Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[C:30]1([CH3:39])[CH:35]=[CH:34][CH:33]=[C:32]([C:36](Cl)=[O:37])[CH:31]=1>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[C:13](=[O:29])[C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:36](=[O:37])[C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH3:39])[CH:31]=3)[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Triethylamine (0.5 g, 5.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and m-toluoyl chloride (0.4 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (20 mL). The residue was dissolved in CH2Cl2 (80 mL), washed with H2O (30 mL) and brine (30 mL), and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (silica gel) to N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3 dihydro-1H-isoindol-4-ylmethyl]-3-methyl-benzamide (0.5 g, 66%) as a white solid: mp 218-220° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.37 (s, 3H, CH3), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.94 (d, J=5.7 Hz, 2H, CH2), 5.14-5.21 (dd, J=5.4 and 12.7 Hz, 1H, CH), 7.37-7.41 (m, 2H, Ar), 7.72-7.86 (m, 5H, Ar), 9.10 (t, J=5.6 Hz, 1H, NH), 11.14 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.91, 21.98, 30.93, 38.30, 48.87, 121.82, 124.42, 127.10, 127.83, 128.24, 131.52, 131.98, 132.99, 133.92, 134.77, 137.64, 139.39, 166.71, 166.96, 167.53, 169.81, 172.73; Anal. calcd. for C22H19N3O5+0.04H2O: C, 65.06; H, 4.74; N, 10.35. Found: C, 64.75; H, 4.68; N, 10.02.
Reaction SMILES: [H-].[Na+].[CH2:3](P([O-])(=O)[O-])[P:4]([O:9][CH2:10][CH3:11])(=[O:8])[O:5][CH2:6][CH3:7].C([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)C1C=CC=CC=1>O1CCCC1>[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:3][P:4](=[O:8])([O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH2:25][CH2:24]1
Reactant: CCOP(=O)(CP(=O)([O-])[O-])OCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(CC1CCNCC1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.11 g (528 mmol) of 60% strength sodium hydride are initially charged in 50 ml of absolute tetrahydrofuran, and 15.7 g (52.8 mmol) of diethyl methanediphosphonate are added dropwise. The mixture is stirred at room temperature for another 30 minutes, and 10.1 g (52.8 mmol) of 1-benzyl-4-piperidone are then added. The mixture is stirred for one hour at room temperature and for one hour under reflux, concentrated, admixed with water and extracted three times with dichloromethane, and the organic phases are dried over sodium sulphate and concentrated. The residue is hydrogenated in 50 ml of ethanol over 1.7 g of 10% palladium-carbon at room temperature and 3 bar. The catalyst is filtered off with suction and the filtrate is concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1.O.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:22][C:13]1[C:12]([O:11][CH2:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([C:31]4[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:32]=4)=[CH:23][C:6]=3[N:7]=2)=[CH:20][CH:19]=[C:18]([F:21])[C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: COc1cccc(B(O)O)c1
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2ccc3sc(COc4ccc(F)c(C(N)=O)c4F)nc3c2)c1
Temperature: 120 °C
Yield: 43.5 %

