Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[S-:9][C:10]#[N:11].[NH4+]>>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][S:9][C:10]#[N:11]
Reactant: N#C[S-]
Reactant: FC(F)=C(F)CCBr
Agent: [NH4+]
Product: N#CSCCC(F)=C(F)F

Procedure:
When, for example, 4-bromo-1,1,2-trifluoro-1-butene and ammonium thiocyanate are used, 3,4,4-trifluoro-3-butenyl thiocyanate is obtained which is then reacted with H2S to give 3,4,4-trifluoro-3-butenyl dithiocarbamate. Further reaction of 3,4,4-trifluoro-3-butenyl dithiocarbamate with chloroacetaldehyde then provides 2-[(3,4,4-trifluoro-3-butenyl)sulphanyl]-1,3-thiazole. This reaction sequence may be schematically represented as follows:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].N1C=CN=C1>ClCCl>[Si:7]([O:4][CH2:3][C:2]([CH3:6])([NH2:1])[CH3:5])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(N)CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a stirred solution of 2-amino-2-methylpropan-1-ol (1.78 g, 0.02 mol) in dichloromethane (25 mL) was added tert-butyldimethylsilyl chloride (5.4 g, 0.036 mol) followed by imidazole (3.4 g, 0.05 mol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with NaHCO3 aqueous, brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with EtOAc to give 1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-amine (3.1 g, 76%) as an oil. 1H NMR (300 MHz, CDCl3): δ 3.26 (s, 2H), 1.02 (s, 6H), 0.88 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=O)[CH:7]=[CH:6]2.Cl.[NH2:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][SH:21].C([O-])(=O)C.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@@H:13]([CH:14]1[NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][S:21]1)[CH3:16])[CH:7]=[CH:6]2
Reactant: N[C@@H](CS)C(=O)O
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2cc([C@H](C)C3N[C@H](C(=O)O)CS3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of (2S)-2-(6-methoxy-2-napthyl)-propanal (8.2 g; 38.3 mmoles) in acetone (50 ml) is added dropwise to a solution of (R)-cysteine hydrochloride (5.94 g; 37.6 mmoles) and of potassium acetate (3.69 g; 37.6 mmoles) in 100 ml of water and acetone (1:1 v/v) kept under stirring at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[CH:5]2
Reactant: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5 mmol of 2-(4-((6-chloro-2-quinolinyl)oxy)phenoxy)propionyl chloride, prepared as in Step A of Example 1 employing the corresponding acid, in 10 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.09 g (5.5 mmol) of 4-aminobenzotrifluoride, hydrochloride, 1.21 g (12.0 mmol) of triethylamine and 50 ml of methylene chloride. The reaction mixture was stirred at room temperature for 3 hours and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was recrystallized from methylcyclohexane to give 1.79 g (74 percent of theoretical) of the desired product as colorless crystals melting at 142°-146° C. The structure of the compound was confirmed by its IR and NMR spectrum. (Compound 6). The carbon, hydrogen and nitrogen contents were determined to be as follows:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:17]1[CH:22]=[C:21]([N:14]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1cc2cccnc2[nH]1
Reactant: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Activated molecular sieves (3.8 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (0.29 g, 1.4 mmol), (3-fluorophenyl)boronic acid (0.59 g, 4.2 mmol), cupric acetate (0.38 g, 2.1 mmol), methylene chloride (35 mL) and then pyridine (0.46 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-50% EtOAc/hexane followed by 0-5% MeOH/dichloromethane) to give the desired product (0.35 g, 83%). LCMS calculated for C16H15FN3O2(M+H)+: m/z=300.1. Found: 300.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(F)c2)n(-c2cccc(OC)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-n2nc(C(=O)O)cc2-c2cccc(F)c2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
34.0 g (99.9 mmol) of the compound of Example 30A are provided in 150 ml of 1,4-dioxane, 150 ml (300 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 1 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is recrystallized from diethyl ether. 26.1 g (84% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>ClCCl>[CH:1]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[CH3:11])=[O:3]
Reactant: Cc1ccccc1N
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1NC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2-methylaniline (10.710 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was washed with a mixture of hexanes/diethyl ether (2×10 mL) and then with hexanes (3×5 mL) to afford N-formyl-2-methylaniline 8b as a white solid (9.70 g, 72%). 1H NMR (CDCl3, 300 MHz): δ=9.03-8.18 (m, 2H, CHO, NH), 7.77-7.03 (m, 4H), 2.30-2.22 (m, 3H); 13C{1H}NMR (CDCl3, 75 MHz): δ=164.41, 160.32, 135.50, 134.99, 131.45, 130.82, 130.50, 129.87, 127.25, 126.80, 126.34, 125.84, 123.75, 121.32, 18.05, 17.99; HRMS (FAB+) calculated for C8H10NO [M]+ 136.0762, observed 136.0783.
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.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>[CH3:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]([C:17]2[CH:18]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:3]1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Cn1cc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)c2c(N)ncnc21

