Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[NH:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19](O)=O.C=O.[OH-].[Na+]>O1CCOCC1>[CH:1]1([CH2:7][CH:8]2[CH:13]([OH:14])[CH2:12][C:11]([CH3:16])([CH3:15])[N:10]([CH3:19])[C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(O)C(CC2CCCCC2)C(C)(C)N1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1C(C)(C)CC(O)C(CC2CCCCC2)C1(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Into a 100 ml-flask equipped with a thermometer, a cooling tube, a dropping funnel and a magnetic stirrer were introduced 3.8 g (15 mmol) of 3-cyclohexylmethyl-2,2,6,6-tetramethyl-4-piperidinol prepared in Example B1, 70 ml of dioxane and 0.78 g (17 mmol) of formic acid, and the content of the flask was heated to 80° C. When the temperature of the content of the flask was constant, 2.44 g (30 mmol) of 37% aqueous formaldehyde dissolved in 20 ml of dioxane was added gradually through the dropping funnel, followed by heating at the temperature for 10 hours. The content of the flask was cooled to room temperature, and 5% aqueous NaOH was added so that the pH became 8, followed by extraction with 200 ml of diethylether. The extract obtained was washed with 30 ml of water 3 times, 10 g of magnesium sulfate was added and, after it was kept standing for ca. 2 hours, the solution was filtered and concentrated to give 3.95 g (yield: 98%) of the title compound as a white solid product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](C)([CH2:9][C@H:10]1[CH2:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)[C:5](OC)=O.[Na+].[Cl-].CS(C)=O>O>[CH3:1][O:2][C:3](=[O:25])[CH:4]([CH3:5])[CH2:9][C@H:10]1[CH2:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:11]1
Reactant: COC(=O)C(C)(C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Yield: 39.5 %

Procedure:
The ester 92 (483 mg, 1.4 mmol), NaCl (104 mg, 1.8 mmol), water (105 μL) and DMSO (5 mL) were heated to reflux for 2 hours. The solution was cooled to room temperature water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (80% to 66% hexane/acetone) of the residue gave the product as an oil (160 mg, 40%). MS m/z 290 (M+H, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:21])=[CH:16][CH:15]=1.I[CH3:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:22]([CH3:35])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:32])([F:33])[F:31])=[O:21])=[CH:18][CH:19]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccccc4C(F)(F)F)cc3)c2)o1
Reactant: CI
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)Cc4ccccc4C(F)(F)F)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide and iodomethane using method L. NMR; δH [2H6]—DMSO 7.90,(1H, d), 7.80-7.51,(9H, m), 7.41,(1H, b), 4.89-4.71,(2H, m), 3.01-2.96,(3H, m), 2.56,(3H, s), 2.33-2.24,(3H, m). LCMS; retention time 3.62 min, MH+ 466.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Cl.[C:15]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[C:22](Cl)=[O:23])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([CH3:13])[C:11]([O:12][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([C:29]([CH3:30])([CH3:31])[CH3:32])[C:27]([OH:28])=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:20]=2)=[C:2]([CH3:1])[CH:3]=1
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.4 grams of methyl 3,5-dimethyl-4-hydroxybenzoate (0.03 moles) is dissolved in 30.8 ml of a 0.99 molar toluene solution of 3,5-di-tert.butyl-4-hydroxybenzoyl chloride and heated at reflux (119° C) for 2 and 1/2 hours the evolved hydrogen chloride being swept out of the reaction by a stream of nitrogen. After this period, sufficient toluene (ca 5 to 10 ml) is removed so as to raise the reaction temperature to 128° to 132° C and heating continued under a nitrogen atmosphere for an additional 2 hours. After cooling to room temperature, the reaction mixture is dissolved in 100 ml of toluene and successively and washed with 2N aqueous sodium hydroxide and then with water until the wash waters were neutral. The washed toluene solution was dried over anhydrous sodium sulfate, filtered and the solvent removed by distillation under vacuum at 50°-60° C initially at about 20 mm Hg. and finally at 0.3 mm Hg. The resulting residue is ground to a powder and triturated with boiling hexane. The ice-cold slurry is then filtered to yield light yellow crystals, which are then recrystallized from a solvent mixture of 50 ml of toluene and 40 ml of n-hexane. The crystals were filtered, washed with same solvent mixture and dried in vacuum. Methyl-4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy)-3,5-dimethylbenzoate is then obtained as white crystals melting at 180°-182° C.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:14]1([CH3:19])[O:18][CH2:17][CH2:16][O:15]1.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C>C1COCC1.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([B:20]([OH:25])[OH:21])=[C:8]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:9]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(c2cc(F)ccc2Br)OCCO1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2cc(F)ccc2B(O)O)OCCO1
Temperature: -78 °C
Yield: 75 %

