Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]C(N)=N)=[CH:5][CH:4]=1.O=[C:15]1[N:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[C:17](=[O:31])O1.[N:32]1C=CC=CC=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:15]2[N:20]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:19]3[C:18]([C:17](=[O:31])[N:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cn1c(=O)oc(=O)c2ccccc21
Reactant: c1ccncc1
Reactant: N=C(N)CCc1ccc(F)cc1
Agent: Cl
Product: CCOC(=O)Cn1c(CCc2ccc(F)cc2)nc(=O)c2ccccc21
Yield: 36 %

Procedure:
A solution of 3-(4-fluorophenyl)-propionamidine hydrochloride (Int. A108) (0.42 g, 2.05 mmol) and ethyl 2-(2,4-dioxo-4H-benzo[d][1,3]oxazin-1-yl)-acetate (0.51 g, 2.05 mmol) in pyridine (20 ml) was heated at reflux for 16 h, allowed to cool then concentrated in vacuo. The residues were chromatographed over silica eluting with ethyl acetate to yield the product as a white solid (0.26 g, 36%). 1H-NMR (CDCl3) δ 1.24 (3H, t,), 3.0 (2H, m), 3.17 (2H, m), 4.24 (2H, q), 5.29 (2H, s), 6.95 (2H, m), 7.2-7.3 (3H, m), 7.40 (1H, m), 7.67 (1H, m), 8.29 (1H, dd); MS (APCI+) found (M+1)=355; C20H19FN2O3 requires 354.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23]>O1CCCC1>[O:8]([C:5]1[N:6]=[CH:7][C:2]([CH:22]=[O:23])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccc(Oc2ccccc2)nc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccccc2)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 5-bromo-2-phenoxy-pyridine described in Manufacturing Example 231-1-1 (18.7 g, 74.6 mmol) in tetrahydrofuran (360 mL) was added n-butyl lithium (31.1 mL, 2.64 M hexane solution, 82.1 mmol) under nitrogen atmosphere at −78° C., which was stirred for 30 minutes at −78° C. To this reaction solution was added N,N-dimethylformamide (7.46 mL, 97 mmol) at −78° C., which was stirred for 1 hour at this temperature. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the title compound (4.75 g, 32%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[CH2:8]([N:33]1[C:29](=[O:39])[C:30]2[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32]1=[O:34])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: OCCc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1ccccc1
Reaction time: 2.5 h

Procedure:
After 2-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (775 mg, 2.95 mmol), phthalimide (434 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (697 mg, 2.95 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 2.5 hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using ethyl acetate (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 30% ethyl acetate-hexane solution) to give 2-phenethyl isoindole-1,3-dione as a white solid substance (579 mg, yield: 94%/2-phenylethyl alcohol).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C(O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N=Cc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of 4-methanesulfonyl-phenylamine (5.6 g, 33 mmol) and 3-nitro-benzaldehyde (5.45 g, 36 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 16 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford (4-methanesulfonyl-phenyl)-(3-nitro-benzylidene)-amine (10 g, 99%) as a white solid: LC/MS m/e calcd for C14H12N2O4S (M+H)+: 305.33, observed: 305.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:24]([S:25][C:26]3[C:34]([Br:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:36])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[C:24]([S:25][C:26]3[C:34]([Br:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[NH2:36])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Nc1ccc(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 154.5 %

Procedure:
To a solution of (4-{2-[6-Amino-8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)purin-9-yl]-ethyl}-phenyl)-carbamic acid tert-butyl ester (0.03 g, 0.04 mmol) in dichloromethane (4.3 mL) was added TFA (0.02 mL, 0.22 mmol) and the reaction mixture was stirred at rt overnight. At the end of this period, reaction was diluted with 100 mL of toluene and then concentrated under reduced pressure. This process was repeated 3 more times to yield the title product (0.03 g, 95%) as TFA salt. 1H NMR (DMSO-d6) δ 8.19 (s, 1H), 7.24 (s, 1H), 7.19-7.02 (m, 4H), 7.00 (s, 1H), 6.13 (s, 2H), 4.45 (t, J=6.8 Hz, 2H), 3.18 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 486.3.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Cc1c([N+](=O)[O-])ccc2c1CCN2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: Cc1c([N+](=O)[O-])ccc2[nH]ccc12
Yield: 88.1 %

