Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:11]([NH:18][CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C(=C/c1ccccc1)\CNCc1ccccc1
Reaction time: 18 h

Procedure:
Cinnamaldehyde and benzylamine were dissolved in 1% acetic acid in methanol under an atmosphere of dry nitrogen. Sodium cyanoborohydride (~1 equivalent) was added, and stirring was continued for 18 hours at which time the solvent was removed under reduced pressure. The residue was suspended in ether, washed with 5% NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo to afford the title compound.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:4].[OH-].[Na+].O.CCCCCC>C(Cl)(Cl)Cl>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCn1ccc2cc([N+](=O)[O-])ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C(O)CCCCn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
To 1-(4-methoxy carbonyl butyl)5-nitroindole (0.5 g) was added molar sodium hydroxide (10 ml) and the solution stirred in an oil bath at 120° C. for 90 minutes. It was then cooled, water (10 ml) added and the solution extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (2×10 ml) and the combined aqueous extracts were acidified with molar HCl and extracted with ethyl acetate. (3×15 ml). The organic extracts were dried over anhydrous sodium sulphate, filtered and rotary evaporated to give a yellow gum. The gum was dissolved in hot chloroform, then hexane (2 ml) added and the solution cooled on ice when yellow crystals separated. These were filtered off and washed with chloroform:hexane (50:50) followed by hexane. The crystals were dried in vacuo (0.423 g, 1.61 mmol, 81%), MP 141-2° C. TLC on silica in toluene:methanol:acetic acid (90:16:8) gave one yellow spot and when viewed under UV. Mass spec and NMR analysis were as expected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3SCC)[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.C(Cl)(Cl)Cl.Cl[C:26]1C=CC=C(C(OO)=O)[CH:27]=1.[S:36]([O-:40])([O-])(=[O:38])=S.[Na+].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:36]([CH2:26][CH3:27])(=[O:40])=[O:38])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCS(=O)(=O)c1ccccc1-c1nc2cc(Br)cnc2n1C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (0.20 g) and chloroform (3 ml), 3-chloroperbenzoic acid (purity: not less than 65%) (0.34 g) was added under ice-cooling, and then heated to room temperature, and stirred for 3.5 hours. Chloroform and saturated aqueous sodium thiosulfate solution were poured thereinto under ice-cooling, and stirred, and then, water was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting solid was washed with hexane, and dried to give 0.20 g of 6-bromo-2-(2-ethylsulfonylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 44).
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[I:16]CI.N(OCCC(C)C)=O>C(#N)C.CCCCCC>[C:7]([C:6]1[C:2]([I:16])=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:4][C:5]=1[S:9][CH3:10])#[N:8]
Reactant: ICI
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1N
Agent: CC(C)CCON=O
Solvent: CCCCCC
Solvent: CC#N
Product: CCOC(=O)c1sc(SC)c(C#N)c1I
Temperature: 40 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (10 g, 41.3 mmol) was dissolved in acetonitrile (50 mL) under atmosphere of argon. Diiodomethane (11.6 mL, 0.144 mol) was added and the mixture was heated at 40° C. Isoamyl nitrite (12.1g, 0.103 mol) was added and the reaction was allowed to cool to room temperature and stirred for 2 hours. Mixture was cooled down at 0° C., diluted with hexane (50 mL) and the precipitate was filtered off, washed with 10:1 hexane-acetonitrile mixture (10 mL), 3:1 hexane-ether (10 mL) and hexane (10 mL). The precipitate was dried to afford ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (6.90 g, 45%). LCMS: (FA) ES+ 354. 1H NMR (400 MHz, d1-chloroform) δ: 4.38 (q, 2H), 2.70 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[F:29][C:28]([F:30])([F:31])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=2)[CH:14]=1)=[O:32]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc(CCl)c1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 37, 3-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide to give the title compound in 94% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 4.85 (s, 2H), 7.25 (d, 1H), 7.6 (m, 3H), 7.8 (m, 2H), 7.95 (d, 2H), 8.05 (s, 1H), 8.16 (m, 2H), 9.96 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M−H− 445.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[C:9](O)=O)=[CH:4][CH:3]=1.[I-].[NH:29]=[C:30]([NH2+:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([C:9]2[NH:38][N:37]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=2)[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CC[C@](C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: N=C([NH2+]N)c1ccccc1
Agent: [I-]
Product: CC[C@@](c1ccc(Cl)cc1)(c1nc(-c2ccccc2)n[nH]1)n1ccc2c(NS(C)(=O)=O)cccc21

