Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: Fc1ccccc1Br
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccccc1C1=CCCCC1
Reaction time: 1.5 h
Yield: 52.5 %

Procedure:
A solution of o-bromofluorobenzene (17.5 g; 0.10 mole) in 150 ml of dry tetrahydrofuran (THF) was chilled to -60° and n-butyllithium (50 ml of 2.4M; 0.12 mole) was added dropwise at a rate such that the reaction temperature did not rise above -55°. When the addition was complete a solution of cyclohexanone (10.0 g; 0.10 mole) in 50 ml of THF was added, again maintaining the reaction temperature below -55°. The reaction was then allowed to come to room temperature over 90 minutes and was quenched by the addition of 10 ml of saturated NH4Cl solution. An additional 400 ml of water was added, then the organic layer was separated and dried. The aqueous phase was extracted again with ethyl acetate, then the combined, dried, organic phases were concentrated to an oil. This oil was dissolved in 200 ml of glacial acetic acid and treated with 1 ml of concentrated H2SO4. The acetic acid was concentrated to about 30 ml on a rotary evaporator, then diluted with 250 ml of water and the solution made basic with 50% NaOH. Extraction with ether, followed by drying and concentration under reduced pressure gave an oil that was distilled at 0.15 mm to give 9.26 g (53%) of 1-(2-fluorophenyl)cyclohexene, b.p. 70°-72°, that was homogeneous to thin layer chromatography (TLC).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([C:18](=O)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]>FC(F)(F)C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1ccc(C(=O)Cc2ccccc2)[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(CCc2ccccc2)[nH]1
Reaction time: 3.5 h

Procedure:
Triethylsilane (0.46 mL, 2.88 mmol) was added to a stirring, room temperature solution of 5-phenylacetyl-1H-pyrrole-2-carboxylic acid ethyl ester (33) (0.240 g, 0.929 mmol) in trifluoroacetic acid (TFA) (2.2 mL, 0.42 M) under N2. The reaction was judged complete by HPLC after 3.5 h. The TFA was removed under vacuum, and the crude product was taken up in EtOAc, washed with brine, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 60:40 Hexanes: CH2Cl2 to obtain 35, which appeared pure by TLC, but impure by HPLC. Pure 35 was obtained by preparative reverse phase HPLC with the following conditions: 0 to 10 min, 35:65 H2O: CH3CN. 10-11 min, 35:65 to 0:100 H2O: CH3CN; 20 mL/min.; λ=254 nM; 50.8 mg/mL, 0.8 mL/injection. 1H (CDCl3, 400 MHz): 9.46 (1H, broad s), 7.33-7.16 (5H, m), 6.85 (1H, t, J=2.9 Hz), 5.99 (1H, t, J=2.9 Hz), 4.29 (2H, q, J=7.1 Hz), 2.97 (4H, s), 1.33 (3H, t, J=7.1 Hz) ppm. 13C (CDCl3, 100 MHz): δ 161.76, 141.16, 138.18, 128.69, 128.52, 126.46, 121.52, 116.06, 108.46, 60.36, 35.89, 29.83, 14.67 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.67; CH2 carbons: 60.36, 35.89, 29.83; CH carbons: 128.69, 128.52, 126.46, 116.06, 108.46 ppm. HPLC: 10.392 min.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[C:9]([CH3:18])[C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[N:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:6][C:7]1[CH:8]=[C:9]([CH3:18])[C:10]([NH:13][C:14](=[O:17])[CH2:15][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:11][CH:12]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Br)cnc1NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cnc1NC(=O)CN1CCCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.81 mL (9.9 mmol) pyrrolidine are added to a suspension of 2.37 g (9.0 mmol) N-(5-bromo-3-methyl-pyridin-2-yl)-2-chloro-acetamide and 2.49 g (18 mmol) K2CO3 in 22.5 mL DMF and the reaction mixture is stirred for 20 h at RT. It is diluted with water, extracted exhaustively with EtOAc, the combined organic phases are washed with water and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is taken up in a little diisopropylether, cooled to 0° C., the crystals precipitated are suction filtered and dried in the air.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>>[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH:27][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CN(C)CCCN
Product: COc1ccc(N(C)c2nc(NCCCN(C)C)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and N1,N1-dimethyl-propane-1,3-diamine (16 μl, 0.070 mmol) by a procedure similar to example 10 and was isolated as white powder (11 mg, 73%). 1H NMR (CDCl3): 7.43 (dd, J=8.4 and 1.2 Hz, 1H), 7.34 (ddd, J=7.8, 6.6 and 1.2 Hz, 1H), 7.11-7.07 (m, 2H), 6.89-6.86 (m, 3H), 6.65 (ddd, J=8.1, 6.6 and 1.2 Hz, 1H), 3.82 (s, 3H), 3.61 (t, J=6.9 Hz, 2H), 3.49 (s, 3H), 2.41 (t, J=6.9 Hz, 2H), 2.28 (s, 6H), 1.89 (m, 2H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[S:5](Cl)([CH3:8])(=[O:7])=[O:6].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:8][S:5]([NH:4][CH2:3][CH2:1][O:2][S:5]([CH3:8])(=[O:7])=[O:6])(=[O:7])=[O:6]
Reactant: NCCO
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CS(=O)(=O)NCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
A stirred solution of ethanolamine (9.15 g) in pyridine (40 ml) was cooled to 0° C. in an ice-salt bath, and mesylchloride (23 ml) was added dropwise at such a rate that the temperature did not rise above 5° C. When the addition was complete the mixture was allowed to rise to room temperature for 1/2 hour. The mixture was poured into citric acid solution and continuously extracted with ehtylacetate for 11/2 hours. The solution was dried over magnesium sulphate and evaporated to give 23.7 g of the title compound.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([O:16]C)=[O:15])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([N:7]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]([C:14]([OH:16])=[O:15])=[CH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(=O)n(C2CCCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(=O)n(C2CCCCC2)c1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a solution of methyl 1-cyclohexyl-6-oxo-1,6-dihydropyridine-3-carboxylate (100 mg, 0.43 mmol) in 10 mL of THF:MeOH (3:1) was added 1M LiOH (1 mL, 1 mmol). The solution was stirred at room temperature until starting material was consumed as determined by LC-MS. The solution was then concentrated in vacuo, acidified with 2 N HCl to pH 2, and extracted with EtOAc (3×). The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give 60 mg (63%) of the title compound as a golden yellow solid. MS m/z: 222.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]
Reactant: COc1ccc(CCC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-methoxy-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH:10]([CH3:33])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC[C@@H](COCC1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@@H](COCC1CC1)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.325 g (0.73 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one (Example 68, Step B) and iodomethane (0.055 mL, 0.874 mmol) in THF (7.0 mL) was added lithium bis(trimethylsilyl)amide (1M solution in THF, 0.8 mL, 0.8 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[I-:15].[Na+]>CC(C)=O>[I:15][CH2:2][CH2:3][CH2:4][CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [I-]
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCC(CCCI)OC(C)=O
Yield: 97.5 %