Procedure:
To a suspension of 4-methyl-5-nitroindoline (4.767 g, 0.0268 mol) in 100 mL of methanol was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.697 g, 0.0295 at room temperature for 1 h. The reaction mixture was then evaporated and the residue was taken up in dichloromethane. This solution was then washed with saturated aqueous NaHCO3 (×4), dried (Na2SO4) and evaporated to give a solid. Crystallization of this material from ethyl acetate-hexane (-20° C.) afforded 4.161 g of the title compound as greenish-gold needles, mp 179°-180° C. Chromatography of the mother liquor (SiO2 /ethyl acetate-hexane, 1:1) gave an additional 0.417 g of the pure product. Total yield=4.578 g (97%): IR (KBr) 3318, 1604, 1585 cm- ; 1H NMR (DMSO-d6, 200 MHz) δ 11.72 (br s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.56 (t, J=2.8 Hz, 1H), 7.39 (d, J=8.9 Hz, 1H), 6.79 (m, 1H), 2.75 (s, 3H). Anal. Calcd for C 9 H8N2O2 : C, 61.35; H, 4.58; N, 15.90. Found: C, 61.32; H, 4.40; N, 15.96.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(N(CC)CC)C>O1CCCC1.O>[Si:15]([O:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:10])([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(O)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed a solution of 1-phenylethane-1,2-diol (10 g, 72.38 mmol, 1.00 equiv), TBSCl (22 g, 145.97 mmol, 2.00 equiv) and triethylamine (14.7 g, 145.27 mmol, 2.00 equiv) in tetrahydrofuran (100 mL). The solution was stirred overnight at room temperature. The next day it was diluted with 150 mL of H2O and the mixture was extracted with 3×80 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10). Purification afforded 17 g (93%) of 2-[(tert-butyldimethylsilyl)oxy]-1-phenylethan-1-ol as a white oil.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(O)C.[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]1[O:11][CH2:10]1>>[CH2:13]([O:12][CH2:8][CH:9]([CH2:10][O:1][CH2:2][CH3:3])[OH:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOCC1CO1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(O)COCC
Temperature: 80 °C
Reaction time: 18 h
Yield: 319.6 %