Procedure:
Compound 64 was synthesized from compound 4a following procedures similar to those presented in Example 6, substituting [imino(phenyl)methyl]hydrazinium iodide for N′-hydrozybenzenecaroximidamide. m/z (ES) 506 (MH)+; IP=C rating.
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=[O:6].[Cl-].[NH4+]>C(OC)(C)(C)C.O1CCCC1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([OH:6])([CH3:2])[CH3:4])=[CH:8][CH:9]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
The reaction flask was charged under argon with 3.45 g of magnesium (142 mmol). A solution of 21.16 g of methyl iodide (147 mmol) in 120 mL of tert-butyl-methyl-ether was added during 45 min at 45° C. under stirring. Then stirring was continued for 1 h at 45° C. and then a solution of 27.12 g of 4-benzyloxyacetophenone (120 mmol) in 100 mL of tetrahydrofuran was added during 45 min., while a temperature of 45° C. was again maintained. Stirring at 45° C. was continued for 1.5 h. After cooling to room temperature, the white suspension was poured into a mixture of 100 mL of 10% aqueous ammonium chloride and of ice and extracted with 150 mL of ethyl acetate. The aqueous phase was separated and extracted with 100 mL of ethyl acetate. The organic phase was washed with 120 mL of 20% aq. sodium chloride, combined, dried (MgSO4) and evaporated under reduced pressure to give 29.9 g of crude product as an oil which partially crystallised. The crude product was taken up in 30 mL of dichloromethane. The solution was concentrated at the rotary evaporator almost to dryness. Then 6 mL of ethyl acetate was added followed by gradual addition of a total of 180 mL of hexane. The suspension was then kept at 0° C. for 30 min. The crystals were collected and washed with cold hexane. After drying for 2 h at 16 mbar/45° C., 26.7 g (92%) 2-(4-benzyloxy-phenyl)-propan-2-ol was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([CH3:26])([C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=1)[C:9](O)=[O:10].Cl.[O:28]=[C:29]1[CH2:34][CH2:33][C:32]([NH2:41])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.N1C=CC=CC=1.Cl>CN(C)C=O.ClCCl>[CH3:7][C:8]([CH3:26])([C:12]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[C:14]([C:22]([F:24])([F:25])[F:23])[CH:13]=1)[C:9]([NH:41][C:32]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30][C:29](=[O:28])[CH2:34][CH2:33]1)=[O:10]
Reactant: CC(C)(C(=O)O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC1(c2ccccc2)CCC(=O)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)NC1(c2ccccc2)CCC(=O)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.4 %

Procedure:
Oxalyl chloride (5.8 mL, 66.6 mmol) was added slowly to a solution of α,α-dimethyl-3,5-bis(trifluoromethyl)benzeneacetic acid (Description 6, 10 g, 33.3 mmol) and dimethylformamide (1 drop) in dichloromethane (100 mL) and. the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (20 mL) and added slowly to a solution of 4-oxo-1-phenylcyclohexylamine hydrochloride (Description 18, 8.2 g, 43.4 mmol) and pyridine (5.7 mL, 66.3 mmol) in dichloromethane (100 mL). The mixture was stirred at room temperature for 24 hours, then hydrochloric acid (2M, 100 mL) was added. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatograph on silica gel, eluting with isohexane:EtOAc (75:25), to give the title compound as a colorless solid (6.5 g, 41%). 1H NMR (400 MHz, CDCl3) δ 7.83 (1H, s), 7.77 (2H, s), 7.35–7.26 (5H, m), 5.44 (1H, s), 2.70–2.66 (2H, m), 2.40–2.30 (6H, m), and 1.62 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2([S:19][CH2:20][CH3:21])[CH2:18][CH2:17]2)([OH:15])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2([S:19]([CH2:20][CH3:21])=[O:30])[CH2:17][CH2:18]2)([OH:15])[CH2:9][C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC1(C(O)(Cc2nc[nH]n2)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CCS(=O)C1(C(O)(Cc2nc[nH]n2)c2ccc(Cl)cc2)CC1
Yield: 57 %

Procedure:
5 g (0.0155 mol) of 1-(4-chlorophenyl)-1-[1-(ethylthio)-1-cyclopropyl]-2-(1,2,4-triazol-yl)-1-ethanol (see Example 1) are stirred with 3.3 g of m-chloroperbenzoic acid (80-90% strength) in 40 ml of methylene chloride overnight at room temperature and then for one hour under reflux. Thereafter, the mixture is washed with twice 20 ml of 5% strength aqueous sodium hydroxide solution and twice with water. The organic phase is dried over sodium sulphate and evaporated down in vacuo. The residue is recrystallized from glycol monomethyl ether acetate. 3 g (57% of theory) of 1-(4-chlorophenyl)-1-[1-(ethylsulphinyl)-1-cyclopropyl]-2-(1,2,4-triazol-yl)-1-ethanol of boiling point 185° C. are obtained.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17](I)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:20]2[C@H:24]([OH:25])[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.[O:44]1CCC[CH2:45]1>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]>[OH:25][C@@H:24]1[C@H:23]([OH:26])[C@@H:22]([CH2:27][OH:28])[O:21][C@H:20]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:45]([NH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:44])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: NCCN1CCCCC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(I)nc32)[C@H](O)[C@@H]1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.17 h

