Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[C:2]1([CH2:1][CH2:8][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(=O)C=Cc1ccccc1
Solvent: CO
Product: CC(=O)CCc1ccccc1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
Activated Ni EnCat (0.26 g, water wet, 20 mol % Ni on substrate) was washed with MeOH three times to remove water and added to benzalacetone (0.148 g, 1 mmol) dissolved in MeOH (4 ml) in a pressure vessel. The vessel was sealed and purged twice with hydrogen then pressurised to 5-6 bar with hydrogen and the contents magnetically stirred at room temperature. Progress of reaction was carried out by GCMS analysis. After 24 h the hydrogen was vented and the Ni EnCat beads removed by filtration. The filtrate was concentrated on a rotary evaporator to give 4-phenylbutanone (0.149 g, 99%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]([NH2:29])[CH3:28])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][CH:24]([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:29]([CH:27]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][CH:24]([F:25])[F:26])=[C:16]([Cl:15])[CH:17]=3)[CH3:28])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1cnc(OCC(F)F)c(Cl)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1cnc(OCC(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (157 mg, colorless oil) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-chloro-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (155 mg, 0.57 mmol, Amine-16, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([Br:27])=[CH:11][C:10]=2[CH2:28]O)=[O:5])[CH3:2].S(Cl)([Cl:32])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=1)=[CH:13][C:12]([Br:27])=[CH:11][C:10]=2[CH2:28][Cl:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(CO)cc(Br)cc2c1NCc1ccc(OC)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cnc2c(CCl)cc(Br)cc2c1NCc1ccc(OC)c(Cl)c1

Procedure:
A solution of 1.73 mmole 6-bromo-4-[[(3-chloro-4-methoxyphenyl)methyl)amino)-8-hydroxymethylquinoline-3-carboxylic acid ethyl ester (i.e., Example 56) in 8 ml of thionyl chloride was stirred at RT for 1.5 hours. The solution was concentrated to give 0.86 g of the title compound as an orange foam. MS: 499; LC: 4.15′.
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[C:8]([Br:9])[C:2]=2[Br:1])=[O:19])=[CH:21][CH:22]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1cccc(Br)c1Br
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(Br)c2Br)cc1

Procedure:
The amide was prepared according to Example 18 from 2,3-dibromoaniline, 4-tert-butylbenzoyl chloride and diisopropylethylamine in dioxane. MS (ESI) m/z 408; HPLC Method B, purity 80.6% at 210-370 nm, 11.4 min.; 74.9% at 240 nm, 11.4 min.; HRMS: calcd for C17H17Br2NO+H+, 409.97496; found (ESI, [M+H]+), 409.9775.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=[C:17]([C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:18][C:19](OCC)=[O:20]>CCO>[C:8]1([N:14]2[C:19](=[O:20])[CH2:18][C:17]([C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=3[F:32])=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CC(c2cc(F)c(F)cc2F)=NN1c1ccccc1
Temperature: 70 °C

Procedure:
Potassium carbonate (153 mg, 1.10 mmol) was added to a stirred mixture of phenyl hydrazine HCl salt (160 mg, 1.10 mmol) and ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate (272 mg, 1.10 mmol) in EtOH (6 mL) and the mixture was heated at 70° C. for 1 hour. The solution was cooled to room temperature and was concentrated to give the title compound, which was taken on to the next step.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4].Br[CH2:29][C:30]#[N:31].CCN(C(C)C)C(C)C>C(#N)C>[C:30]([CH2:29][NH:1][C@@H:2]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4])#[N:31]
Reactant: N#CCBr
Reactant: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCC#N)n(C)n2)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a rt solution of 23.D (750 mg, 2036 μmol) and bromoacetonitrile (244 mg, 2036 μmol) in acetonitrile was added n,n-diisopropylethylamine (426 μl, 2443 μmol). After stirring at 60° C. for 2 hr, organic solvents were removed under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-12% MeOH/CH2Cl2 for elution gave the title product 23.E as yellow syrup (706 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH:13]NC(=O)C2C=CC=CC=2)=[S:12])[N:4]=1.[OH-].[Na+].Cl>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][C:11]([NH2:13])=[S:12])[N:4]=1
Reactant: COc1cc(C)nc(NC(=S)NNC(=O)c2ccccc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C)nc(NC(N)=S)n1
Yield: 102.5 %

