Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22]C=C)[C@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:52])([C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH:29]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[C:30]([O:32]CC)=[O:31]>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH:29]([CH2:28][CH2:27][C:26]([F:52])([F:25])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:46])([F:47])[F:45])[C:30]([OH:32])=[O:31])[C@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CC[C@@H]1c2ccc(OC)cc2SC[C@]1(C)c1ccc(OC)cc1
Reactant: C=CCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: C[C@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@H]1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3S,4S)-7-methoxy-3-(4-methoxyphenyl)-3-methyl-4-(2-propenyl)thiochroman resolved as Peak 1 in Example 17 and the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-8-nonenoate prepared in Example 3, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)decanoic acid.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH2:18][NH:19][C:20]([CH3:34])([CH3:33])[CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:13][C:12]=1[CH2:43][OH:44])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CO>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[CH2:18][NH:19][C:20]([CH3:34])([CH3:33])[CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=2)=[CH:13][C:12]=1[CH2:43][OH:44])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(CO)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
Lithium hydroxide solution (1M in water, 16.2 mL, 16.2 mmol) was added to a solution of methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate (preparation 147), (4.80 g, 8.1 mmol) in tetrahydrofuran (49 mL) and methanol (17 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified to pH 7 with 1M hydrochloric acid. The resulting precipitate was filtered off and washed with water to afford the title compound as a pale yellow solid in 94% yield, 4.37 g 1H NMR (400 MHz, DMSO-d6) δ: 7.45-7.38 (6H, m), 7.31 (2H, m), 7.13 (1H, m) 7.02 (3H, m), 5.04 (3H, m), 4.52 (2H, d), 3.52 (2H, d), 2.43 (2H, d), 3.37 (2H, d), 1.24 (6H, m), 0.78 (9H, s), 0.02 (3H, s), -0.92 (3H, s) ppm; LRMS ESI m/z 659 [M+H]+
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:16][C:17]([NH2:19])=[S:18].[O-]CC.[Na+]>C(O)C>[CH:8]1([O:7][CH2:6][C:5]2[NH:19][C:17](=[S:18])[NH:16][C:3](=[O:2])[CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC(N)=S
Reactant: COC(=O)CC(=O)COC1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(COC2CCCCC2)[nH]c(=S)[nH]1
Reaction time: 16 h
Yield: 84.7 %

Procedure:
4-Cyclohexyloxy-3-oxo-butyric acid methyl ester (8.0 g) was added to a mixture of thiourea (34.7 g), sodium ethoxide (180 mL of 3 M ethanol solution) and ethanol (70 mL). The reaction was heated at reflux under nitrogen for 16 h. The ethanol was removed under vacuum. Residue was dissolved in water (400 mL) and the solution was cooled in an ice-bath. The solution was acidified with conc. hydrochloric acid to pH˜1 and stood at rt for 16 h. The solid that formed was collected by filtration to afford 6-cyclohexyloxymethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (7.6 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[OH:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][C:4]([O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])=[O:5]
Reactant: O=C1CCC(=O)N1O
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
A solution of methoxyacetyl chloride (108.5 g, 1 mol) in absolute dichloromethane (170 mL) was added dropwise at 0° C. to a solution of N-hydroxysuccinimide (115 g, 1 mol) and TEA (111 g, 1 mol) in dichloromethane (900 mL). The reaction mixture was stirred at room temperature for 48 hours, and a saturated NaHCO3 solution (500 mL) was added under stirring. The organic layer was separated, and the aqueous layer was subjected to extraction twice with chloroform. The combined organic extract was washed with saturated NaHCO3 solution (200 mL), brine (200 mL), and dried over Na2SO4. The solution was concentrated in vacuo to afford the title compound as a yellow oil (147.8 g, 79%). Taken directly on to the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[OH:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2C=O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2O)C1
Reaction time: 18 h

Procedure:
To a CH2Cl2 (25 mL) solution of the title compound of Step A (1.4 g, 4.3 mmol) was added 77% m-CPBA (1.4 g, 6.2 mmol). After 18 h, additional CH2Cl2 was added and the reaction washed with saturated NaHCO3 (aq.) and 10% Na2S2O5 until KI paper negative. The combined organic layers were dried then treated with MeOH (25 mL) and 1N NaOH (25 mL). After 15 h, the reaction was acidified with 1M KHSO4 then extracted with EtOAc (2×). The combined organic layers were washed with brine and dried to give the title compound as a white solid. 1H NMR (CDCl3): 6.96 (s, 1H), 6.82-6.80 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 5.62 (s, 1H), 4.91 (s, 1H), 3.66-3.46 (m, 4H), 2.20-2.11 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([O:29][C:30](Cl)=[O:31])[CH2:26][CH2:27][CH3:28]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:30]([O:29][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)Cl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 4.4 g 4-amino-piperidine-1-carboxylic acid benzyl ester hydrotrifluoroacetate and 5.3 ml triethylamine in 100 ml dichloromethane were added 1.8 ml butylchloroformate dropwise at 0° C. The suspension was stirred for 12 h, diluted with dichloromethane and washed with 0.1 M HCl and aqueous NaHCO3. The crude product was purified by flash chromatography on silica using ethyl acetate/heptan 1:2 as eluent.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2Br)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:28](=[O:30])=[O:29]>CCOCC>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[C:28]([OH:30])=[O:29])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(F)ccc2Br)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(F)ccc2C(=O)O)CC1
Temperature: -78 °C
Yield: 78 %