Procedure:
A mixture of 1-chloro-4-acetoxynonane (Ex. 1, Step B-3) (35.3 g., 0.16 mole) and sodium iodide (120 g., 0.8 mole) in acetone (350 ml.) is stirred and heated at reflux with exclusion of light for 10 hours. The resulting suspension is filtered and the collected sodium chloride washed with acetone. The combined filtrate and washings are evaporated in vacuo leaving a residual mass which is partitioned between ether and water. The organic extract is washed with dilute aqueous sodium thiosulfate and water, dried over sodium sulfate and evaporated in vacuo providing the title compound as a colorless liquid (48.7 g., 98%), pmr (CDCl3) δ 2.0 (s, 3H), 3.18 (t, 2H) and 4.98 (m, H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:12]([CH3:21])[CH:11]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[CH2:28][OH:29]>>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([S:17]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[CH2:28][OH:29])(=[O:19])=[O:18])=[C:12]([CH3:21])[CH:11]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: OCC1CCCCN1
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of triethylamine (2.5 eq) and 4-methoxy-2,6-dimethylbenzenesulfonyl chloride (13.04 mmol, 1 eq) in MC (10 ml) was added dropwise to a solution of piperidin-2-ylmethanol (13.04 mmol) in MC (30 ml) at 0° C. and the mixture was stirred at 0° C. for 30 min. It was then stirred at room temperature for 14 h, MC (50 ml) was subsequently added to the mixture and the mixture was washed with water and sat. sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography. Yield: 3.2 g (79%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].Cl[CH2:13][CH2:14][CH2:15][C:16](Cl)=O.[OH-].[Na+]>OS(O)(=O)=O>[CH2:14]1[CH:13]2[N:11]([S:8](=[O:9])(=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1]2)[CH2:16][CH2:15]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C(Cl)CCCCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=S1(=O)c2ccccc2NC2CCCN21
Temperature: 100 °C

