Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:21])[CH2:19][CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[CH2:10][CH2:11][O:12][C:8]=2[CH:7]=1.[OH-:22].[Na+].[BH4-].[Na+].[CH3:26]O>>[CH3:26][O:22][C:18]([CH3:21])([CH2:19][CH3:20])[CH2:17][CH2:16][CH2:15][C:2]([CH3:1])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]2[CH2:10][CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: [OH-]
Reactant: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCC2
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(CCCC(C)=CCOc1ccc2c(c1)OCC2)OC
Temperature: 0 °C

Procedure:
An ice-cold solution of 6.0 g. of 6-[(3,7-dimethyl-2,6-nonadienyl)-oxy]-2,3-dihydrobenzofuran in 40 ml. of absolute methanol is treated dropwise while stirring with a solution of 6.7 g. of mercuric acetate in 100 ml. of methanol. The mixture is stirred for 2 hours at room temperature, after which there are added in the cold 23 ml. of 10% by weight aqueous sodium hydroxide followed by 0.4 g. of sodium borohydride in 23 ml. of 10% by weight aqueous sodium hydroxide. The mixture is stirred for 20 minutes at room temperature, filtered through diatomaceous earth, the filtrate saturated with sodium chloride and extracted three times with diethyl ether. The extracts are washed neutral with sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (19:1 parts by volume) there is obtained pure 2,3-dihydro-6-[(7-methoxy-3,7-dimethyl-2-nonenyl)-oxy]-benzofuran which is distilled in a bulb-tube at 125° C./0.03 mmHg; nD20 = 1.5236.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>C(Cl)Cl>[C:20]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1
Reactant: NCCCOc1ccncc1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccncc1)c1cccnc1
Yield: 88.7 %

Procedure:
To a solution of 700 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 1.54 ml (11.0 mmol) of triethylamine in 30 ml of methylene chloride, 830 mg (4.66 mmol) of nicotinoyl chloride hydrochloride was added under ice-cooling within stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10 to 1:5) to obtain 1.05 g of the desired compound (yield: 85.8%, colorless crystals).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH2:13]([N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][NH:21][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11])[CH3:14]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Yield: 63.8 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3.0 g, 17.9 mmol) reacted with diethylamino propylamine (2.57 g, 19.7 mmol) to give 3.19 g (64%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide.
Reaction SMILES: [C:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].C=O.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[C:22](=O)([O-])O.[Na+]>C(OCC)(=O)C.C(O)C>[N:17]1([CH2:22][CH:2]([CH2:3][CH3:4])[C:1]([C:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][N:7]=2)=[O:5])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCCC(=O)c1noc2ccccc12
Reactant: C1CCNC1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(CN1CCCC1)C(=O)c1noc2ccccc12

Procedure:
Added to 10 ml of ethanol were 1.55 g (8.2 mmol) of 3-butyryl-l,2-benzisoxazole prepared above in the procedure (1), 0.52 ml (9.9 mmol) of a 37% aqueous solution of formaldehyde and 0.82 ml (9.8 mmol) of pyrrolidine. The resultant mixture was heated under reflux for 3 hours. After cooling, the solvent was distilled off. The residue thus obtained was added to 50 ml of ethyl acetate, followed by extraction with 50 ml of dilute hydrochloric acid. A water layer thus obtained was alkalinized with an aqueous solution of sodium hydrogencarbonate, followed by extraction with 50 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then distilled off, whereby 3-{2(1-pyrrolidinylmethyl)butyryl}-1,2-benzisoxazole was obtained as oil.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].N1C=CC=CC=1.[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41])=[O:36].[OH2:54]>ClCCl>[F:19][C:18]([F:21])([F:20])[C:14]([OH:36])=[O:54].[Cl:26][C:23]1[CH:24]=[CH:25][C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[O:36])[CH:38]=2)=[C:3]([C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)[CH:22]=1
Reactant: O
