Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].C[O-].[Na+].BrCC[CH2:19][C:20]([F:23])([F:22])[F:21]>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:7])([S:8][CH2:9][CH2:10][CH2:19][C:20]([F:23])([F:22])[F:21])[CH3:6])[CH3:2]
Reactant: FC(F)(F)CCCBr
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCCCC(F)(F)F
Temperature: 85 °C
Yield: 84.3 %

Procedure:
To a solution of 149 g (785.4 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester in ethanol (1.2 L, degassed under nitrogen for 1 h) are added 169.7 g (105 mmol) of sodium methoxide, followed by a solution of 150 g (785.4 mmol) of 1-bromo-4,4,4-trifluorobutane. The reaction is heated to 85° C. for 3 d. The solvent is removed under reduced pressure. The residue is dissolved in DCM (1 L) and washed with saturated aqueous NaHCO3 solution (2×1 L). The organic layer is dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to afford 171 g of 2-methyl-2-(4,4,4-trifluoro-butylsulfanyl)-propionic acid ethyl ester as a brown oil. Yield: 84%; ES-MS: m/z 259 [M+H]; 1 H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29 (3 H, t, J=7.17 Hz), 1.51 (6 H, s), 1.76-1.86 (2 H, m), 2.12-2.27 (2 H, m), 2.69 (2 H, t, J=7.17 Hz), 4.18 (2 H, q, J=7.17 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (30 mg, 0.15 mmol) in THF (1.5 mL) at −78° C. was added 2.0 M 4-tert-butylphenylmagnesium bromide in THF (0.15 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(4-tert-butyl-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO.C(Cl)[Cl:17]>>[Cl:17][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: ClCCl
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CO
Product: O=C(CCl)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(4-Fluoro-3-nitrophenyl)ethanone (18.4249 g; manufactured by Sigma-Aldrich Co.) was dissolved in CH2Cl2 (400 mL), added with methanol (3.04 mL), followed by replacement with nitrogen gas and cooling to 0° C. To the resulting solution, SO2Cl2-CH2Cl2 solution [109.32 mL; solution obtained by dissolving SO2Cl2 (9.32 mL; manufactured by Wako Pure Chemical Industries, Ltd.) in CH2Cl2 (100 mL)] was added dropwise over 30 minutes, and the mixture was stirred overnight while warming to room temperature. The reaction solution was cooled to 0° C., added with methanol (1.52 mL), and then SO2Cl2-CH2Cl2 solution [64.66 mL; solution obtained by dissolving SO2Cl2 (4.66 mL; manufactured by Wako Pure Chemical Industries, Ltd.) in CH2Cl2 (60 mL)] was added dropwise thereto. While warming to room temperature, the mixture was stirred for 3 hours. The reaction solution was washed once with a saturated aqueous solution of sodium carbonate and once with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The solidified crystal, which had been obtained during purification of the resulting residue by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=88:12→67:33), was extracted with ethyl acetate, and then filtered. The filtrate was evaporated under reduced pressure, and as a result, the title compound was obtained (6.403 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[CH3:23][S:24]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][C:5]1[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(O)Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC(O)Cc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 0 °C
Yield: 48.5 %

Procedure:
A mixture of 3-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)propane-1,2-diol (100 mg, 0.31 mmol) and TEA (94 mg, 0.93 mmol) in THF (6 mL) was stirred under N2 at 0° C., MsCl (36 mg, 0.31 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and RT overnight. Water was added and after extraction with EA, the organic layer was washed with water, brine, dried over Na2SO4 and concentrated on a rotary evaporator. The residue was purified by column chromatography (PE:EA=2:1˜1:1) to give the product of 3-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)-2-hydroxypropyl methanesulfonate (60 mg, yield: 48%). 1H-NMR (MeOD, 400 MHz) δ 7.80 (d, J=7.6 Hz, 1H), 7.26˜7.32 (m, 2H), 7.09˜7.11 (m, 1H), 7.04 (s, 1H), 6.70 (t, J=7.6 Hz, 1H), 4.20˜4.29 (m, 3H), 3.09˜3.13 (m, 5H). MS (M+H)+: 399/401.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6](=[O:18])[C:5]2=O.CCOCC>CCCCCC>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1C(=O)N(Cc2ccccc2)c2ccc(F)cc21
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1Cc2cc(F)ccc2N1Cc1ccccc1
Yield: 75.2 %