Procedure:
Under nitrogen stream, 30 g of sodium ethoxide was added to 851.8 g (18.5 mol) of ethanol, and the mixture was heated to 80° C. Then, 500 g (1.85 mol) of tetradecyl glycidyl ether were added dropwise thereto. The mixture was stirred for 18 hours at the same temperature. Thereafter, ethanol was distilled off, and 10.8 g of 85% phosphoric acid was added thereto, followed by washing the resultant mixture with water three times. After water washing, distillation was performed under reduced pressure, to thereby obtain 446 g of 1-tetradecyl-3-ethylglycerol (yield 76.2%).
Reaction SMILES: [O:1]([C:9]1[CH:10]([CH:18]([CH:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[C:21]2[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH3:19])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Li]CCCC.Cl[Si:43]([CH3:46])([CH3:45])[CH3:44]>C1COCC1.CCCCCC>[CH3:44][Si:43]([CH3:46])([CH3:45])[CH:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([Si:2]([CH3:5])([CH3:4])[CH3:3])[C:21]=2[O:29][Si:30]([C:33]([CH3:35])([CH3:34])[CH3:36])([CH3:31])[CH3:32])[CH3:19])=[C:9]1[O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C1C(O[Si](C)(C)C(C)(C)C)=Cc2ccccc21)C1C(O[Si](C)(C)C(C)(C)C)=Cc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C1=C(O[Si](C)(C)C(C)(C)C)C([Si](C)(C)C)c2ccccc21)C1=C(O[Si](C)(C)C(C)(C)C)C([Si](C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of bis(2-(tert-butyldimethylsiloxy)indenyl)ethane (10.38 g, 20.0 mmol) in THF (100 mL) at −20° C. was added dropwise n-BuLi (16.1 mL of a 2.5 M solution in hexane, 40.2 mmol) and the reaction mixture was stirred for 3 hours at room temperature. To the resulting solution was added dropwise chlorotrimethylsilane (6.85 g, 63.0 mmol, 8.0 mL) at 0° C. After completed addition the reaction mixture was stirred overnight at room temperature and the solvents were evaporated. The remaining orange solid was extracted with CH2Cl2 and filtrated through celite. The solvent was evaporated and the product was dissolved in Et2O (150 mL). Concentration and cooling to 0° C. gave 10.29 g (77.6%) of a 2:1 diastereomeric mixture of the title compound as off-white crystals. EIMS (calcd/found): m/e 662.3827/662.3834. 1H NMR (CD2Cl2, δ, major/minor diastereomer): 7.51-7.49 (m, 2H, major); 7.42-7.40 (m, 2H, minor); 7.29-7.24 (m, 4+2H, major/minor); 7.22-7.17 (m, 2H, minor); 7.08-7.02 (m, 2+2H, major/minor); 3.29 (s, 1H, minor); 3.27 (s, 1H, major); 3.00-2.96 (m, AA′, 2H, minor); 2.72-2.65 (m, AA′BB′, 4H, major); 2.44-2.40 (m, BB′, 2H, minor); 1.02 (s, 18H, major); 1.01 (s, 18H, minor); 0.20 (s, 6H, minor); 0.19 (s, 6H, major); 0.10 (s, 6H, minor); 0.05 (s, 6H, major); 0.02 (s, 18H, minor); 0.01 (s, 18H, major). 13C NMR (CD2Cl2, δ, major diastereomer): 158.32; 144.56; 139.24; 125.09; 122.74; 121.98; 119.89; 118.08; 45.08; 26.14; 24.06; 18.52; −2.39; −3.40; −4.66. 13C NMR (CDCl3, δ, minor diastereomer): 158.08; 144.50; 139.14; 124.97; 122.62; 121.95; 119.95; 118.50; 45.13; 26.14; 23.86; 18.47; −2.29; −3.40; −4.24.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH:1]1([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCC2N1CCCCC1
Reaction time: 48 h

Procedure:
A mixture of 100 g. of 1-indanone (0.758 mole) and 125 ml. of piperidine in 750 ml. of toluene is treated with 0.5 g. of p-toluenesulfonic acid and heated under reflux with a water take-off trap attached. Heating is continued for 48 hours. Solvent and excess piperidine are removed in vacuo and the residue is dissolved in 1500 ml. of absolute methanol. The resulting solution is stirred and treated portionwise with 50 g. of sodium borohydride below 30° C. After stirring several hours longer, the mixture is treated with a small amount of acetic acid then made strongly basic by the addition of sodium hydroxide solution. After 400 ml. of water is added, most of the methanol is removed in vacuo. Product is extracted into ether, dried over potassium hydroxide and distilled. 119.7 g. of 1-(1-indanyl)piperidine is collected at 101°-102° (0.2 mm.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:27](=[O:28])[C:11]3=[CH:12][NH:13][C:14]([CH3:26])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24]O)=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Cl-].[Li+].CS([Cl:43])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:27](=[O:28])[C:11]3=[CH:12][NH:13][C:14]([CH3:26])=[C:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][Cl:43])=[CH:18][CH:17]=4)[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(C#CCO)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(C#CCCl)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.6 %

