Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][NH2:13]>CO>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:13][CH3:12])[CH:7]=1
Reactant: CN
Reactant: ClCCCOc1cccnc1
Solvent: CO
Product: CNCCCOc1cccnc1
Temperature: 80 °C

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (4.90 g, 28.55 mmol) was dissolved in methanol (60 mL) and added to a 40 wt % solution of methylamine (60 mL) in a heavy-walled pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 80° C. for 15 h. After cooling, the mixture was concentrated by rotary evaporation, a saturated NaCl solution (25 mL) was added, and the mixture was basified with 20% NaOH solution (5.0 mL). The mixture was extracted with chloroform (4×30 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 3.64 g of a brown oil. The product was purified by column chromatography on silica gel (100 g) eluting with chloroform-methanol-triethylamine (70:30:2.5, v/v/v). Selected fractions containing the product (Rf 0.30) were combined and concentrated by rotary evaporation. The resulting residue was dissolved in chloroform (15 mL), dried (Na2SO4), filtered, and concentrated by rotary evaporation to give 1.92 g (40.4%) of a brown oil.
Reaction SMILES: C(OC([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([O:25][C@H:26]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]3[CH2:51][CH2:50]3)[CH:38]=2)[CH2:27][C:28]2[C:33]([Cl:34])=[CH:32][N+:31]([O-:35])=[CH:30][C:29]=2[Cl:36])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:36][C:29]1[CH:30]=[N+:31]([O-:35])[CH:32]=[C:33]([Cl:34])[C:28]=1[CH2:27][C@@H:26]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:45])[F:46])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[O:25][C:23](=[O:24])[CH2:22][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:14]1
Reactant: CC(C)(C)OC(=O)N(c1cn(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c2ccccc12)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cn(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c2ccccc12
Yield: 81.3 %

Procedure:
A solution of (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (297 mg, 0.385 mmol) and 4N HCl in dioxane (2 ml, 8.00 mmol) in DCM (4 ml) was stirred at room temperature for 18 hours. The volatiles were removed under vacuum and the crude was purified by flash chromatography on silica gel (DCM:EtOAc=6:4) to give (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (210 mg, 0.313 mmol, 81% yield). MS/ESI+ 670.36 [MH]+; [αD]=+7.7, c=0.6, MeOH; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.18 (br. s., 1H), 8.51 (s, 2H), 7.67 (d, 1H), 7.29 (s, 1H), 7.04-7.20 (m, 4H), 7.02 (d, 1H), 6.91 (dd, 1H), 7.06 (t, 1H), 6.01 (dd, 1H), 5.23 (d, 1H), 5.06 (d, 1H), 3.85 (d, 2H), 3.42 (dd, 1H), 3.20 (dd, 1H), 2.86 (s, 3H), 1.08-1.31 (m, 1H), 0.54-0.68 (m, 2H), 0.30-0.48 (m, 2H))
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[NH3:13]>CO>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:13])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: N
Solvent: CO
Product: Nc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 1-bromo-2,5-difluoro-4-nitro-benzene (1.50 g, 6.30 mmol) and 7M ammonia in methanol (25 mL) was heated in a sealed tube at 60° C. for 15 h. The reaction mixture was transferred to a round bottom flask, washing the sealed tube with EtOAc. The reaction mixture was concentrated, and the crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH2:13].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(C(C)C)CC)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCBr
Reactant: COc1ccc(OC)c(CCN)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNCCc1cc(OC)ccc1OC
Yield: 93.7 %