Procedure:
In a manner similar to the method of N-benzylisatin, 5-fluoroisatin (10.0 g, 60.5 mmol) yielded 5-fluoro-N-benzylisatin as an orange red powder (14.5 g, 93%). The crude product was used for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.33-7.21 (m, 5H), 6.95 (d, J=7.6 Hz, 1H), 6.84 (t, 1H), 6.60 (m, 1H), 4.89 (s, 2H); MS ESI 255.9 [M+H]+, calcd for [C15H10FNO2+H]+ 255.07. The title compound was prepared in a manner similar to the method of N-Benzyl-oxindole using 5-fluoro-N-benzylisatin (14.5 g, 56.8 mmol). Trituration using Et2O:hexane yielded the title compound as a pale yellow solid (10.3 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.26 (m, 5H), 7.00 (d, J=7.6 Hz, 1H), 6.87 (t, 1H), 6.63 (m, 1H), 4.91 (s, 2H), 3.63 (s, 2H); MS ESI 241.9 [M+H]+, calcd for [C15H10FNO2+H]+ 241.09.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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.CO>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:20](=[O:22])[CH3:21])=[N:3][C:4]=1[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: CC(=O)Nc1ccccc1B(O)O
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 150 °C
Yield: 26.9 %

Procedure:
A solution of 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (100 mg, 0.31 mmol), 2-ethanamidophenylboronic acid (56.25 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium (18.17 mg, 0.015 mmol) and Na2CO3 (471 μL, 2M aqueous solution) were added to a 10 mL microwave vial. Dioxane (3 mL) was then added and the vial sealed. The reaction mixture was heated in the microwave at 150° C. for 30 min. After this time methanol was added and the reaction mixture filtered. The solid was then washed with water (5 mL) and MeOH (5 mL) and dried under vacuum to give the product (31.0 mg, 28% yield); 1H NMR (400.0 MHz, DMSO) d 2.04 (s, 3H), 7.26 (t, 1H), 7.44-7.40 (m, 1H), 7.69-7.67 (m, 4H), 7.80 (d, 2H), 8.15-8.13 (m, 3H), 8.73 (s, 1H) and 10.76 (s, 1H) ppm; MS (ES+) 373.0
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[I:29]I.O>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]3[C:20]([C:21]=2[I:29])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2ccccc21
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(I)c2ccccc21
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 81.5 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)indol-2-yl]phtalimide (300 mg, 0.795 mmol) was dissolved in ethanol (21 mL), and the solution was added with iodine (242 mg, 0.954 mmol) and silver sulfate (248 mg, 0.795 mmol), followed by stirring at room temperature for 1.3 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using chloroform to obtain 3-amino-6-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]phtalimide (326 mg, yield 82%).
Reaction SMILES: O[CH:2]([CH2:11][C:12](=[O:28])[C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=2[CH:14]=1)/[C:3](/C)=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[O:28]=[C:12]([C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:26])([CH3:27])[C:15]=2[CH:14]=1)/[CH:11]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C(\C)C(O)CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/C=C/C(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 41 (0.33 g, 0.85 mmol) in 8 mL of THF at 0° C. was added triethylamine (0.5 mL, 4 mmol), and a solution of methylsulfonyl chloride (0.106 g, 0.93 mmol) in 2 mL of THF slowly. The mixture was stirred for 1 h at 0° C. and warmed to room temperature for 30 min. The mixture was filtered through a plug of silica gel with 10% ethyl acetate/hexane. The filtrate was concentrated to afford 42 as a light-yellow solid. Recrystallization from dichloromethane/hexane afforded the desired acid 42 as a yellow powder (0.3 g, 95%): m.p. 101°-102° C.; Rf 0.42 (10% ethyl acetate/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH3:22])[CH2:19][CH2:18][C:17]2=[O:23].[CH3:24][Li]>O1CCCC1>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]([CH3:22])[CH2:19][CH2:18][C:17]2([OH:23])[CH3:24]
Reactant: [Li]C
Reactant: CN1CCC(=O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Solvent: C1CCOC1
Product: CN1CCC(C)(O)c2cccc(CSc3nc4ccccc4[nH]3)c21
Temperature: -10 °C