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccn(-c3cccc(C(F)(F)F)c3)n2)c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 6d (150 mg, 0.39 mmol, 1.00 equiv) in dichloromethane (6 mL), and pyridine (93.6 mg, 1.18 mmol, 3.00 equiv). To this was added dropwise, a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoyl chloride 1f (147 mg, 0.47 mmol, 1.20 equiv) in dichloromethane (2 mL) over 10 min with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 2 mL of water, and adjusted to pH 8 with NH3H2O (2 mol/L). The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. The crude product (150 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 67.2 mg (22%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.67 (s, 1H), 11.54 (s, 1H), 9.62 (s, 1H), 8.68-8.67 (d, J=2.7 Hz, 1H), 8.71-8.38 (d, J=9.0 Hz, 1H), 8.16-8.02 (m, 5H), 7.79-7.65 (m, 5H), 6.968-6.960 (d, J=2.4 Hz, 1H), 4.01(s, 2H), 3.84 (s, 2H), 3.42 (s, 6H), 3.18 (s, 2H), 2.98(s, 3H). MS (ES, m/z): 655 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[C:11]([CH3:25])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.O.NN>C1COCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:25])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2cccc(F)c2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of 2-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-isoindole-1,3-dione (6.3 g, 19 mmol) in THF (252 mL) and ethanol (22 mL) at 0° C. was added hydrazine hydrate (7.0 g, 6.8 mL, 140 mmol) and the resulting mixture stirred at room temperature overnight. The mixture was then filtered and the filtrate diluted with HCl (1 N) and extracted with ethyl acetate. The combined organic extracts were then washed with HCl (1 N) and the aqueous layer made basic with NaOH (6 N). The aqueous layers were extracted with ethyl acetate and the combined organic layers washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (NH2—SiO2, dichloromethane) afforded the title compound (3.0 g, 77%) as a yellow oil. MS: m/e=207.3 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](O)=[O:41])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2].[NH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH2:51])=[O:50].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40](=[O:41])[NH:47][C:48]([C:49](=[O:50])[NH2:51])([CH3:53])[CH3:52])=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(N)C(N)=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)NC(C)(C)C(N)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]-methyl}-5-isopropyl-1H-pyrazole (0.2 g) in N,N-dimethyl-formamide (3 mL) were added 2-amino-2-methylpropionamide (47 mg), 1-hydroxybenzotriazole (50 mg), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (118 mg) and triethylamine (0.13 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over an hydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1) to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carbamoyl-1-(methyl)ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (0.12 g). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.06 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.1 mL), and the resulting mixture was concentrated under reduced pressure. The residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@H:13]([O:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])[CH2:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:41][C:42](OC(C)=O)=[O:43].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CCOC(C)=O.O>[C:42]([O:38][CH2:37][C:36]([O:35][C@@H:13]([C:3]1[C:4]([CH3:12])=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Cl:1])[CH2:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:40])[CH3:39])(=[O:43])[CH3:41]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(C)(C)CO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC(C)(C)O[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1c(C)cc2ccccc2c1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At 23° C., a flask containing (S)-2-(1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropan-1-ol (1.31 g, 2.21 mmol) was charged with Ac2O (5.00 mL) immediately followed by pyridine (5.00 mL). 