Procedure:
A mixture of 25 g of the compound from Example 3 and 55 ml of 10% aqueous sodium hydroxide was heated on the steam bath for 30 minutes, cooled, neutralized with aqueous HCl to pH 8, filtered, washed with water, dried by suction, and washed with ether to afford 16 g of the title compound, m.p. 220° d.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.O[C:20]1[CH:29]=[C:28]2[C:23]([C:24](=[O:36])[CH:25]=[C:26]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:27]2)=[CH:22][CH:21]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:20]2[CH:29]=[C:28]3[C:23]([C:24](=[O:36])[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:27]3)=[CH:22][CH:21]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 7-hydroxyflavone and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])[C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[C:26]([O:28]CC)=[O:27])=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1.[OH-].[Na+].Cl>C(O)C>[C:26]([C@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[N:19]([C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[NH:4][N:3]=[N:2][N:1]=2)=[CH:13][CH:14]=1)([OH:28])=[O:27]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H]1CCCC[C@H]1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@@H]1CCCC[C@@H]1C(=O)O

Procedure:
649 mg of ethyl rac-cis-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-2-aminocyclohexane-1-carboxylate are heated at 80° for 18 hours together with 10 ml of ethanol and 2 ml of 2N NaOH. The mixture is neutralized with 2 ml of 2N HCl and evaporated. The crude product is purified on silica gel 60 (40-63 μm) using CH2Cl2 -MeOH (95:5), Rf =0.30 (system N8). MS (FAB): m/e 462 (M+ +H), 484 (M+ +Na).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15](=O)[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15]([C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])=[S:35])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=S)c1cc(Cl)ccc1OC
Temperature: 80 °C

Procedure:
To a solution of Example 6B (1.4 g, 3.7 mmol) in toluene (50 mL) was added Lawesson's reagent (1.6 g, 4 mmol) and the mixture was refluxed at 80° C. for 30 minutes. After cooling to room temperature, the mixture was diluted with EtOAc, washed with 10% solution of bicarbonate, brine and dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (2:1 Hexane-EtOAc) provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.89 (t, J=7 Hz, 3H), 1.25 (sextet, J=7 Hz, 2H), 1.36 (s, 9H), 1.76 (m, 2H), 3.74 (s, 3H), 4.25 (t, J=7 Hz, 2H), 7.06 (d, J=9 Hz, 1H), 7.35 (m, 2H), 7.45 (s, 1H); MS (ESI+) m/z 397 (M+H)+. Anal. calcd for C19H25ClN2OS2: C, 57.48; H, 6.35; N, 7.06. Found: C, 57.26; H, 6.17; N, 6.79.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:6]=[C:5]2[CH2:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17]
Reactant: CN1CCC[C@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1Cc1cn([Si](C)(C)C(C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a solution of (S)-5-bromo-3-[(N-methylpyrrolidin-2-yl)methyl]-l H-indole (Example 3c, 1.00 g, 3.41 mmol) in THF (15 mL) under argon, was added sodium hexamethyldisilazide (6.82 mL, 6.82 mmol and the resulting solution was stirred at room temperature for 20 min. The reaction mixture was cooled to 0° C. and to this was added a solution of t-butydimethylsilyl chloride (1.03 g, 6.82 mmol) in THF (4 mL) and the resulting culture was warmed to room temperature and stirred for 1 hour. The solvent as removed in vacuo and the resulting product was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The ethyl acetate extract was washed with brine (10 mL), dried (Na2SO4), filtered and the filtrate was evaporated to dryness. The crude residue was subjected to flash silica gel chromography to afford the title compound as a yellow oil (1.07 g, 79%). 13C NMR (CDCl3)δ: 140.1, 133.1, 129.8, 124.1, 121.5, 115.8, 115.2, 112.7, 66.2, 7.6, 40.9, 31.6, 30.1, 26.2, 21.9, 19.5, −3.96
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH:14]C(=O)C>CCO.O>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[CH:6][C:5]=1[NH2:14]
Reactant: COc1cc(NC(C)=O)c(Cl)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c(Cl)c(OC)c1
Yield: 81.6 %

Procedure:
Potassium hydroxide (2.19 g, 39.18 mmol) was added to a solution of N-(2-chloro-3,5-dimethoxyphenyl)acetamide (1.8 g, 7.837 mmol) in EtOH (100 mL) and water (10 mL) and the reaction mixture heated to reflux for 12 h. Excess EtOH was removed under reduced pressure to obtain a residue. The residue was then partitioned between water and diethyl ether. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (1.2 g, 82% of yield) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 5.97 (s, 2H), 4.08 (brs, 2H), 3.84 (s, 3H), 3.75 (s, 3H); MS (ESI): 188.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([C:33](O)=[O:34])[CH:27]=[CH:26]2)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH2:20][CH3:21])[CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:22])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH2:37]([O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43])[CH3:38]>>[CH2:37]([O:39][C:40](=[O:44])[CH2:41][N:42]([C:33]([C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:3]([CH2:1][CH3:2])([C:6]3[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH2:20][CH3:21])[CH:14]([OH:19])[C:15]([CH3:16])([CH3:17])[CH3:18])=[C:8]([CH3:22])[CH:7]=3)[CH2:4][CH3:5])[CH:24]=2)[CH:29]=1)=[O:34])[CH3:43])[CH3:38]
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)O)ccc3c2)cc1C)C(O)C(C)(C)C
Reactant: CCOC(=O)CNC
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)c1ccc2cc(C(CC)(CC)c3ccc(OC(CC)C(O)C(C)(C)C)c(C)c3)ccc2c1
Yield: 88 %