Procedure:
To the solution of compound 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.300 g, 0.755 mmol) in dry DMF:H2O (5 mL: 2.5 mL), added 3-methoxyphenyl boronic acid (0.228 g, 1.5 mmol), and K3PO4 (0.190 g, 0.9 mmol) under the inert condition at room temperature and degassed for half an hour. Then to the reaction mixture added dichlorobis[(triphenylphosphine)-palladium (II) (0.078 g, 0.075 mmol) and again degassed for half an hour. The reaction mixture was heated at 120° C. for 2 hrs under nitrogen atmosphere. DMF was distilled off, after cooling to r.t. water was added into reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by chromatography on silica (230-400μ) using ethyl acetate/hexane (50:50 as the eluent to provide the title compound as white solid (0.140 g, 43%). 1H NMR (DMSO-d6, 400 MHz); δ 3.85 (s, 3H), 5.72 (s, 2H), 6.97 (t, 1H, J=6.8 Hz (o-coupling), 7.11 (t, 1H, J=8.8 Hz, (o-coupling), 7.30 (broad s, 1H), 7.34 (d, 1H, J=8.8 Hz (o-coupling), 7.40 (dd, 2H, J=8.0 Hz (o-coupling), 7.79 (d, 1H, J=8.0 Hz (o-coupling), 7.90 (broad s, 1H), 8.18 (broad s, 1H), 8.21 (d, 1H, J=8.0 Hz); MS ES+ (427.14), HPLC (method 5) Rt=16.48 min.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=1.[OH-].[Na+].Cl>CCO>[CH2:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:14])=[O:2])[CH:11]([CH3:13])[CH3:12]
Reactant: COC(=O)c1cccc(CC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
94A (1.07 g, 5.5 mmol) was suspended in EtOH (10 mL) and aqueous NaOH (1 M, 20 mL) and was heated to 80° C. for forty-five minutes. Upon cooling to room temperature, the solution was acidified with HCl (conc.), was cooled to 0° C., and was filtered. The white crystalline precipitate was dried under vacuum (262 mg, 27%). NMR 1H (ppm, CDCl3): 7.94-7.89 (m, 2H), 7.39-7.33 (m, 2H), 2.53 (d, J3=7.2 Hz, 2H), 1.94-1.85 (m, 1H), 0.90 (t, J3=6.6 Hz, 6H).
Reaction SMILES: O.Cl.[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].O.C(O[CH:16](OCC)[CH2:17][CH:18](OCC)OCC)C>C(O)C>[C:3]1([CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:18]=[CH:17][CH:16]=[N:10]1
Reactant: CCOC(CC(OCC)OCC)OCC
Reactant: Cc1ccccc1NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-n1cccn1
Yield: 83 %

Procedure:
Into a 1 liter, 2-neck flask, fitted with a condenser and a magnetic stirrer, is successively added 90.0 g. (0.570 M.) of o-tolyl-hydrazine hydrochloride hydrate, 100 ml. of water, 63 ml. of 100% ethanol and 139.0 g. (0.633 M.) of 1,1,3,3-tetraethoxypropane. The reaction mixture is then heated slowly to between 80° C. and 90° C., and after maintaining the mixture at this temperature range for a period of about 3 hours, the reaction mixture is quenched on ice water and extracted with ethylacetate/ether. After drying the organic solution over anhydrous sodium sulfate, the solvents are evaporated to obtain a very dark liquid. Distillation in an air oven at a temperature between 110°-120° C. and a pressure of 1 mm. of Hg. yielded a light yellow oil (Yield: 83%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH2:22]([O:29][C:30]1[C:31]([CH3:38])=[CH:32][C:33]([F:37])=[C:34]([CH:36]=1)[NH2:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC>CN(C=O)C.C(O)(C)C>[C:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:35][C:34]3[CH:36]=[C:30]([O:29][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:31]([CH3:38])=[CH:32][C:33]=3[F:37])=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: Cc1cc(F)c(N)cc1OCc1ccccc1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: COc1cc2c(Nc3cc(OCc4ccccc4)c(C)cc3F)ncnc2cc1OC(C)=O
Yield: 41.6 %

Procedure:
A mixture of 7-acetoxy-6-methoxy-3,4-dihydroquinazolin-4-one (1.69 g, 7.2 mmol), thionyl chloride (50 ml) and DMF (3 drops) was heated at reflux for 2 hours. The excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The residue was partitioned between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried (MgSO4) and the solvent removed by evaporation. 5-Benzyloxy-2-fluoro-4-methylaniline (1.8 g, 7.8 mmol) in isopropanol (50 ml) was added to the residue and the mixture heated at reflux for 2 hours. The mixture was allowed to cool, hexane added and the precipitated product collected by filtration to give 7-acetoxy-4-(5-benzyloxy-2-fluoro-4-methylanilino)-6-methoxyquinazoline (1.34 g, 43%).
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OC)(C)(C)C>[CH3:23][S:24]([O:1][C@@H:2]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5])(=[O:26])=[O:25]
Reactant: CCC[C@@H](O)c1ccc(C(=O)OC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCC[C@@H](OS(C)(=O)=O)c1ccc(C(=O)OC)cc1