Procedure:
(2,5-Dimethoxyphenyl)ethylamine 3 (8.33 gm, 0.046 moles), ethyl 4-bromobutyrate (11.64 gm, 0.060 moles) and diisopropylethylamine (7.76 gm, 0.060 moles) were stirred at 110-120° C. for 18 hours, cooled, and partitioned between 50 ml DCM and 50 ml water. The aqueous layer was extracted thrice with 50 ml portions of DCM. The combined organic extracts were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with a gradient mixture of ethyl acetate and hexane. Ethyl 4-[(2,5-dimethoxyphenyl)ethylamino]butanoate 4 (12.73 gm, 94% yield) was isolated after removing the solvent. 1H NMR (CDCl3) δ 6.44-6.78, 3H, m; 4.11, 2H, q; 3.79, 3H, s; 3.76, 3H, s; 3.08-3.19, 4H, m; 2.30, 2H, t; 1.79, 2H, m; 1.24, 3H, t; 1.03, 3H, t.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9](=[N:11][OH:12])[CH3:10])[CH:3]=1.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:18]=1[CH2:19]Cl>CN(C)C=O>[CH3:26][O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[C:18]=1[CH2:19][O:12][N:11]=[C:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[CH3:10]
Reactant: COc1cccc(OC)c1CCl
Reactant: CC(=NO)c1cc(Cl)cc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1CON=C(C)c1cc(Cl)cc(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
On the other hand, 1.66 g (9.0 mmol) of 1-(4-chloro-6-methyl-2-pyridinyl)ethanone oxime was dissolved in 15 ml of N,N-dimethylformamide, and the resultant solution was added with 0.18 g (4.39 mmol) of sodium hydride (60%, oiliness) while cooling the solution with ice. The mixture was stirred for 15 min. at a temperature below 0° C. and was added with the whole amount of the crude product of 2,6-dimethoxybenzyl chloride prepared previously while cooling the mixture with ice. The resultant mixture was stirred for 2.3 hours at a room temperature to complete a reaction. The reacted mixture was then poured into ice water. At that time, the target compound was precipitated in the ice water. The precipitation was taken out by filtering, washed with hexane and dried to thereby obtain the target compound in an amount of 2.3 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[CH:4]2[O:14][CH:3]12.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[ClH:22]>C(O)C>[ClH:22].[CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:5]=2[C@@H:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C@@H:3]1[OH:14]
Reactant: C1CCNCC1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: Cl
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCCC2)[C@@H]1O

Procedure:
Treatment of 2,2-dimethyl-3,4-epoxy-6-cyano-3,4-dihydro-2H-benzo[b]pyran (2.09 g) with piperidine (0.86 g) in refluxing ethanol (60 ml) for 24 hours followed by evaporation of solvent gave a yellow oil which was dissolved in the minimum quantity of ethanol and treated with ethereal hydrogen chloride to give crystals of trans-2,2-dimethyl-4-piperidino-6-cyano-3,4-dihydro-2H-benzo[b]pyran-3-ol hydrochloride on standing (2.06 g) of m.p. 253°-257° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C(#N)C>[C:13]1([C@@H:19]([NH:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In another embodiment, the present invention may utilize ethyl 2-oxocyclohexane carboxylate (6) to prepare (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) as described in FIG. 4 by modification of methods of synthesis using an aprotic solvent to produce an amine [See Xu D et al., Tetrahedron Asymmetry, Vol. 8, No. 9, pp/1445-51, 1997]. The current embodiment may comprise reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of an aprotic solvent including, but not limited to, toluene and acetonitrile, to produce (S)-Ethyl 241-phenylethylamino)cyclohex-1-enecarboxylate (8). The ratio of compound (6) to compound (7) generally ranges from approximately 10:1 to approximately 1:10. In one embodiment, the ratio of compound (6) to compound (7) ranges from approximately 5:1 to approximately 1:5. In another embodiment, the ratio of compound (6) to compound (7) ranges from approximately 2:1 to approximately 1:2. In an additional embodiment, the ratio of compound (6) to compound (7) comprises approximately 1:1.05.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[C:18]1([C@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:26]2[CH2:27][CH2:28][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: c1ccc([C@H]2CCNC[C@H]2c2ccccc2)cc1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=478.2 (M+H+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3,4-diphenylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC=CC=1.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.8 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)naphthalenylidene]methanamine (Ketimine) (50 g), toluene (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 75 to 80/25 to 20. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.80 to 0.82%].
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH:10]=[CH2:11])[C:5]([CH3:12])=[CH:4][CH:3]=1.[OH-:13].[Na+].OO>O1CCCC1>[Cl:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][CH2:10][CH2:11][OH:13])[C:5]([CH3:12])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: C=CCc1c(C)ccc(Cl)c1O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(O)c1CCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Under nitrogen atmosphere, a solution of 6-chloro-3-methyl-2-(prop-2-en-1-yl)phenol (7b) (8.70 g, 47.6 mmol) in anhydrous tetrahydrofuran (300 mL) was cooled to 0° C. Borane-tetrahydrofuran complex, 1.0M solution in tetrahydrofuran (100 mL, 0.10 mol) was dropwise added. The reaction mixture was stirred at room temperature for 2 hours then cooled again to 0° C. A 10N sodium hydroxide solution (32.7 mL) was added dropwise, followed by a 30% hydrogen peroxide solution. The resulting mixture was warm to room temperature and stirred for 90 minutes. The reaction mixture was quenched with a 10% hydrochloric acid solution (163 mL). Layers were separated and the aqueous layer was extract with ethyl acetate (2×70 mL). The combined organics layers were washed with brine (3×100 mL) then cooled with an ice bath. A saturated solution of sodium sulfite (150 mL) was carefully added and the mixture was stirred for few minutes. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 75/25), to provide 6-chloro-2-(3-hydroxypropyl)-3-methylphenol (7c) (6.74 g, 33.6 mmol, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH2:25])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]([NH:40][C@H:41]([C:43](O)=[O:44])[CH3:42])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].O=P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:24]=[C:23]([NH:25][C:43](=[O:44])[CH:41]([NH:40][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH3:42])[N:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)(c2cc(N)n(C(C)(C)C)n2)CC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1cc(C2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)nn1C(C)(C)C
Reaction time: 0.42 h