4-(N,N-dimethylamino)-pyridine (20 mg, 0.164 mmol) was added. After 1.5 h, the reaction was poured onto 50 mL of crushed ice and H2O. A white precipitate developed. EtOAc (50 mL) was added after several hours had passed. Solid NaHCO3 was added portionwise (bubbling) until the aq. layer had a pH of 9. The slurry was extracted with EtOAc (2×25 mL). The combined organic layers were washed with 1.0 M aq. CuSO4 monohydrate (3×25 mL) and H2O (25 mL). The final organic phase was dried over Na2SO4, filtered, and concentrated. The residue was treated with benzene and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (S)-2-(1-(1-chloro-3-methylnaphthalen-2-yl)-2-(trityloxy)ethoxy)-2-methylpropyl acetate. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=8.6 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.52-7.41 (m, 9H), 7.26-7.16 (m, 9H), 5.99 (dd, J=8.2, 4.7 Hz, 1H), 4.02 (app. s, 2H), 3.55 (dd, J=8.6, 8.4 Hz, 1H), 3.12 (dd, J=9.8 Hz, 4.7 Hz, 1H), 2.52 (s, 3H), 1.86 (s, 3H), 1.32 (s, 3H), 1.15 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)[N:9]=3)[CH:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.8) (0.385 g, 0.9 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.19 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.4 g), which was subsequently deprotected.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][N:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(C(F)(F)F)n2)CC1
Yield: 45.3 %

Procedure:
To a tetrahydrofuran solution (1.0 mL) of 3-(trifluoromethyl)-1H-pyrazole (272 mg, 2.00 mmol), tert-butyl 4-hydroxy-piperidine-1-carboxylate (402 mg, 2.00 mmol), and triphenylphosphine (629 mg, 2.40 mmol), diisopropyl azodicarboxylate (1.36 mL, 2.60 mmol, toluene solution) was added at room temperature and the resultant solution was stirred at room temperature for 22 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain the title compound (289 mg, yield 45%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[Br:10]Br.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1.[CH2:29]([OH:32])[CH2:30]O>O>[Br:10][CH2:8][C:7]1([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:32][CH2:29][CH2:30][O:9]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(Cl)s1
Reactant: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Clc1ccc(C2(CBr)OCCO2)s1
Yield: 64.5 %

Procedure:
57 Parts of 1-(5-chloro-2-thienyl)-1-ethanone are dissolved in 220 parts of 1,2-ethanediol at 50° C. While stirring, there are added dropwise, during a 1 hour-period, 64 parts of bromine without external heating. After stirring for 1 hour at room temperature, 4 parts of 4-methylbenzenesulfonic acid and 360 parts of benzene are added. The whole is stirred and refluxed overnight with water-separator. The reaction mixture is evaporated and the residue is taken up in 2,2'-oxybispropane. The resulting solution is washed successively once with a diluted sodium hydroxide solution and three times with water, dried, filtered and evaporated. The residue is distilled, yielding 73.3 parts (64.5%) of 2-(bromomethyl)-2-(5-chloro-2-thienyl)-1,3-dioxolane; bp. 125° -127° C. at 0.1 mm. pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.ClC(OCC(C)C)=O.C[Si]([CH:38]=[N+:39]=[N-:40])(C)C>O1CCCC1.C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[CH:38]=[N+:39]=[N-:40])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
A solution of (R)-(+)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.00 g, 4.4 mmol) in dry tetrahydrofuran (9.6 mL) was cooled to 0° C. and treated with diisopropylethylamine (0.95 g, 1.3 mL) and isobutyl chloroformate (0.89 g, 0.86 mL, 6.5 mmol). A white suspension formed, which was stirred at 0° C. for 4 h. The mixture was then diluted with acetonitrile (6.6 mL) until a clear solution was obtained. A cooled (0° C.) solution of trimethylsilyl diazomethane (2N in hexanes, 4.4 mL, 8.7 mmol) in dry tetrahydrofuran (3 mL) and acetonitrile (3 mL) was added to the reaction mixture during 3 min. The mixture was then stirred at 0° C. for 3 h, and at room temperature for 16 h. The volatiles were evaporated and the residue purified by flash chromatography (heptane/ethyl acetate gradient) to yield 2-(2-diazo-acetyl)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.26 g, 23%), MS (ISP): 254.14 (M+H)+..