Procedure:
To a solution of (R)-methyl 4-(1-hydroxybutyl)benzoate, intermediate (26) (10 g, 48 mmol) in methyl t-butyl ether (80 mL) containing triethylamine (6.32 g, 62 mmol) was added methanesulfonyl chloride (6.05 g, 53 mmol) slowly at 20° C. The solution was filtered to remove triethylamine salts and the solution used in the next step without isolation.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][C:11]1[CH:12]=[C:13]([OH:19])[C:14](=[CH:16][C:17]=1[CH3:18])[OH:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][C:11]1[C:17]([CH3:18])=[CH:16][C:14]2[O:15][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][O:19][C:13]=2[CH:12]=1
Reactant: Cc1cc(O)c(O)cc1C
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2cc(C)c(C)cc2O1
Temperature: 30 °C

Procedure:
86 g of ethyl 2,3-dibromopropionate was added, over a 15-minute period, to a stirred mixture of 41 g of 6A, 97 g of potassium carbonate and 300 ml of acetone. The temperature of the mixture rose to 60° C. The mixture was refluxed for 19 hours, cooled to 30° C. and filtered. The solvent was evaporated from the filtrate under reduced pressure. The residue was recrystallized from hexane to give 6, mp: 71°-72° C.
Reaction SMILES: [CH:1](N1CCCCC1)=[O:2].[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([Li])=[C:22]([F:27])[C:21]=2[F:28])=[CH:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].C1C=CC=CC=1.C([Li])CCC>O1CCCC1.O1CCCC1.CN(C)CCN(C)C>[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:1]=[O:2])=[C:22]([F:27])[C:21]=2[F:28])=[CH:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=CN1CCCCC1
Reactant: [Li]c1ccc(C2=CCC(CCCCC)CC2)c(F)c1F
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCC1CC=C(c2ccc(C=O)c(F)c2F)CC1
Temperature: -20 °C

Procedure:
0.12 mol of N-formylpiperidine in 20 ml of tetrahydrofuran is added at -70° C. to 0.1 mol of 4-(4-pentylcyclohex-1-enyl)-2,3-difluorophenyllithium (prepared from the benzene with n-butyllithium in tetrahydrofuran/tetramethylethylenediamine analogously to Example 1a)) and the mixture is warmed to -20° C. during the course of 1 hour. Acidifying and customary working up gives the aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)[N:14]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1cccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CCc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
tert-Butyl 4-(4-((4-((3-(methoxycarbonyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I32) (0.180 g, 0.309 mmol) was dissolved in dry DMF (10 mL) under an atmosphere of nitrogen. 10% Pd/C (0.100 g) in EtOAc (10 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours after which the reaction was flushed with nitrogen gas and Pearlman's catalyst (0.150 g) in EtOAc (5 mL) was added. The atmosphere was again changed to hydrogen gas (balloon) and the reaction was sealed with balloon and stirred for 20 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5×10 mL). The solvent was removed in vacuo to give a yellow oil which was purified by silica gel chromatography (Biotage Isolera, 40 g Si Cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I33) (0.120 g, 66% yield) as a yellow foam; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.60 (s, 1H), 7.88-7.77 (m, 2H), 7.61-7.39 (m, 4H), 6.93 (d, J=9.1 Hz, 2H), 3.85 (s, 3H), 3.52-3.42 (m, 4H), 3.21-2.99 (m, 8H), 1.42 (s, 9H). LCMS Method C: rt 6.86 min; m/z 586.3 [M+H]+.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[CH2:9]([OH:11])[CH3:10].[C:12]1([CH2:22][C:23]([OH:25])=O)[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([OH:21])=O>O>[CH2:9]([O:11][C:19]([CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][C:23]1=[O:25])=[O:21])[CH3:10]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1C(=O)Cc2ccccc21