Procedure:
A solution of 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (5 mg, 0.018 mmol), 3-biphenylboronic acid (18 mg, 0.091 mmol), K3PO4 (19.3 mg, 0.091 mmol) and Pd(PPh3)4 (12.5 mg, 0.011 mmol) in DMF (3 mL) was heated to 60° C. under an argon atmosphere. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 301.1, found 301.3.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:36]1[C:45]2[C:44](=[O:46])[NH:43][CH:42]=[CH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:43]4[C:44](=[O:46])[C:45]5[N:36]=[CH:37][CH:38]=[CH:39][C:40]=5[CH:41]=[CH:42]4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=c1[nH]ccc2cccnc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ccc5cccnc5c4=O)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A suspension of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (27.0 mg, 0.051 mmol), 1,7-naphthyridin-8(7H)-one (22.4 mg, 0.153 mmol) and Cs2CO3 (66.5 mg, 0.204 mmol) in anhydrous DMF (1.0 mL) was heated in a microwave at 150° C. for 50 min. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 90% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H32ClN4O4S: 639.2; found: 639.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH:9]1([CH2:12][NH2:13])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:13][CH2:12][CH:9]2[CH2:11][CH2:10]2)[CH:7]=1
Reactant: NCC1CC1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1cc(NCC2CC2)ncn1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
In a microwave reaction vessel, slurry 4,6-dichloropyrimidine (540 mg, 3.6 mmol), cyclopropylmethylamine (2800 L, 3.24 mmol), and diisopropylethylamine (1.25 mL, 7.2 mmol) in iso-propanol (3 mL). Irradiate in microwave (300 watts) at 140° C. for 40 min. Cool to room temperature and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (9:1 to 3:1 over 30 min; 40 mL/min) to obtain the desired intermediate (567 mg, 86%) as an off-white solid. MS (ES+) m/z: 184 (M+H)+.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>O1CCCC1.CCCCCC>[CH2:31]([C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:42][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCc1ccc(C=O)cc1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC=Cc1ccc(CCCCCCCCC)cc1
Reaction time: 0.5 h

Procedure:
A suspension of 13.9 g of pentyltriphenylphosphonium bromide in 150 ml of tetrahydrofuran is cooled to -20° under argon, 21.2 ml of 1.6M butyllithium solution in hexane are added within a period of 5 minutes and the whole is stirred for a further 30 minutes at 0°-10°. 6 g of 4-nonylbenzaldehyde in 40 ml of tetrahydrofuran are added dropwise over a period of 30 minutes to the mixture, which has been cooled to from -60° to -70°. The reaction mixture is allowed to warm spontaneously to 0°-10°, stirred at this temperature for a further 45 minutes and concentrated by evaporation. The residue is taken up in hexane/ethyl acetate (1:) and filtered over silica gel. The filtrate is concentrated by evaporation and chromatographed on silica gel with hexane. The title compound (mixture of cis- and trans-isomers) is obtained in the form of a colourless oil, which is used directly in the next stage.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]1[C:25]2[CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[CH:20]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].CO>C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:33]3[CH2:32][CH2:31][CH:30]([CH:20]4[C:19]5[CH:18]=[CH:17][CH:16]=[CH:15][C:25]=5[CH2:24][CH2:23][C:22]5[CH:26]=[CH:27][CH:28]=[CH:29][C:21]4=5)[CH2:35][CH2:34]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc2c(c1)CCc1ccccc1C2C1CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C2c3ccccc3CCc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 89% overall yield. FDMS m/e=466 (M+ of free base). α[D]589 =-10.02(c=0.72, methanol).
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43])[CH:35]=O.O>C1COCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43]
Reactant: COCOc1ccc(C=O)cc1OC
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(/C=C/CCO)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
n-Butyllithium (1.6 M in hexane, 25 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (8.03 g) in dry THF (50 ml) cooled to 0° under nitrogen. The resulting blood-red solution was stirred at 0° for 10 min and then 3methoxy-4-(methoxymethoxy)benzaldehyde (3.60 g) in dry THF (10 ml) was added dropwise over 5 min. The mixture was allowed to warm to room temperature, stirred for 4 h water (10 ml) was added and the majority of the solvent was removed in vacuo at 40°. A solution of the residual oil in ER (200 ml) was washed with water (150 ml), dried, treated with charcoal, concentrated and purified by [FCS] eluting with EA/hexane (1:1) to give the title compound (1.55 g). T.l.c. (EA-hexane 1:1) Rf 0.30.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([OH:31])=O)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:36][CH2:37][CH2:38][NH2:39])(=[O:35])[CH3:34]>>[C:1]([NH:6][C@H:7]([C:29]([NH:39][CH2:38][CH2:37][S:36][C:33](=[O:35])[CH3:34])=[O:31])[CH2:8][S:9][C:10]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CC(=O)SCCN
Agent: Cl
Product: CC(=O)SCCNC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C(C)C
Yield: 67 %