Procedure:
A 1.6M solution of butyllithium in hexanes (2.5 mL, 4.0 mmol) was added in three portions over 2 hours into a solution of 4-(2-bromo-5-fluoro-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.34 mmol) in anhydrous Et2O cooled at −78° C. After one additional hour at −78° C., an excess of dry ice was added and the cooling bath was removed. The reaction mixture was allowed to warm up to RT and was concentrated under vacuum. The residue was taken up with a saturated aqueous solution of NH4Cl and extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum to give the title compound as a yellow oil (391 mg, 78%), used without further purification. HPLC (max plot) 92.1%; Rt 2.47 min. UPLC/MS: (MS+) 339.3 ([M+H]+), (MS−) 337.4 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Br[C:11]#[N:12]>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:11]#[N:12]
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: N#CBr
Solvent: O
Product: N#CNc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
To a heterogeneous slurry of 2,5-dichloroaniline (3.0 g, 18.5 mmol) in 60 mL of water at 4° C. was added solid BrCN (1.22 g, 11.3 mmol) slowly. After 5 minutes the cooling bath was removed and the heterogeneous reaction mixture was stirred at room temperature for 24 hours to yield the product in water suspension. The product was collected by filtration, washed with water (100 mL), and dried under vacuum to yield the pure product (2 g, 60% yield).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[H-].[Na+].[CH3:16][N:17]1[CH:21]=[C:20]([CH:22]=O)[N:19]=[CH:18]1>O1CCCC1>[CH3:16][N:17]1[CH:21]=[C:20](/[CH:22]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[N:19]=[CH:18]1
Reactant: Cn1cnc(C=O)c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cn(C)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
1 ml (5.5 mmol) of methyl diethylphosphonoacetate are added to a suspension of 220 mg (5.5 mmol) of sodium hydride at 60% in 5 ml of tetrahydrofuran cooled to 0° C. After stirring for 1 h, 500 mg (4.5 mmol) of 1-methyl-1H-imidazole-4-carbaldehyde are added and the mixture is stirred for 4 hours at ambient temperature and then hydrolysed with water and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered and evaporated. The product obtained is precipitated from heptane and filtered. 430 mg of methyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate are obtained in the form of a yellow powder with a yield of 57%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:30])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26]C(=O)C)[CH:19]=2)[CH2:10][CH2:9]1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[CH3:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:30])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:19]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2.07 g of potassium carbonate was added to a solution of 4.97 g of N-(trans-4-methylcyclohexyl)-3-acetoxy-4-methoxycinnamamide (Example 193) in 200 ml of ethanol. The solution was stirred for 20 minutes, while it was refluxed. Next, 2.0 ml of ethyl bromoacetate was slowly added dropwise to the solution .by means of a dropping funnel. Thereafter, the solution was stirred for 2 hours. After reaction, the solution was allowed to cool to room temperature. The crystal and the potassium carbonate, both precipitated from the reaction solution, were filtered out, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 1.46 g of N-(trans-4-methylcyclohexyl)-3-(ethoxycarbonylmethoxy)-4-methoxycinnamamide (a compound the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:23][CH:24]([CH3:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([CH:24]([CH3:34])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCNC(C)Cc1ccc(OC)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1)C(C)Cc1ccc(OC)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and ethyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H31NO6 [M+H]+: 430.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COc1ccc(Br)c(OC)c1-c1ccccc1C
Reactant: OB(O)c1ccccc1
Product: COc1ccc(-c2ccccc2)c(OC)c1-c1ccccc1C