Procedure:
A solution of 0.68 g (1.7 mmol) of 4-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester and 0.39 g (1.7 mmol) of carbobenzyloxy-L-alanine in 9.0 mL of dry pyridine was stirred at −10° C. as 0.18 mL (1.9 mmol) of POCl3 was added. After 25 min, the reaction mixture was poured into 1M HCl and extracted with EtOAc. The organic layer washed with sat. aq. NaHCO3, dried over MgSO4 and concentrated. Purification on silica gel using 50:50 EtOAc-hexanes as eluant afforded 4-[5-(2-benzyloxycarbonylamino-propionylamino)-1-tert-butyl-1H-pyrazol-3-yl]-4-phenylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12][Br:33])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.6 g, 6.3 mmol) and triphenylphosphine (3.3 g, 12.6 mmol) were combined in tetrahydrofuran (30 mL) and cooled to 0° C. N-Bromosuccinimide (2.4 g, 13.2 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (100% hexanes) gave 1.53 g (76%) as a light brown oil. 1H-NMR (CDCl3, 500 MHz) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 4.44 (s, 2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:28][OH:29])[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([O:22]CC=C)=[O:21])=[CH:18][CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:28][OH:29])[CH2:14][O:15][C:16]2[CH:27]=[CH:26][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:9][C:8]=1[C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)c1ccc(OCC(=NO)c2ccc(NCCC(C)=O)c(C(C)(C)C)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: CC(=O)CCNc1ccc(C(COc2ccc(C(=O)O)cc2)=NO)cc1C(C)(C)C
Reaction time: 0.08 h