Procedure:
2-Aminobenzenesulfonamide was used as starting material for the following transformation sequence: Method E (using 4-chlorobutanoyl chloride. The reaction mixture was NOT subjected to NaOH catalyzed ring closure, but dissolved in H2SO4 and heated at 100° C. for 72 h and precipitated on ice). M.p. 149-154° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[Cl:21][C:22]1[N:23]=[C:24]([N:29]([CH3:31])[CH3:30])[S:25][C:26]=1[CH:27]=O.C([O-])(=O)C.[NH4+]>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:27]([C:26]3[S:25][C:24]([N:29]([CH3:31])[CH3:30])=[N:23][C:22]=3[Cl:21])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1nc(Cl)c(C=O)s1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN(C)c1nc(Cl)c(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Br)cnc3[nH]2)s1
Yield: 28.4 %

Procedure:
In a similar fashion to Compound CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (75.00 mg, 0.2553 mmol), 4-Chloro-2-dimethylamino-thiazole-5-carbaldehyde (53.5 mg, 0.281 mmol), and Ammonium acetate (39.4 mg, 0.511 mmol) were reacted to produce 36.84 mg (33%) of the title compound. (300 MHz, DMSO-d6) 12.56 (s, 1H), 8.00 (s, 1H), 7.73 (s, 1H), 7.18 (m, 2H), 6.34 (s, 2H), 5.04 (t, J=17 Hz, 8.5 Hz, 1H), 3.11 (s, 6H), 2.87 (s, 1H), 2.75 (s, 1H), 2.58 (s, 1H), 2.19 (d, J=8 Hz, 1H), 1.36 (d, J=8 Hz, 1H). MS=509 (M+H), HPLC: 2.39 min. (G Method).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH2:10][OH:11])[CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:17]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:10][O:11][CH3:17])[CH2:8][OH:9])=[CH:12][CH:13]=1
Reactant: CI
Reactant: OCC(CO)Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(CO)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Dissolve 2-(4-fluorophenoxy)propane-1,3-diol (186 mg, 0.99 mmol) in THF (5 mL), and add sodium hydride (60% dispersion in mineral oil, 24 mg, 1 mmol). Stir the mixture for 30 minutes at ambient temperature then add iodomethane (0.4 mL, 4.09 mmol). Stir the reaction at ambient temperature for 16 hours. Remove the solvents under reduced pressure and add water to the residue. Extract with EtOAc three times; collect the EtOAc extracts; dry; and remove the solvents under reduced pressure. Purify the residue via prep-TLC using 1:1 EtOAc:petroleum ether, to give the title compound (50 mg, 31.0%). 1H NMR (300 MHz, CDCl3) δ 7.0 (m, 4H), 4.2-4.5 (m, 2H), 3.8 (m, 2H), 3.55 (m, 1H), 3.35 (m, 2H), 2.35 (bs, 1H), 2.0 (s, 3H).
Reaction SMILES: C(Cl)Cl.[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CCN(CC)CC>[Br:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH:7][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccccc1Br
Reaction time: 0.42 h