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:12]([I:13])=[C:11]([CH3:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].O>C(O)C>[I:13][C:12]1[C:11]([CH3:14])=[CH:10][CH:9]=[C:6]2[C:5]=1[NH:3][N:2]=[C:7]2[NH2:8]
Reactant: Cc1ccc(C#N)c(F)c1I
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(N)n[nH]c2c1I
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A solution of hydrazine monohydrate (0.56 mL, 11.6 mmol) and 2-fluoro-3-iodo-4-methylbenzonitrile (WO2006094187, 1.00 g, 3.8 mmol) in ethanol (7 mL) was stirred and heated to 100° C. in a sealed tube. After stirring overnight, the mixture was cooled and water was added. The resultant precipitate was filtered, washed with water and hexanes, and then dried in vacuo to give the title compound (0.91 g, 87%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9]O)=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1.S(Cl)([Cl:15])=O>C(Cl)Cl.N1C=CC=CC=1.CCOCC>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][Cl:15])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1
Reactant: Cn1nc(Cl)c(Cl)c1SCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cn1nc(Cl)c(Cl)c1SCCCl

Procedure:
To a stirred mixture of 48.4 g (0.213 moles) 1-methyl-3,4-dichloro-5-(2-hydroxyethylthio)pyrazole and 50 ml thionyl chloride in 200 ml methylene chloride, about 1 ml pyridine was added. The reaction mixture was heated at reflux for about 12 hours over 2 days time. The solvent was stripped, and the residue was taken up in ether. The etheral solution was washed 5 times with water and then dried over magnesium sulfate. Stripping of the ether gave 52.2 g of the product as a brown-red oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[F:9][C:10]([F:17])([F:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([F:17])([F:16])[F:9])=[N:6][CH:7]=1
Reactant: FC(F)(F)[C@@H]1CCCN1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: FC(F)(F)[C@@H]1CCCN1c1ncc(Br)cn1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
A flask was charged with 5-bromo-2-chloropyrimidine (36.62 g, 189 mmol), (S)-2-(trifluoromethyl)pyrrolidine (34.2 g, 246 mmol), potassium carbonate (39.2 g, 284 mmol)) and t-amyl alcohol (189 mL). The reaction mixture was stirred at 85° C. for 72 hours. The reaction mixture was then filtered over Celite®, washed with CH2Cl2 (2×) and concentrated in vacuo. The crude residue was redissolved in CH2Cl2 and washed with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give crystalline solids. The solids were washed with cold water (3×) and triturated with toluene to give the title product as pale orange crystals, 43.4 g (147 mmol, 77%); 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 2H), 5.06-4.83 (m, 1H), 3.71-3.44 (m, 2H), 2.30-1.89 (m, 4H); m/z found [M+H]+=295.99.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18].[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:25]/[S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])/[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)Cc2ccccc2)ccc1F
Reactant: CC(C)(C)[S@](N)=O
Solvent: C1CCOC1
Product: COc1cc(/C(Cc2ccccc2)=N/[S@](=O)C(C)(C)C)ccc1F
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a solution of 1-(4-fluoro-3-methoxyphenyl)-2-phenylethanone (13 g, 53 mmol) dissolved in THF (266 mL) was added (R)-2-methylpropane-2-sulfinamide (7.8 g, 64 mmol) at rt, followed by Ti(OEt)4 (17 mL, 80 mmol). The reaction mixture was heated to reflux for 48 h, then allowed to cool to rt. The reaction mixture was concentrated under reduced pressure and the residue was diluted with Et2O. H2O was added and the solid was filtered and washed with Et2O. The filtrate was washed with H2O, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, eluting with 0-100% EtOAc/hexane) to yield (R,E)-N-(1-(4-fluoro-3-methoxyphenyl)-2-phenylethylidene)-2-methylpropane-2-sulfinamide (12 g, 67% yield). LCMS: RT=3.655 min [M+H] 348.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); 1H NMR (500 MHz, CDCl3) δ ppm 7.60-7.53 (m, 1H), 7.43-7.36 (m, 1H), 7.29-7.15 (m, 5H), 7.03 (dd, J=11, 8 Hz, 1H), 4.75 (d, J=15 Hz, 1H), 4.54 (d, J=15 Hz, 1H), 3.84 (s, 3H), 1.34 (s, 9H).