Procedure:
Following a procedure analogous to Example 7E esterify the diastereomeric isomer pair 1 of 6-{1-ethyl-1-[4-(1-ethyl-2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-naphthalene-2-carboxylic acid using N-methyl glycine ethyl ester hydrochloride to provide the title compound as a white foam (315 mg, 88%). 1NMR (400 MHz, CDCl3) δ ppm: 0.64 (t, J=7.2 Hz, 6H), 0.93 (t, J=8.4 Hz, 3H), 0.93 (s, 9H), 1.31 (m, 3H), 1.68 (m, 1H), 1.80 (m, 1H), 2.12 (s, 3H), 2.17 (q, 4H), 2.60 (bs, 1H), 3.11 (s, 2H), 3.16 (s, 1H), 3.27 (s, 1H), 4.05 (s, 0.73H), 4.27 (m, 3H), 4.32 (s, 1.27H), 6.63 (d, J=8.8 Hz, 1H), 6.90 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.16 (d, J=10.0 Hz, 1H), 7.49 (m, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.68 (m, 1H), 7.81 (s, 1H), 7.87 (m, 2H). High Res. ES-MS: 598.3488; calc. for C36H49NO5+Na: 598.3509. Analysis for C36H49NO5; Calcd: C, 75.10; H, 8.58; N, 2.43. Found: C, 75.04; H, 8.58; N, 2.43.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:16]1([CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)SCCCCl)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)SCCCN2CCOCC2)cc1

Procedure:
Toluene-4-thiosulfonic acid S-(3-chloro-propyl) ester (61.7 g, 233 mmol, 1.00 eq.), morpholine (22.2 g, 255 mmol, 1.09 eq.) and potassium carbonate (33.8 g, 240 mmol, 1.06 eq.) were stirred together in acetonitrile (1 L) for 64 hours at 50° C. The mixture was concentrated, then partitioned between ethyl acetate and water. The organic solution was washed with water (2×), dried using MgSO4, and concentrated to produce a light yellow oil weighing 61.5 g (84%).
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][C:4]#[CH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][CH:2]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:3][C:4]#[CH:5]
Reactant: C1=COCCC1
Reactant: C#CCC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCC(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(+/−)-4-Pentyn-2-ol (5.58 ml, 59.4 mmol) and 3,4-dihydro-2H-pyran (8.08 ml, 89 mmol) were dissolved in DCM (100 ml). 4-Toluenesulfonic acid pyridine salt (1.494 g, 5.94 mmol) was added and the resulting mixture was stirred for 4 h at RT with CaCl2-tube. The mixture was concentrated. 50 ml of diethyl ether was added, extracted with brine and dried with MgSO, filtered and evaporated. The product was used in the subsequent steps without further purifications. LC-MS: [M+1]=169.23.
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].[C:28](Br)#[N:29]>C(Cl)Cl.O>[CH2:2]([C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:28]#[N:29])[CH2:19][CH2:18]2)[N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cc(Cc2ccccc2)nc(NC2CCNCC2)n1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Cc2ccccc2)nc(NC2CCN(C#N)CC2)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (4-benzyl-6-methyl-pyrimidin-2-yl)-piperidin-4-yl-amine hydrochloride (255 mg, 0.8 mmol) in CH2Cl2 (1.5 mL) was added at 0° C. a suspension of sodium hydrogencarbonate (202 mg, 2.49 mmol) in water (0.5 mL) and then within 1 minute a solution of bromocyan (106 mg, 0.97 mmol) in CH2Cl2 (1 mL). The reaction was stirred at 0° C. for 45 minutes and then at room temperature over night. The reaction was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 solution and with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a colorless oil (135 mg, 55%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[C:1]([S:3][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: O=C(O)[C@H](Cl)Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 24 h
Yield: 83.4 %