Procedure:
DCM (670 Kg) and Et3N (76.4 Kg) were added to a 1000 L glass-lined reactor at 0° C. Then, 2-bromoaniline (3a) (100 Kg, 581 moles, 1.0 equiv.) was added with stirring. The resulting mixture was cooled to 0˜10° C. and pivaloyl chloride (77.1 kg, 640 moles, 1.1 equiv.) was added dropwise (5 kg/h) while maintaining the same temperature. The mixture was stirred at this temperature for 1 h 25 min and reaction progress monitored by HPLC. When it was deemed complete, the reaction was quenched by addition of a 5% aqueous solution of Na2CO3 (120 kg) at a rate of 2 kg/min. After addition, the mixture was stirred for 1.5 h and the pH value tested to be between 7 and 8. The reaction was allowed to stand for 20-30 min and the organic phase was separated out. The aqueous layer was extracted with DCM twice (60×2 kg). During each extraction, the bi-phasic mixture was stirred for 15-20 min and then held for 15˜20° C. to allow for layer separation. All the organic layers were combined and a 3% aqueous solution of HCl (251.8 kg) was added to adjust the pH value between 5 and 6. Then the aqueous layer was separated and the organic layer was washed with saturated NaHCO3 (150 L). During the washing, the bi-phasic mixture was stirred for 30 min and held for 30 min. The organic phase was separated and dried over NaSO4 (50 kg) with stirring for 13 h. The resulting slurry was filtered under vacuum using a 50 L vacuum filter. The filtration cake was washed with DCM twice (25 kg×2). The filtrate was concentrated by evaporation at T<50° C. under atmospheric pressure until no solvent distilled out. Then it was additionally concentrated by evaporation under vacuum (P≦MPa) at 65˜70° C. After concentration, the mixture was cooled to 55˜60° C. and THF was added (993 kg). Then the mixture was concentrated by evaporation again under the same conditions as above. The content of DCM was monitored by GC using method F until <0.1%. The mixture was cooled to 20˜30° C. under N2 and then filtered though silica gel (8 kg) under vacuum in order to dry it. The silica plug was washed twice with THF (20 kg×2) to give a solution of crude (3b) which was transferred into 200 L drums for the following step. Typical retention time for starting material (3a) is 8.0 min and for product (3b) is 8.9 min.
Reaction SMILES: [CH3:1][C:2]([NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=1)=O)([C:6](=[S:8])[NH2:7])[CH:3]([CH3:5])[CH3:4]>C1COCC1.[OH-].[Na+]>[CH:3]([C:2]1([CH3:1])[C:6](=[S:8])[NH:7][C:10]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[N:9]1)([CH3:5])[CH3:4]
Reactant: Cc1cccc(C(=O)NC(C)(C(N)=S)C(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(C2=NC(C)(C(C)C)C(=S)N2)c1
Temperature: 65 °C

Procedure:
A solution containing 4.7 g N-[1,2-dimethyl-1-(thiocarbamoyl)propyl]-m-toluamide in 75 mL THF and 35 mL 10% NaOH is heated at 65° C. for 18 hours. The THF is removed in vacuo and the pH of the cooled residue adjusted to 3 with concentrated H2SO4. The product is extracted into CH2Cl2, the extract washed with brine, dried and concentrated to give a yellow solid. This is recrystallized from acetonitrile to give analytically pure 4-isopropyl-4-methyl-2-m-tolyl-2-imidazolin-5-thione, mp 122°-123° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([N:36]([CH3:44])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 9.1 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (1.2 g) synthesized in Example 29(4) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (1.0 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.17 g, 8%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:21][CH:22](Br)[CH3:23]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[O:14][CH2:23][CH2:22][Br:21])(=[O:3])[CH3:2]
Reactant: CC(Br)Br
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
A portion (9.6 g, 0.049 mol) of the 2-acetamido-4-nitrophenol produced in (1) above and potassium carbonate (33.86 g, 0.245 mol) were dissolved in dimethylformamide (100 ml), followed by heating at 70° C., addition of dibromoethane (21 ml, 0.245 mol) and stirring for 20 min. Thereafter, the reaction solution was filtered to remove the insoluble matter and the solvent was evaporated, with the residue being thereafter diluted with sodium bicarbonate and subjected to two extractions with ethyl acetate. The organic extracts were dried with sodium sulfate and the solvent was evaporated, with the resulting residue being purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing n-hexane (50%) to yield the end compound 1-(2-acetamido-4-nitrophenoxy)-2-bromoethane (8.2 g) as a pale yellow solid mass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].Br[C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:29]([CH3:38])([CH3:37])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C(CCc1ccc(O)c(Cl)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc1Cl

Procedure:
Tert-butyl 2-(2-chloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate is prepared from 3-(3-chloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and tert-butyl bromoisobutyrate according to general procedure D.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])[CH3:2].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:24])[CH3:25])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[O:27][CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32])[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1O
Reactant: OC[C@H](O)CCl
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1OC[C@@H](O)CO

Procedure:
(S)-3-(2-Ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxa-diazol-3-yl}-6-methyl-phenoxy)-propane-1,2-diol is prepared from 2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol and (S)-3-chloro-1,2-propanediol in analogy to Example 3; LC-MS: tR=1.07 min; [M+1]+=441.37; 1H NMR (CDCl3): δ 1.24 (d, J=6.5 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.05 (t, J=5.1 Hz, 1H), 2.41 (s, 3H), 2.51 (s, 3H), 2.73 (d, J=5.5 Hz, 1H), 2.78 (q, J=7.5 Hz, 2H), 2.97 (s, 3H), 3.81-4.00 (m, 4H), 4.12-4.21 (m, 1H), 4.95-5.05 (m, 1H), 7.06 (s, 1H), 7.13 (s, 1H), 7.88 (s, 1H), 7.89 (s, 1H).