in vacuo to give a further batch of the N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one (−)-3BCS salt: yield 2.2 g, ee 99.2% (S) isomer. Total weight of (−)-3BCS salt: 20.28 g, 97% yield. A sample (0.5 g) of the (−)-3BCS salt was retained and the remainder converted back to free base. The salt was partitioned between isopropyl acetate (50 ml) and water (100 ml) containing 0.88 ammonia soln. (3 ml). The layers were separated and the aqueous phase extracted with isopropyl acetate (25 ml). The combined organic phases were washed with water (25 ml). The organic phase was concentrated to residue and flushed with isopropyl acetate to give the 3-(S)-(4-fluorophenyl)-4-phenylmethyl-2-morpholinone (i.e. N-benzyl-3-(S)-(4-fluorophenyl)-1,4-oxazin-2-one) as the free base: yield 8.7 g, 93% recovery, ee 98.4% (S) isomer.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCl>[CH3:21][S:18]([O:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:20])=[O:19]
Reactant: OCCCC1CCCOC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC1CCCOC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(tetrahydro-2H-pyran-3-yl)-1-propanol (2.64 g) in dry dichloromethane (78 ml) at 0° C. was added triethylamine (6.21 ml) followed by mesyl chloride (1.85 ml). The reaction mixture was allowed to warm to room temperature as the ice melted and allowed to stir for three hours. The reaction mixture was washed with sodium hydrogen carbonate. The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo. to give a yellow oil (4.42 g). The product was purified by silica chromatography (80 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a clear oil (3.79 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(OCC)(OCC)O[CH2:16][CH3:17]>>[N+:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:16][CH3:17])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(OCC)OCC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1O

Procedure:
1.5 kg (8.2 mol) of 5-nitrosalicylic acid was dissolved in 2000 ml of triethyl orthoformate. The obtained solution was refluxed under heating for 3 hours to remove formed ethanol by distillation. The reaction mixture was cooled and then concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether to give 1.74 kg of the title compound as a colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=4[Cl:36])[N:23]=[N:24][C:25]=3[CH:26]([CH3:28])[CH3:27])=[CH:15][C:14]=2[CH3:37])[CH:6]=1)[CH3:2].[H-].[Na+].I[CH3:42]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[C:30]([Cl:36])=[CH:31][CH:32]=[CH:33][C:34]=4[Cl:35])[N:23]=[N:24][C:25]=3[CH:26]([CH3:27])[CH3:28])=[CH:15][C:14]=2[CH3:37])[CH3:42])[CH:6]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cccc(NCc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(N(C)Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
To a mixture of 3-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzylamino}-benzoic acid ethyl ester (160 mg, 0.29 mmol) and sodium hydride (13 mg, 0.33 mmol) in anhydrous N,N-dimethyl formamide is added iodomethane (50 mg, 0.35 mmol). After three hours, more iodomethane (50 mg, 0.35 mmol) is added and the mixture is heated to 60° C. After three hours, more iodomethane (50 mg, 0.35 mmol) is added and the mixture is stirred at room temperature over night. The mixture is then partitioned between diethylether and water. The aqueous layer is extracted three times with diethylether. The combined ether layers are dried (MgSO4) and concentrated under reduced pressure. The crude residue is purified on 12 g of silica with ethyl acetate in heptane gradient to provide 3-({4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-benzyl}-methyl-amino)-benzoic acid ethyl ester (20 mg, 12%) LC-MS: 567.0 (M+1).