Procedure:
Potassium thioacetate (68 mg, 0.64 mmol) was added to a solution of 100 mg (0.54 mmol) of the (2R)-2-chloro-3-phenylpropionic acid obtained in Example 14 in 2 ml of dimethylformamide at room temperature, and the mixture was stirred for 24 hours. A 6% aqueous solution of sodium thiosulfate (0.5 ml) was added to the reaction mixture, and the whole mixture was extracted with 30 ml of ethyl acetate. The organic phase was washed with 3 ml of 6% sodium thiosulfate aqueous solution, 3 ml of water and 3 ml of a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. The solvent was removed under reduced pressure to give 101 mg (yield 83%) of the desired (2S)-2-acetylthio-3-phenylpropionic acid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]([C:8]([Cl:14])=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nc(C)c(C(=O)O)o1
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)Cl)o1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2,4-dimethyl-oxazole-5-carboxylic acid (30 mg) in DCM (2.0 mL), oxalyl chloride (3.0 eq) was added at room temperature. The reaction mixture was stirred for 30 minutes. Solvents were evaporated and dried under vaccuo to afford 2,4-dimethyl-oxazole-5-carbonyl chloride.
Reaction SMILES: [Na].[CH2:2]([SH:4])[CH3:3].O1CCCC1.[Cl:10][C:11]1[C:12]([NH:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29]Cl)=[CH:24][C:23]=2[CH3:31])=[N:13][CH:14]=[N:15][C:16]=1[CH3:17]>O>[Cl:10][C:11]1[C:12]([NH:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][S:4][CH2:2][CH3:3])=[CH:24][C:23]=2[CH3:31])=[N:13][CH:14]=[N:15][C:16]=1[CH3:17]
Reactant: CCS
Reactant: Cc1cc(CCCl)ccc1OCCNc1ncnc(C)c1Cl
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CCSCCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1

Procedure:
0.5 g of the sodium salt of ethyl mercaptan was added to 30 ml of anhydrous tetrahydrofuran. 1.7 g of 5-chloro-4-{2-[4-(2-chloroethyl)-2-methylphenoxy]ethylamino]-6-methylpyrimidine was added to the mixture, which was then heated for 3 hours whilst stirring. At the end of this time, water was added to the mixture, and the oily product which separated was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was removed by distillation under reduced pressure. The oily product obtained was subjected to column chromatography (Wakogen C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate), to afford 1.2 g of the title compound as a pale yellow oily liquid, n20.8 =1.5478.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([O:8][P:9]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].CO.[OH-].[K+].Cl>O>[CH2:20]([O:19][P:9]([O:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:27])=[O:2])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H](OP(=O)(OCc1ccccc1)OCc1ccccc1)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[C@H](OP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 96.5 %

Procedure:
To a 50 mL flask containing (S)-methyl2-(bis(benzyloxy)phosphoryloxy)-3-methylbutanoate (699 mg, 1.78 mmol, 1.0 eq.) (prepared as in Example 18 or 19) was added methanol (9.2 mL). All starting material dissolved. Then a solution of potassium hydroxide in water (1 N, 3.56 mL, 3.56 mmol, 2.0 eq.) was added at ice-bath temperature. The resulting mixture was stirred at room temperature for 40 hrs. The reaction was monitored by LC-MS, and almost no starting remained. The reaction mixture was diluted with water (15 mL) and neutralized by hydrochloric acid (1 N, 3.6 mL, 3.6 mmol, 2.02 eq.) to reach pH 3 at 0° C. which was extracted by ethyl acetate (3×30 mL). The combined organic phase was washed with water (30 mL), brine (30 mL), and dried over Na2SO4 and concentrated under reduced pressure to afford crude compound 20, (S)-2-(bis(benzyloxy)phosphoryloxy)-3-methylbutanoic acid (650 mg) which was used directly in the next step without further purification. MS: m/z=379.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+].C1C=CC=CC=1>CS(C)=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:11][C:8]2[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=C(O)c1cc(O)ccc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=C(O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1O

Procedure:
77 g of 2,5-dihydroxybenzoic acid and 78.5 g of p-chloronitrobenzene were dissolved in 300 ml of dimethyl sulphoxide under a nitrogen atmosphere, and 40 g of sodium hydroxide and 225 ml of benzene were added to the resulting solution. The mixture was then distilled under reflux at 90° to 95° C on a water separator until no more water was separated off (about 2 hours). The benzene was distilled off in a water jet vacuum, the residue poured into 2.5 liters of water, the mixture acidified with concentrated hydrochloric acid while stirring vigorously, the crude, pale brown 5-(4-nitrophenoxy)-salicylic acid which was precipitated was filtered off under suction and washed acid free with water. Drying in vacuo at 80° C gave 126 g (92% of the theoretical yield) of 5-(4-nitrophenoxy)-salicylic acid, recrystallised from methanol (and active carbon, optionally with a little water added) 120 g (87% of the theoretical) of yellow crystals melting at 193° to 194° C.