Procedure:
360 mg (0.8 mmol) of allyl 4-{2-[4-(acetylethylamino)-3-tert-butylphenyl]-2-hydroxyiminoethoxy}benzoate are dissolved in 10 ml of THF. 48 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium are added and the medium is stirred for 5 min. 73 μl (0.8 mmol) of morpholine are then added and the reaction medium is stirred for 15 hours. After treatment with 1N hydrochloric acid solution and extraction with ethyl acetate, the residue is purified by chromatography (eluent: 5/5 heptane/ethyl acetate). A white powder is obtained (m.p.=192° C., m=200 mg, yield=60%); (1H NMR (DMSO): 1.05-1.07 (t, 3H); 1.29 (s, 9H); 1.64 (s, 3H); 2.73 (m, 1H); 4.13 (m, 1H); 5.33 (s, 2H); 6.46 (1H); 6.6 (1H); 7.07-7.09 (d, J=8.1 Hz, 1H); 7.51-7.53 (d, J=8 Hz, 1H); 7.54-7.64 (m, 2H); 7.86 (s, 1H); 12.1 (s, 1H)).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([SH:10])[CH3:9].C(N(CC)CC)C>C(OCC)C>[C:2](=[O:3])([S:10][CH2:8][CH3:9])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCS
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCSC(=O)OC(C)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
A solution of 1-chloroethyl chloroformate (71.5 g, 0.5 mol) in diethyl ether (600 mL) was cooled to 0-4° C. in an ice-water bath and a solution of ethanethiol (37 mL, 0.5 mol) and triethylamine (69.3 mL, 0.5 mol) in diethyl ether (200 mL) was added dropwise over 1 h. The reaction mixture was removed from the ice bath and stirred at ambient temperature for 4 h. Triethylamine hydrochloride was removed by filtration, the filtrate concentrated under reduced pressure and the residue purified by vacuum distillation (67-68° C. at 240 mTorr) to afford the title compound (2) as a colorless liquid (75 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 1.35 (t, 3H), 1.8 (d, 3H), 2.9 (dq, 2H), 6.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]([CH2:20][NH:21][CH3:22])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH3:34][O:35][C:36](=[O:40])[CH:37](Br)[CH3:38]>O>[CH3:34][O:35][C:36](=[O:40])[CH:37]([N:21]([CH3:22])[CH2:20][C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=2)[C@H:10]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:38]
Reactant: COC(=O)C(C)Br
Reactant: CNC[C@H]1CCc2cc(OC)ccc2[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)N(C)C[C@H]1CCc2cc(OC)ccc2[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of cis-6-methoxy-2-methylaminomethyl-1-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride (1.00 g; prepared according to the procedures in Process 1), cesium carbonate (5.13 g) and N,N-dimethylformamide (20 cm3) was added methyl-2-bromopropionate (0.35 cm3) and the resultant mixture was stirred at 75° C. for 5 h. The reaction was then allowed to cool to room temperature and water (100 cm3) was added. The resulting mixture was extracted with diethyl ether (2×100 cm3) and the combined organic extracts were washed with water (100 cm3), dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product (1.11 g) was purified by column chromatography [basic alumina, eluting with toluene-hexane (1:1)] to afford the title compound as a gum (284 mg); positive ion ESI (M+H)+ 368.4.
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH3:8][NH:9][O:10][CH3:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:11][O:10][N:9]([CH3:8])[C:1](=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CNOC
Reactant: CCCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a mixture of butanoic acid (1.01 g, 0.0115 mol) and N,O-dimethylhydroxylamine hydrochloride (1.12 g, 0.0115 mol) in DCM (50 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (5.6 g, 0.013 mol) and TEA (3.2 mL, 0.023 mol). The mixture was stirred overnight at room temperature. The solution was then washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography (ether/hexanes). The solvent was removed (235 mbar/40° C.) to afford the product (1.33 g, 88%). 1H NMR (300 MHz, CDCl3): δ 3.68 (s, 3H), 3.18 (s, 3H), 2.40 (t, 2H), 1.74-1.59 (m, 2H), 0.96 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl

Procedure:
254 g (1 mol) of 2,4-dichloro-5-fluoro-3-nitro-benzoic acid are refluxed in 700 ml of thionyl chloride with addition of 3 drops of dimethylformamide until the gas evolution ceases. Excess thionyl chloride is removed by distillation, and the residue is fractionated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19].C(N(CC)CC)C>CN(C)C=O>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][N:9]=2)=[CH:6][CH:7]=1)=[O:22])[CH3:19]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A suspension of 4.6 g (20 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 2.36 ml (30 mmol) of ethyl isocyanate, and 70 ml of dimethylformamide is stirred at room temperature and 2.8 ml (20 mmol) of triethylamine is added. The resulting solution is allowed to stand overnight at room temperature and another 2.36 ml (20 mmol) of ethyl isocyanate is added. After 6 hrs the dimethylformamide is evaporated under high vacuum and the residue is treated with 100 ml of water. The solid is filtered and dried to give 1.5 g of 2-[4-(N-ethylcarbamoylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid. The filtrate is acidified to pH 2.5 with hydrochloric acid and another 3.10 g of acid is obtained.