Procedure:
To a stirred mixture of sodium hydride (126 g. of a 57% suspension in nujol), 2000 ml. of benzene and 2 ml. of ethanol heated at its reflux temperature under dry nitrogen is added dropwise the diethyl ester of o-phenylene-diacetic acid (335.6 g.) in 700 ml. of benzene. The mixture is refluxed 1.5 hours, poured into water and extracted with ether. The ether extracts are dried and concentrated to give an oil which is crystallized from ethanol-water to give 220 g. of the title product with m.p. 58°-61°.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[C:13]1([S:19][CH2:20][CH:21]([OH:24])[CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:24][CH:21]([CH2:20][S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:22][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: OCC(O)CSc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCO
Product: Clc1ccc(C2(CBr)OCC(CSc3ccccc3)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 11.1 parts of 3-(phenylthio)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is evaporated and the residue is dissolved in trichloromethane. The solution is stirred with silica gel for 30 minutes. The latter is filtered off and the filtrate is evaporated, yielding A + B 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(phenylthiomethyl)-1,3-dioxolane as a residue.
Reaction SMILES: [Na].Cl.[CH3:3][C:4]([CH3:17])([CH:11](Cl)[CH:12]=[C:13]([Cl:15])[Cl:14])[CH2:5][C:6]([O:8][CH2:9]C)=[O:7]>CO>[CH3:3][C:4]1([CH3:17])[CH:11]([CH:12]=[C:13]([Cl:15])[Cl:14])[CH:5]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C1C(C=C(Cl)Cl)C1(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
0.4 Part of metallic sodium was dissolved in 30 parts of anhydrous methanol, and 2.7 parts of ethyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate prepared in the same manner as in Example 3 was added to the solution. The mixture was agitated for 2 hours under reflux of methanol. The liquid reaction mixture was cooled with ice water and neutralized with hydrogen chloride-saturated methanol. The precipitated solids were removed by filtration, and the filtrate was concentrated until the volume was reduced to 1/10. The concentrate was diluted with diethyl ether, washed with water and dried. Then, the solvent was removed by distillation, and the residue was subjected to distillation under reduced pressure to obtain 2.0 parts of methyl 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-carboxylate having a boiling point of 68° - 70° C. under 0.2 mm Hg. The yield was 90 %. the cis : trans ratio of the product determined by gas chromatography was 22 : 78.
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:28])[NH:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N+:2]=[N-:3].[CH2:29]([O:32][C:33]1[CH:45]=[CH:44][C:36]2[N:37]=[C:38]([S:40]([NH2:43])(=[O:42])=[O:41])[S:39][C:35]=2[CH:34]=1)[C:30]#[CH:31].CCN(C(C)C)C(C)C>[Cu]I.C1COCC1>[O:28]=[C:5]([NH:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:4][N:1]1[CH:31]=[C:30]([CH2:29][O:32][C:33]2[CH:45]=[CH:44][C:36]3[N:37]=[C:38]([S:40](=[O:42])(=[O:41])[NH2:43])[S:39][C:35]=3[CH:34]=2)[N:3]=[N:2]1
Reactant: C#CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Reactant: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)CN=[N+]=[N-]
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCOCCOCCOCCCNC(=O)Cn1cc(COc2ccc3nc(S(N)(=O)=O)sc3c2)nn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar, rubber septum, and argon inlet containing tert-butyl 1-azido-2-oxo-7,10,13-trioxa-3-azahexadecan-16-ylcarbamate (130 mg, 0.36 mmol), 6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (Alkyne, 107 mg, 0.4 mmol), CuI (6.9 mg, 0.036 mmol), and THF (3 mL) was added DIPEA (52 mg, 0.4 mmol). The mixture was stirred at rt for 15 h and concentrated. The crude material was purified with silical chromatography (gradient 10% to 90% EtOAc in hexane) to afford compound 142 as a clear wax (125 mg, 52%). MS (ESI) m/z 694(M+Na+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][NH:26][N:25]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:26]2[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:24]([C:21]3[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=3)=[N:25]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccc(F)cc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.8 %