Procedure:
A solution of (2R,3R,4S,5R)-2-{6-[(2,2-diphenylethyl)amino]-2-iodo-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol (59, 8.7 mmol) (Preparation 2), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (1:1 complex with dichloromethane) (0.7 g, 0.9 mmol) and 1-(2-aminoethyl)piperidine (3.49, 26.5 mmol) in anhydrous tetrahydrofuran (250 ml) was heated at 60° C., under a carbon monoxide atmosphere at 345 kPa (50 psi) in a sealed vessel for 24 hours. The mixture was cooled, filtered through a pad of Arbocel (trade mark) and the filtrate diluted with tetrahydrofuran (150 ml) and ethyl acetate (400 ml). The resulting solution was washed with water (3×300 ml) and the organic phase extracted with 2 M aqueous hydrochloric acid solution (50 ml). The acidic aqueous phase was washed with ethyl acetate (20 ml) then the pH adjusted to >7 by addition of 0.88 aqueous ammonia solution. Ethyl acetate (100 ml) was added and the mixture stirred for 10 minutes after which time a white solid formed. This solid was filtered, washed sequentially with water and ethyl acetate and dried at 70° C. under reduced pressure to yield the title compound as a white solid (2.8 g).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[O:13][C:14]([CH3:17])(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:22])C>[Rh](Cl)(Cl)Cl.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:1]1([CH2:7][C:20]([O:13][CH2:14][CH3:17])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(C)(C)C
Agent: Cl[Rh](Cl)Cl
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), rhodium trichloride (1.1 mg, 1 mol %), and Xantphos (2.9 mg) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 39 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 48%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 29 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 90%.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([C:39](Cl)=[O:40])=[N:33]1>CC1CCCO1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([C:39]([NH:2][C@H:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:40])=[N:33]1
Reactant: CCOC(=O)C[C@H](N)c1ccccc1C
Reactant: COc1cc(C(=O)Cl)nn1-c1ccccc1F
Agent: Cl
Solvent: CC1CCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NC(=O)c1cc(OC)n(-c2ccccc2F)n1)c1ccccc1C

Procedure:
A solution of ethyl (S)-3-amino-3-(2-methyl-phenyl)-propionate hydrochloride (42.4 g, 174 mmol) in 2-methyltetrahydrofuran (200 ml) was added to the suspension of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carbonyl chloride in ca. 200 ml of 2-methyltetrahydrofuran obtained in step 1. Triethylamine (33.5 g, 331 mmol) was added dropwise under ice cooling. After the complete addition of the triethylamine the conversion was complete and water was added. The phases were separated and the organic phase was washed with water and evaporated. The residue was dissolved in 2-methyltetrahydrofuran (500 ml) and washed with 1 M hydrochloric acid. The organic phase was dried and the solvent was removed under reduced pressure to give 70.4 g (99% over two step) of the title compound as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(OC([NH:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([O:37][CH:38]([CH3:40])[CH3:39])[C:34]([O-:36])=[O:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH:22][CH2:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([O:37][CH:38]([CH3:40])[CH3:39])[C:34]([OH:36])=[O:35])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])=[O:6]
Reactant: CC(C)Oc1ccc(C(=O)O)c(Cl)c1
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(OC(C)C)cc1Cl