Procedure:
To a solution of 8-(2-benzimidazolyl)thiomethyl-1-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (300 mg) in tetrahydrofuran (10 ml) was added dropwise methyl lithium (1.5M solution in tetrahydrofuran) (1.33 ml) with stirring at -10° C. Then the mixture was stirred for 30 minutes at the same temperature. After distilling off the solvent, the residue was extracted with dichloromethane, washed with water, and dried, then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent:n-hexane-ethyl acetate-dichloromethane (10:5:2)], and recrystallized from dichloromethane-diethyl ether to give 8-(2-benzimidazolyl)thiomethyl-4-hydroxy-1,4-dimethyl-1,2,3,4-tetrahydroquinoline (96 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](=[O:12])([OH:11])[OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][CH:16]([CH2:19]O)[CH2:17]O>>[CH3:15][CH:16]1[CH2:19][O:11][P:9](=[O:10])([CH2:8][C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:12][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(CP(=O)(O)O)cc1
Reactant: CC(CO)CO
Product: CC1COP(=O)(Cc2ccc([N+](=O)[O-])cc2)OC1

Procedure:
With 4-nitrobenzylphosphonic acid and 2-methyl-1,3-propanediol, the same procedure as in Reference Example 11 was followed, to yield 5-methyl-2-(4-nitrobenzyl)-1,3,2-dioxaphosphorinane-2-oxide, which was then recrystallized from ethanol-hexane to yield colorless prisms having a melting point of 170° to 171° C.
Reaction SMILES: C(N[C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[O:19][C:20](=[O:24])[N:21]([CH3:23])[N:22]=1)(=[O:11])=[O:10])=[O:7])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[CH3:23][N:21]1[C:20](=[O:24])[O:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9]([N:8]=[C:6]=[O:7])(=[O:11])=[O:10])=[N:22]1
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccccc1-c1nn(C)c(=O)o1
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: Cn1nc(-c2ccccc2S(=O)(=O)N=C=O)oc1=O
Temperature: 25 °C
Yield: 108.7 %

Procedure:
A suspension of 8 g of the product of Example 7 and 0.4 g of DABCO in 90 ml of xylenes was heated under N2 at 130°-135° C. while 1.8 ml of phosgene was added portionwise at a rate to maintain a reflux temperature of about 130°-135° C. The mixture was refluxed an additional two hours, cooled under N2 to room temperature, filtered, and the filtrate was concentrated in vacuo to yield 6.9 g of the subject compound as a crude oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[C:26]([CH3:34])=[CH:27][C:28]([Cl:33])=[C:29]([CH:32]=3)[C:30]#[N:31])[C@@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:37])[C:36]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[C:29]([C:30]#[N:31])[C:28]([Cl:33])=[CH:27][C:26]=1[CH3:34])([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(N)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(Cl)c(C#N)cc1N[C@@H](c1nnc(-c2ccc(NC(=O)c3ccccc3)cc2)o1)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a pre-cooled (0° C.) solution of 5-((1R,2S)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-4-methyl-benzonitrile (290 mg, 0.58 mmol) in CH2Cl2 (10.0 mL) and pyridine (1.2 mL) was added, portion wise, acetyl chloride (0.34 mL, 2.9 mmol). Upon complete addition the reaction mixture was warmed slowly to room temperature and stirred for 23 h. The reaction mixture was then cooled to 0° C. and quenched with 10% aq HCl (5 mL) then H2O (15 mL) was added. The solution was extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide an orange oil, which was used without further purification (400 mg). 1H NMR (400 MHz, d6-acetone, δ in ppm) 8.36 (d, J=8.4 Hz, 2 H), 8.27 (br s, 1 H), 8.16 (d, J=8.6 Hz, 2 H), 8.08 (d, J=8.2 Hz, 1 H), 8.02 (d, J=8.6 Hz, 2 H), 7.94-7.83 (m, 3H), 7.53 (d, J=8.2 Hz, 1 H), 5.57 (d, J=8.9 Hz, 1 H), 4.99 (dd, J=1.8, 8.9 Hz, 1 H), 4.76-4.68 (m, 1 H), 2.58 (s, 3 H), 1.61 (d, J=6.3 Hz, 3 H), 1.09 (s, 9 H), 0.26 (s, 3 H), 0.01 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[CH2:6][N:5]=[C:4]2[S:9][CH:10]=[CH:11][C:3]=12.[Cl:12][C:13]1[CH:22]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:20]=[C:19]([CH3:26])[C:14]=1[O:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:12][C:13]1[CH:22]=[C:21]([CH2:23][CH2:24][CH3:25])[CH:20]=[C:19]([CH3:26])[C:14]=1[O:15][CH2:16][CH2:17][NH:18][C:2]1[N:7]([CH3:8])[CH2:6][N:5]=[C:4]2[S:9][CH:10]=[CH:11][C:3]=12
Reactant: CN1CN=c2sccc2=C1Cl
Reactant: CCCc1cc(C)c(OCCN)c(Cl)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCc1cc(C)c(OCCNC2=c3ccsc3=NCN2C)c(Cl)c1
Yield: 59.5 %