Procedure:
To a solution of the product of Example 68 (0.6 g, 1.5 mmol), 2,6-lutidine (0.72 ml, 6.2 mmol) and lithium chloride (0.262 g, 6.2 mmol) in N,N-dimethylformamide (6 ml) at 0° C. was added methanesulphonyl chloride (0.36 ml, 4.6 mmol) dropwise and the solution allowed to warm to ambient temperature with stirring for 7 hours. The solvent was removed in vacuo and the crude product purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) to give the product as a yellow solid (0.463 g, 74%). 1H NMR (360 MHz, DMSO-d6) δ12.49 (1H, br s), 8.59 (1H, s), 8.13 (2H, d, J 9.0 Hz), 7.59 (4H, m), 7.41 (2H, d, J 9.0 Hz), 4.75 (2H, s), 2.26 (3H, s); MS (ES+) m/z 408/410/412 [MH]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].O.[NH2:10][NH2:11]>C(O)C>[NH2:6][C:5]1[NH:11][N:10]=[C:3]([CH:2]([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)C(=O)CC#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)c1cc(N)[nH]n1
Temperature: 25 °C
Yield: 87 %

Procedure:
4-Methyl-3-oxopentanonitrile (A) was dissolved in ethanol (140 ml) and stirred at room temperature. Hydrazine hydrate (15.7 g) was added and the resulting mixture was stirred for 1 hour at room temperature, followed by heating under refluxing for 5 hours. The solvent was distilled off under reduced pressure and the residue was subjected to distillation under reduced pressure (133°-153° C./0.06 mmHg) to obtain 33.3 g (87%) of 5-amino-3-(1-methylethyl)pyrazole (B).
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1C=C[C:36]2N(O)N=[N:39][C:37]=2[CH:38]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.C1(N)CC1>CN(C=O)C>[CH:37]1([NH:39][C:6]([CH:4]2[CH2:5][C:2]([F:1])([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH2:19][C:18]([C:24]5[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=5)([C:20]([F:21])([F:22])[F:23])[O:17][N:16]=4)=[CH:13][CH:14]=3)[CH2:3]2)=[O:8])[CH2:38][CH2:36]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.1 g, 0.195 mmol) in DMF (3 mL) was added HOBt (0.026 g, 0.195 mmol), DIPEA (0.051 g, 0.391 mmol) followed by addition of EDCl.HCl (0.056 g, 0.293 mmol) and cyclopropyl amine (0.011 g, 0.195 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with EtOAc (5×20 mL). Combined organic layer was washed with saturated water (100 mL), brine (100 mL), dried over sodium sulphate and evaporated in vacuo to get a yellow semisolid (0.108 g, crude). Crude was purified by column chromatography on silica gel (100-200 mesh). Compound was eluted using 0.5% methanol in DCM to afford off white solid (0.020 g, 19%, CR963-125249-74-1). 1H-NMR (400 MHz, CDCl3) δ: 0.49-0.51 (m, 2H), 0.76-0.81 (m, 2H), 2.52-2.58 (m, 1H), 2.67-2.76 (m, 3H), 2.93-3.06 (m, 2H), 3.68 (d, 1H, J=17.04 Hz), 4.08 (d, 1H, J=17.16 Hz), 5.55 (bs, 1H), 7.51 (d, 2H, J=8.08 Hz), 7.63 (s, 2H), 7.68 (d, 2H, J=8.20 Hz); LC-MS (m/z): [M−H] 546.80.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][CH3:16])[C:11]([F:17])=[CH:10][C:9]=1[O:18][CH3:19].[OH2:20]>CO>[Br:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:16])(=[O:1])=[O:20])[C:11]([F:17])=[CH:10][C:9]=1[O:18][CH3:19]
Reactant: O=S([O-])OO
Reactant: COc1cc(F)c(CSC)cc1Br
Reactant: O
Agent: [K+]
Solvent: CO
Product: COc1cc(F)c(CS(C)(=O)=O)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