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 3 using 1,3-dimethoxy-2-(tol-2-yl)-4-bromobenzene 2 and phenyl boronic acid to yield 34.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:36][CH:37]([CH3:39])[CH3:38])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:28])[CH2:26][CH3:27])[CH2:22][N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:20]1)=[O:17].[BH4-].[Na+]>C(O)C>[OH:28][CH:25]([C@@H:23]1[CH2:24][C@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:20][N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:22]1)[CH2:26][CH3:27]
Reactant: CCC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3ccccc3n2CCCCOC)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-propanoyl-piperidine-1-carboxylate (2.60 g) in ethanol (30 ml) was added sodium borohydride (181 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water, acidified with 5% aqueous potassium hydrogen sulfate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:1) was concentrated under reduced pressure to give the object product (2.02 g).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CN)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
A solution containing 1 g (2.3 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoate in 10 ml of dichloromethane and 2.6 ml (3.4 mmol) of trifluoroacetic acid is stirred at ambient temperature for 18 h. After addition of a saturated aqueous solution of sodium hydrogen carbonate up to a pH of 8, the reaction medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. 780 mg (100%) of methyl (S)-3-amino-2-[4-(toluene-4-sulphonyl)piperazin-1-yl]propanoate are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[CH3:25][O:26][C:27](=[O:41])[CH:28]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30].CCCCCCC>C1C=CC=CC=1>[CH3:32][O:31][C:29](=[O:30])[CH:28]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:38][CH:39]=1)[C:27]([O:26][CH3:25])=[O:41]
Reactant: OCCOCc1ccccc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCCOCc2ccccc2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, 2-benzyloxyethanol (30.4 g, 0.2 mol), tributylphosphine (50.4 g, 0.2 mol) and 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (example 1b) (42.9 g, 0.18 mol) were successively dissolved in dry benzene (1.5 L). Solid azodicarboxylic dipiperidide (ADDP) (40.4 g, 0.2 mol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (0.5 L) was added and the precipitate was filtered off. After evaporation of the solvent the product was chromatographed eluting with heptane graduated with ethyl acetate to give 64.0 g (96%) of 2-[4-(2-benzyloxy-ethoxy)-benzyl]-malonic acid dimethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:13]O.C([O-])=O.[Na+].O>C(O)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Reactant: NO
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1c[nH]c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 6-fluoro-1H-indole-3-carbaldehyde (0.97 g) in 90% formic acid (25 mL) were added hydroxylamine (0.65 g) and sodium formate (0.81 g), and this mixture was stirred at 100° C. for 3 hours. After cooling to ambient temperature, water was added to this reaction mixture and the precipitated solid was collected by filtration, and washed with water, dried to give the title compound (0.57 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([O:16]CC2C=CC=CC=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:24])[CH:11]=2)[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc2ccc(F)cc2c(O)c1C
Yield: 81.9 %

Procedure:
To a stirred solution of (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (15.8 g, 46.7 mmol) in MeOH (150 mL) was added 10% palladium on carbon (2.4 g). The resulting mixture was vigorously stirred under a balloon of hydrogen overnight. The reaction mixture was filtered through celite. The filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (10% ethyl acetate in hexanes) to yield (6-fluoro-4-hydroxy-3-methyl-naphthalen-2-yl)-acetic acid methyl ester (9.5 g, 82%) as a white solid. MS calcd. for C14H14FO3 [(M+H)+] 249, obsd. 249.1.
Reaction SMILES: [P:1]([S:20][CH2:21][CH2:22][CH3:23])([O:17][CH2:18][CH3:19])([S:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]([O:14][CH2:15][CH3:16])[N:6]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>C1(C)C=CC=CC=1>[P:1]([O:17][CH2:18][CH3:19])([S:20][CH2:21][CH2:22][CH3:23])([S:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[N:8]=[C:7]([O:14][CH2:15][CH3:16])[N:6]=1)=[S:25]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCSP(=O)(OCC)SCc1cc(OCC)nc(OCC)n1
Solvent: Cc1ccccc1
Product: CCCSP(=S)(OCC)SCc1cc(OCC)nc(OCC)n1

Procedure:
2 g (0.053 mol) of O-ethyl S-(2,6-diethoxy-4-pyrimidinylmethyl) S-(n-propyl) dithiophosphate (see Example 2) and 0.3 g (0.0145 mol) of phosphorus pentasulphide in 10 ml of toluene are left at 60° C. for 16 hours. The mixture is then diluted with 50 ml of toluene and the solution is washed once with 0.5N hydrochloric acid and twice with saturated sodium chloride solution. The solvent is subsequently removed by evaporation under reduced pressure and the resulting crude product is purified by chromatography on silica gel with 15% diethyl ether in n-hexane. There is obtained O-ethyl S-(2,6-diethoxy-4-pyrimidinylmethyl) S-(n-propyl) trithiophosphate as a yellow oil, nD23 1.5648.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[C@@H:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=2)[CH2:26][CH2:25]1)[CH3:23])(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][CH:22]([CH:24]2[CH2:25][CH2:26][N:27]([C:30]3[O:34][N:33]=[C:32]([CH:35]([CH3:36])[CH3:37])[N:31]=3)[CH2:28][CH2:29]2)[CH3:23])=[CH:12][N:11]=1
Reactant: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Reactant: CC(C)c1noc(N2CCC([C@@H](C)OS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(-c2cnc(OC(C)C3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Alternative synthesis, Step 4, 0.40 g, 1.69 mmol), crude (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.75 g, 2.29 mmol) and K2CO3 (0.48 g, 3.39 mmol) in DMF (16 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extract was washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown oil, which was purified by chromatography on an ISCO silica gel column using 0 to 30% EtOAc/hexanes to give 0.335 g (43%) of 2-[2-fluoro-4-(methylthio)phenyl]-5-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]pyrazine as a yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 8.52 (s, 1H), 8.23 (d, 1H, J=1.0 Hz), 7.85 (t, 1H, J=8.2 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.6 Hz), 5.20-5.05 (m, 1H), 4.25-4.15 (m, 2H), 3.10-2.95 (m, 2H), 2.87 (septet, 1H, J=6.9 Hz), 2.50 (s, 3H), 2.00-1.75 (m, 3H), 1.55-1.40 (m, 2H), 1.33 (d, 3H, J=6.4 Hz), 1.26 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 458 (M+H).