Procedure:
3.7 g (0.02 mole) of 4-chloro-3-methylthieno[2,3-d]pyrimidine, 4.6 g (0.02 mole) of 2-(2-chloro-6-methyl-4-propylphenoxy)ethylamine and 2 g (0.02 mole) of triethylamine were dissolved in 50 ml of benzene, and the solution was heated under reflux for 6 hours. At the end of this time, the solvent was distilled off and the residue was washed with water and dried in air. It was then recrystallised from a mixture of benzene and hexane, to give 4.5 g (yield 60%) of the desired Compound No. 19 in the form of colourless needles melting at 66°-68° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[N:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[S@@](=O)N=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
To a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (5 g, 20.7 mmol) and (R)-2-methylpropane-2-sulfinamide (3.3 g, 26.9 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (5.9 g, 24.8 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered off and the filtrate was extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (5.5 g, yield: 78%); m/z (ES+): 346 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([C:13]2[CH:14]=[C:15]([CH:17]=[C:18]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:19]=2)[NH2:16])=[N:9][CH:10]=[CH:11][CH:12]=1.CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:13]2[CH:14]=[C:15]([NH:16][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[C:18]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:19]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Reaction time: 8 h
Yield: 37.5 %

Procedure:
Methanesulfonyl chloride (10.0 μL, 0.12 mmol) was added to a solution of Example 183 (32.1 mg, 0.1 mmol) in CH2Cl2 (2 mL) followed by Et3N (20.0 μL, 0.15 mmol) at 0° C. The resulting mixture was stirred overnight and saturated NH4Cl solution (50 mL) was added and the mixture extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting material was purified by LCMS (acetonitrile-water gradient) to give the title compound (15 mg, 38%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.99 (s, 3H) 7.33 (dd, J=7.21, 4.42, Hz, 1 H) 7.52 (dd, J=5.27, 3.48 Hz, 1 H) 7.83 (t, J=5.21 Hz, 1 H) 7.87 (d, J=5.11 Hz, 2 H) 8.03 (t, J=5.11 Hz, 1 H) 8.21 (t, J=5.11 Hz, 1 H) 8.34 (d, J=5.11 Hz, 2 H) 8.51 (d, J=5.42, Hz, 1 H) 8.56 (d, J=5.91 Hz, 1 H). MS (ES) [M+H] calculated for C18H15ClN5O2S, 400.06; found 400.02.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][CH2:6][C@H:7]([OH:34])[CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[N:21]=[C:20]([C:22]3[S:23][C:24]([CH2:28][NH:29][CH:30]([CH3:32])[CH3:31])=[C:25]([CH3:27])[CH:26]=3)[O:19][N:18]=2)=[CH:12][C:11]=1[CH3:33])=[O:4].[CH2:35](I)[CH3:36].CCN(C(C)C)C(C)C>CN(C=O)C.N>[NH3:5].[CH2:35]([N:29]([CH2:28][C:24]1[S:23][C:22]([C:20]2[O:19][N:18]=[C:17]([C:13]3[CH:14]=[C:15]([CH3:16])[C:10]([O:9][CH2:8][C@@H:7]([OH:34])[CH2:6][NH:5][C:3](=[O:4])[CH2:2][OH:1])=[C:11]([CH3:33])[CH:12]=3)[N:21]=2)=[CH:26][C:25]=1[CH3:27])[CH:30]([CH3:31])[CH3:32])[CH3:36]
Reactant: Cc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(C)c3)no2)sc1CNC(C)C
Reactant: CCI
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1sc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(C)c3)no2)cc1C)C(C)C
Reaction time: 20 h
Yield: 81.2 %