Oxone (20.9 g, 34.1 mmol) in H2O (100 mL) was added drop-wise to a solution of 1-bromo-4-fluoro-2-methoxy-5-(methylsulfanylmethyl)benzene (4.3 g, 16.2 mmol) in MeOH (100 mL) at 0° C. The mixture was then stirred at room temperature for 3 h and then poured into water. Extractive work up with ethyl acetate, washing with saturated aqueous Na2SO3 (40 mL) and brine, gave a solid that was triturated with 1:10/EA:MTBE to give the title compound (4.40 g, 93.0%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, J=8.0 Hz, 1H), 6.72 (d, J=11.2 Hz, 1H), 4.22 (s, 2H), 3.92 (s, 3H), 2.83 (s, 3H). LCMS: 318.9 (M+Na)+
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][CH3:15])[CH:6]=1>CN1CCCC1=O.O>[CH3:15][O:14][C:7]1[CH:6]=[C:5]([NH:2][NH2:3])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: NN
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(NN)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
4.5 ml of hydrazine hydrate were added dropwise to the solution of 3.2 g of 4-fluoro-2-methoxynitrobenzene in 15 ml of N-methylpyrolidone and the mixture was stirred for 2 hours, which initially resulted in gentle heating. The mixture was then diluted with 50 ml of water and stirred, and a precipitate formed which was filtered off with suction and dried under reduced pressure.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[O:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:42]3[CH2:43][CH2:44][C:39]4([O:35][CH2:36][CH2:37][CH2:38]4)[CH2:40][CH2:41]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: C1COC2(C1)CCNCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC4(CCCO4)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 1-oxa-8-aza-spiro[4.5]decane trifluoroacetate and N-ethyldiisopropylamine in chloroform. [α]D20=+25.8° (c=1.01, CHCl3), ES-MS m/e (%): 434 (M+H+, 100).
Reaction SMILES: [CH2:1](N(CCCC)CCCC)[CH2:2][CH2:3]C.[Cl:14][C:15]1[C:20]([O:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][C:18]([NH:27][C:28](=[O:32])[O:29][CH2:30][CH3:31])=[C:17]([F:33])[CH:16]=1.[OH:34]C(C(C)=C)C(OCC)=O.C(O)C>CCCCCC.C1(C)C=CC=CC=1>[Cl:14][C:15]1[C:20]([O:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)=[CH:19][C:18]([N:27]2[C:31](=[O:34])[C:30](=[C:2]([CH3:3])[CH3:1])[O:29][C:28]2=[O:32])=[C:17]([F:33])[CH:16]=1
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CCCCN(CCCC)CCCC
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCO
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 200 °C
Yield: 850.8 %

Procedure:
Ferric chloride hexahydrate (2.7 g, 0.01 mol), tributylamine (9.3 g, 0.05 mol) and ethyl N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)carbamate (151 g, 0.5 mol) were introduced into a three-necked flask (1 L) equipped with a mechanical stirrer and a Dean Stark, and the resulting mixture was heated to 200° C. with stirring to form a homogeneous solution. Then, ethyl 2-hydroxy-3-methyl-3-butenoate (108 g, 0.75 mol) was added dropwise over 4.8 hours, and after the addition, the solution was stirred for another 2 hours. The ethanol generated during the heating and stirring was distilled away by means of the Dean Stark. After completion of the reaction, the reaction mixture was allowed to cool to about 100° C., and then toluene (500 mL) was added to form a solution. The solution was washed with 1N hydrochloric acid (250 mL) and water (250 mL). The organic layer was concentrated under reduced pressure, and the resulting oily crude product was crystallized in ethanol (200 mL) acidified with sulfuric acid. The precipitated crystals were collected by filtration and washed with a small amount of acidic ethanol and then hexane to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (150.5 g, yield 85.1%) as white crystals.