Procedure:
The coupling reaction of 13 (3.93 mmol) with S-acetylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 60%). 14 is collected in the form of a colorless foam with a yield of 67%. Rf (AcOEt/petroleum ether, 6/4): 0.5. [α]D20=+9.3° (c 0.97, CHCl3).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.Cl[Si](CC)(CC)CC.C([Li])(CC)C.[F:25][C:26]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>C1COCC1>[F:25][C:26]1[CH:33]=[C:32]([CH:34]([OH:35])[C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1-Methylimidazole (15.88 mL, 0.199 mol), dissolved in anhydrous THF (500 mL) in flame-dried glassware under Ar, was cooled to −78° C. and treated with n-butyl lithium (1.6M in hexane)(124 mL, 0.199 mol) via syringe. After stirring for 1 hr chlorotriethylsilane (33.4 mL, 0.199 mol) was added and the reaction mixture was left to warm to ambient temperature overnight. The THF was removed in vacuo with gentle warming, and the residue was redissolved in dry THF (500 mL), cooled to −78° C., and treated with sec-butyl lithium (1.3M in cyclohexane) (153 mL, 0.199 mol) dropwise. After 1 hr this solution was cannulated into a solution of 2-fluoro-4-formylbenzonitrile (27 g, 0.181 mol) in THF (200 mL). After 15 min the cooling bath was removed, the mixture was stirred for 2 hr at ambient temperature, then was quenched with saturated NH4Cl solution. After 15 min 10% HCl was added to pH=3. After 0.5 hr the THF was removed in vacuo, the mixture was made basic with solid Na2CO3 and extracted with EtOAc (3×200 mL). The organics were combined, washed with 10% HCl (3×), the aqueous acidic layers combined, made basic with solid Na2CO3, extracted with EtOAc (3×), the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)=[O:4]>CO.C(Cl)(Cl)Cl>[Br:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cccc(C(=O)CBr)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)Nc1cccc(C(O)CBr)c1

Procedure:
The above-identified compound (50.76 g) was obtained by processing Intermediate 14 (45 g) through reaction and after-treatment in accordance with the procedures of synthesis of Intermediate 41. Rf=0.27 (methanol/chloroform of 1/10).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:32])[C:19]([CH3:31])([S:21]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[CH2:33]([Li])CCC.CI>C1COCC1>[CH3:11][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:32])[C:19]([CH3:31])([S:21]([CH:24]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH3:33])(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:1])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: [Li]CCCC
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1
Solvent: C1CCOC1
Solvent: CI
Product: CC(C1CCOCC1)S(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 0.4 g (0.85 mmol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide (synthesized according to method B, step 1) in anhydrous THF (5 mL) under nitrogen is cooled to −78° C. A 2.5 M solution of n-butyl lithium in hexanes (1 mL) is added dropwise. The reaction mixture is stirred at −78° C. for 1 h, followed by addition of 0.11 mL (1.69 mmol) of methyl iodide. The reaction is allowed to warm to room temperature and stirred for 18 h. The mixture is quenched by addition of water (5 mL) and the organic solvent is removed under reduced pressure. The aqueous residue is extracted with DCM (2×10 mL). The combined organic extracts are washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by mass-triggered preparative LC (neutral method) to afford 0.1 g of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-[1-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide. Yield: 24%, ES-MS: 403 [M+H].
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH2:8])([O-:4])=[O:3].[CH3:13][C:14]([CH3:16])=O.C([BH3-])#N.[Na+]>CO>[CH:14]([NH:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=1[N+:2]([O-:4])=[O:3])([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: NCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-nitrobenzylamine hydrochloride (500 mg, 2.65 mmol) and acetone (0.39 ml, 5.30 mmol) in methanol (13 ml) was added sodium cyanoborohydride (500 mg, 7.95 mmol) at 0° C. The temperature was warm up to room temperature. After stirring for 3 hr, the mixture was concentrated in vacuo and extracted with dichloromethane. The combined organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give N-isopropyl-2-nitrobenzylamine as yellow oil. This compound was used in next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[CH3:19][C:18]([CH3:21])([CH3:20])[C:17]([O:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Cl:1])=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(O)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(=O)C(C)(C)C)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a mixture of 2-chloro-4-methylphenol (100 g), triethylamine (92.3 g) and anhydrous tetrahydrofuran (1 liter) was added dropwise pivalic chloride (93.0 g) at 5° to 10° C. under stirring over 1 hour. Then, after stirring at the same temperature for 3 hours, the reaction mixture was poured into ice water, which was extracted with diethyl ether. The organic layer was washed with 3% aqueous hydrochloric acid solution and then water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was distilled under reduced pressure, which afforded 155.3 g of 2-chloro-4-methylphenyl 2,2-dimethylpropanoate as a colorless clear liquid. Yield, 97.7%.