Procedure:
A solution of 2-hydroxy-N-[(2S)-2-hydroxy-3-(4-{5-[5-(isopropylamino-methyl)-4-methyl-thiophen-2-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propyl]-acetamide (284 mg, 0.448 mmol, Example 91), ethyl iodide (423 mg, 2.69 mmol) and DIPEA (354 mg, 2.69 mmol) in DMF (3 mL) is stirred at rt for 1 h, then at 40° C. for 17 h before another portion of DIPEA (54 mg, 0.421 mmol) and ethyl iodide (304 mg, 1.95 mmol) is added. Stirring is continued at 40° C. for 20 h. The mixture is diluted with aq. sat. NH3 (1 mL) and separated by prep. HPLC (Waters XBridge Prep C18, 75×30 mm ID, 10 μm, gradient of acetonitrile in water containing 0.5% of sat. aq. NH3) to give the title compound (94 mg) as a colourless resin; LC-MS*: tR=1.08 min; [M+1]+=517.32.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[C:28]([O:27][C:25](=[O:26])[CH2:24][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 71 h
Yield: 49.4 %

Procedure:
To a suspension of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (700 mg, 2.90 mmol) and K2CO3 (1201 mg, 8.69 mmol) in DMF (7 ml), t-butyl bromoacetate (0.535 ml, 3.62 mmol) is added. After stirring for 71 hours, aqueous K2CO3 (1.5 g of K2CO3/40 ml of H2O) is added to the reaction mixture. The products are extracted with EtOAc. The organic layer is washed twice with water and once with brine, dried over K2CO3, filtered, and concentrated to give (S)-benzyl 1-(2-tert-butoxy-2-oxoethyl)pyrrolidine-2-carboxylate (458 mg); HPLC retention time=1.38 minutes (condition D); MS (m+1)=320.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 1.81-2.03 (m, 3H) 2.13-2.14 (m, 1H) 2.82-2.88 (m, 1H) 3.13-3.17 (m, 1H) 3.46 (A of AB, J=17.3 Hz, 1H) 3.49 (B of AB, J=17.3 Hz, 1H) 3.73 (dd, J=8.8 and 4.8 Hz, 1H) 5.15 (A of AB, J=12.4 Hz, 1H) 5.17 (B of AB, J=12.4 Hz, 1H) 7.29-7.38 (m, 5H).
Reaction SMILES: [OH:1]/[CH:2]=[C:3]1/[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8]/1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:4]2([OH:11])[CH2:5][CH2:6][C:7]([CH3:9])([CH3:10])[CH2:8]/[C:3]/2=[CH:2]\[OH:1])=[CH:15][CH:14]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC1(C)CCC(=O)/C(=C/O)C1
Product: CC1(C)CCC(O)(c2ccc(Cl)cc2)/C(=C/O)C1

Procedure:
reacting the first protected (2E)-2-(hydroxymethylene)-4,4-dimethylcyclohexanone and 4-chlorophenyl magnesium bromide to provide the first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and isolating or not isolating the first protected (2E)-1-(4-chlorophenyl)-2-(hydroxymethylene)-4,4-dimethylcyclohexanol; and