Procedure:
Using 2-chloro-4-isopropoxybenzoic acid and 3-(3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-chloro-4-isopropoxybenzoyl)amino]methyl-4-methoxyphenyl)-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [CH2:1]([CH:3]1[CH:6]([CH2:7][CH3:8])[C:5](=[O:9])[N:4]1S(Cl)(=O)=O)[CH3:2].C1(S)C=CC=CC=1.N1C=CC=CC=1.O>CC(C)=O>[CH2:7]([CH:6]1[CH:3]([CH2:1][CH3:2])[NH:4][C:5]1=[O:9])[CH3:8]
Reactant: CCC1C(=O)N(S(=O)(=O)Cl)C1CC
Agent: Sc1ccccc1
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCC1NC(=O)C1CC
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
(2RS,3RS)-2,3-Diethyl-4-oxoazetidine-1-sulfonyl chloride (step 1) (3.2 g, 14.18 mmol) in acetone (7 ml) was treated with thiophenol (2.92 ml, 28.4 mmol) and cooled to −30° C. Pyridine (1.376 ml, 17.01 mmol) in acetone (2.55 ml) was added dropwise over 30 mins, maintaining the temperature around −30° C. After stirring for 30 minutes, water (10 ml) was added slowly and the mixture was filtered. The filtrate was extracted with diethyl ether (5×25 ml) and the combined organic layers were dried MgSO4, filtered and evaporated to dryness (colorless oil 2.3 g). Purification by chromatography on silica eluting with iso-hexane followed by diethyl ether afforded the title compound;
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[S:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:12])[CH3:11]>>[C:10]([SH:7]=[CH:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C=S)cc1
Product: CC(=O)[SH]=Cc1ccccc1

Procedure:
Two other S-protected p-thiobenzaldehydes were obtained as shown in Scheme 2 (FIG. 15). The thiocyanato-benzaldehyde 8 was prepared according to a general procedure (Suzuki and Abe (1996) Synth. Commun., 26: 3413–3419) in 20% yield. All attempts to improve the yield by replacement of DMF with 1,3-dimethyl-2-imidazolidinone, increasing the temperature, or prolonging the reaction time were unsuccessful. S-Acetylthiobenzaldehyde 9 was prepared in a two-step one-flask procedure. Cleavage of the methyl group of 4-methylthiobenzaldehyde according to a general procedure (Tiecco et al. (1982) Synthesis, 478–480) followed by trapping of the resulting anion with acetyl chloride afforded the desired S-acetylthiobenzaldehyde 9 in 55% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:8]=[C:9]1[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]1=[O:16])([CH3:4])([CH3:3])[CH3:2].ClS([N:29]=[C:30]=[O:31])(=O)=O.C(O)(=O)C.O>C1(C)C=CC=CC=1>[C:30]([N:11]1[C:12]([CH3:14])([CH3:15])[CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=2)[C:10]1=[O:16])(=[O:31])[NH2:29]
Reactant: CC1(C)CC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C(=O)N1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C=C2CC(C)(C)N(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 90 °C
Yield: 29 %

Procedure:
To a suspension of 329 mg (1 mmol) of the thus obtained 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-5,5-dimethylpyrrolidin-2-one in 2 ml of dry toluene was added 96 μl (1.1 mmol) of chlorosulfonyl isocyanate under a nitrogen atmosphere. The reaction mixture was heated at 90° C. for 10 minutes and evaporated to give a residue, which was added with 2.4 ml of acetic acid/water (2/1) and heated at 90° C. for 10 minutes. The reaction mixture was then poured into ice-water and extracted with dichloromethane three times. The organic layers were collected and washed with water, dried over magnesium sulfate and then evaporated to give a residue, which was chromatographed on silica gel (toluene/ethyl acetate=1/1) and recrystallized from ether to give 107 mg of the objective compound (Id-1) in 29% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:10][C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:17][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CN(Cc1ccc(Cl)s1)c1ccc(N)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)s1)c1ccc(NC(=O)Cc2ccc(Cl)cc2)c(Cl)c1
Temperature: 150 °C
Yield: 16.5 %

Procedure:
2-Chloro-N(4)-(5-chloro-thiophen-2-ylmethyl)-N(4)-methyl-benzene-1,4-diamine (100 mg) was added to a solution of 4-chlorophenylacetyl chloride (69 mg) in dry acetonitrile (2 mL) in a rubber-capped glass vial. The reaction mixture was heated in a microwave device to 150° C. for 15 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (5 mL). The organic phase was washed with water (5 mL) and brine (5 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (heptane/ethyl acetate, gradient) to furnish 25.2 mg title compound. Yield: 16%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][C@H:16]1[CH2:15][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:13][C@@H:12]([CH3:11])[O:17]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)O1

Procedure:
1-Fluoro-4-nitrobenzene (4.9 g, 34.75 mmol) was added to cis-2,6-dimethylmorpholine (44.4 g, 38.26 mmol) and anhydrous potassium carbonate (2.5 g, 18.12 mmol) in acetonitrile (50 ml). The reaction was heated under reflux for 19 hours, cooled, filtered and the solid washed with acetonitrile. Evaporation of the filtrate gave the title compound as a yellow solid. (8.1 g, 99%) NMR (CDCl3) 1.28 (d, 6H), 2.61 (t, 2H), 3.66 (td, 2H), 3.76 (m, 2H), 6.82 (d, 2H), 8.13 (d, 2H); m/z 237.