Procedure:
A mixture of 4-benzyloxybenzyl chloride (11.60 g), ethyl 3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (11.70 g), potassium carbonate (13.80 g) and N,N-dimethylformamide (150 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain ethyl 1-(4-benzyloxybenzyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carboxylate (16.90 g, yield: 79%). This was recrystallized from ethyl acetate-hexane. Melting point: 103–104° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[S:5])[CH3:2].[NH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1)=[S:5])[CH3:2]
Reactant: Nc1nccs1
Reactant: CCN=C=S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNC(=S)Nc1nccs1
Temperature: 25 °C
Yield: 12.8 %

Procedure:
A solution of ethyl isothiocyanate (1.74 g, 20 mmol) and 2-aminothiazole (2.0 g, 20 mmol) in N,N-dimethylformamide (50 mL) was heated at 100° C. for 23 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the residue recrystallized twice from ethyl acetate to provide 0.48 g (13%) of the title product:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4](=O)[CH:5]([CH3:18])[C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[CH3:21][NH:22][NH2:23]>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:18])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:22]([CH3:21])[N:23]=1)=[O:20]
Reactant: CNN
Reactant: COC(=O)C(=O)C(C)C(=O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1nn(C)c(-c2cccc(C(F)(F)F)c2)c1C

Procedure:
A solution of 500 mg (2.47 mmol) of trifluoromethylpropiophenone and 0.335 mL (2.47 mmol) of diethyloxalate in 10 mL of MeOH was treated with 133 mg (2.47 mmol) of sodium methylate and stirred at room temperature for 3 hrs. The reaction was quenched by the addition of 10% aqueous KHSO4 and extracted with EtOAc (3×). The organic phases were washed with 10% aqueous KHSO4 and brine, dried over magnesium sulfate and evaporated to give crude 3-methyl-2,4-dioxo-4-(3-trifluoromethyl-phenyl)-butyric acid methyl ester. In analogy to the procedure described in Example 16A], crude 3-methyl-2,4-dioxo-4-(3-trifluoromethyl-phenyl)-butyric acid methyl ester and methylhydrazine gave after purification by flash column chromatography (n-heptane/AcOEt 2:1) 79.2 mg (3%) of the title compound as a rose powder. MS: 299.1 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:14][N:15](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:14]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)nc(OC)c1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Under N2, methyl 2-chloro-6-methoxyisonicotinate (CAS 42521-10-8) (3.97 g, 19.7 mmol, Eq: 1.00), zinc cyanide (2.77 g, 23.6 mmol, Eq: 1.2) and Tetrakis-triphenylphosphin-palladium (1.14 g, 985 μmol, Eq: 0.05) were mixed in DMF (67.5 ml). The RM was stirred under microwave at 160° C. for 30 minutes. Control with LC-MS: the reaction was finished.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]=[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=1[O:28][CH2:29][CH3:30])[CH3:6].Cl>CO.[OH-].[Na+]>[CH2:29]([O:28][C:17]1[C:18]([CH:25]([CH3:27])[CH3:26])=[CH:19][C:20]([CH:22]([CH3:23])[CH3:24])=[CH:21][C:16]=1[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:31])=[O:2])[CH:8]=2)[NH:12][N:11]=1)[CH3:30]
Reactant: CCOc1c(-c2n[nH]c3ccc(C(C)=CC(=O)OC)cc23)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1c(-c2n[nH]c3ccc(C(C)=CC(=O)O)cc23)cc(C(C)C)cc1C(C)C
Yield: 10 %

Procedure:
A solution of 3-[3-(2-ethoxy-3,5-diisopropyl-phenyl)-1H-indazol-5-yl]-but-2-enoic acid methyl ester in 2 ml of methanol and 2 ml of 1N NaOH solution was heated to 60° C. for 3 h, then cooled and brought to pH 7 with 1N HCl. The reaction mixture was extracted with ethyl acetate (2×10 mL), and the organic layers were dried over MgSO4 and evaporated to a residue. The residue was purifed by silica gel chromatography (50% ethyl acetate in hexanes) to give a white solid (6.1 mg, 10%).