Procedure:
A solution of t-butyl lithium (19.0 mL) was added dropwise to a solution of 2-(2-bromo-5-fluorophenyl)-2-methyl-1,3-dioxolane (4.02 g, 15.40 mmols) and triisopropyl borate (4.6 mL, 19.93 mmols in anhydrous THF (40 mL), stirring under an inert atmosphere at −78° C. The resulting yellow solution was stirred at −78° C. for ½ h and then allowed to warm to −15° C. The resulting boronic ester was hydrolyzed in situ with sat'd NH3Cl (aq) at room temperature. The reaction mixture was transferred to a separatory funnel, diluted with H2O (50 mL), and extracted with EtOAc (3×50 mL). The combined organics were washed with H2O, brine, dried over Na2SO4, and concentrated. The resulting residue was recrystallized from EtOAc and hexanes to give 4-fluoro-2-(2-methyl-1,3-dioxolan-2-yl)phenylboronic acid as an orange solid (2.62 g, 75%). 1H NMR (DMSO, 300 MHz) δ1.60 (s, 3H), 3.61-3.67 (m, 2H), 3.87-3.93 (m, 2H), 7.02-7.08 (m, 2H), 7.24-7.30 (m, 1H), 7.59 (s, 1H) ppm; 1H NMR (DMSO+D2O, 300 MHz) δ1.61 (s, 3H), 3.61-3.67 (m, 2H), 3.78 (brs, 2H) 3.89-3.94 (m, 2H), 7.04-7.10 (m, 2H), 7.26-7.31 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:41](Cl)([O:43]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:18]=4)[CH2:15][NH:16][C:41]3=[O:43])=[CH:9][CH:8]=2)=[CH:31][CH:32]=1
Reactant: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(OCc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCC(c2cccc(OCc3ccccc3)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 98.7 %

Procedure:
To the diamine (440 mg, 0.98 mmol) from Step 2, and triethylamine (330 μL, 2.4 mmol) in THF (20 mL) is added triphosgene (180 mg, 0.6 mmol) in THF at 0° C. After complete addition, the mixture is quenched with water and THF is removed by evaporation. The residue is extracted with ethyl acetate and washed with water. Evaporation of the organics gives a solid which is triturated with ethyl acetate, filtered, and washed with 40% ethyl acetate/hexane to give 279 mg of the title compound. Purification of the filtrate gives an additional 127 mg of product (combined yield, 88%). HPLC-MS calculated for C28H23ClN2O3 (M+H+): 471.1, found 471.1.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14](=[O:15])[NH:23][NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NNc1ccccc1
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)NNc2ccccc2)CCCCC1

Procedure:
To 6.6 grams (0.0315 moles) of 1-t-butylazo-1-isocyanatocyclohexane cooled to 5° C. and stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added dropwise 3.42 grams (0.0315 moles) of phenylhydrazine. The reaction was very exothermic and rapid. Pentane was added to slurry the solid product and the slurry was filtered. The white solid filter cake was air dried and weighed 10.0 grams (100% crude yield). The product melted at 140°-142° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1670 cm-1 and NH bands at 3100, 3230 and 3320 cm-1. The isocyanate band at 2225 cm-1 was absent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].O.[CH2:24]([C@H:26]1[CH2:31][C@H:30]2[C@H:32]3[C@H:41]([CH2:42][CH2:43][C@:28]2([CH3:29])[C@H:27]1[O:45][C:46](=[O:49])[CH2:47]Br)[C@@H:40]1[C:35](=[CH:36][C:37](=[O:44])[CH2:38][CH2:39]1)[CH2:34][CH2:33]3)[CH3:25]>CC(C)=O>[CH2:24]([C@H:26]1[CH2:31][C@H:30]2[C@H:32]3[C@H:41]([CH2:42][CH2:43][C@:28]2([CH3:29])[C@H:27]1[O:45][C:46](=[O:49])[CH2:47][O:15][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@@H:40]1[C:35](=[CH:36][C:37](=[O:44])[CH2:38][CH2:39]1)[CH2:34][CH2:33]3)[CH3:25]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Yield: 80.5 %

Procedure:
In 40 ml of acetone is dissolved 1.2 g of N-t-butoxycarbonylleucine, and 1.2 g of potassium t-butoxide and 8 ml of water are added, followed by addition of 1.1 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one. The mixture is refluxed for 12 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with 150 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to column chromatography. After serial passage of diisopropyl ether-n-hexane mixtures (1:3, 400 ml and 5:2, 750 ml), elution is carried out with 1000 ml of a 4:1 mixture of the same solvents. The eluate is evaporated under reduced pressure to remove the solvent, giving 1.2 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CS(C)=O>[C:10]1([S:16]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1ccccc1F
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 95 °C
Yield: 21.2 %

Procedure:
A mixture of 2-fluorobenzaldehyde (4.67 g, 37.6 mmol), sodium benzenesulfinate (6.79 g, 41.3 mmol), and dimethylsulfoxide (30 mL) was heated at 95° C. for 18 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated to give a white solid. NMR analysis of this crude mixture indicated unreacted 2-fluorobenzaldehyde to be the major component. The crude mixture was redissolved in dimethylsulfoxide (30 mL), then sodium benzenesulfinate (5.0 g, 30 mmol) was added. The resulting mixture was heated at 95° C. for another 16 hours. The reaction mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic phase was dried over MgSO4, filtered, and concentrated. A solution of this crude product and dichloromethane was evaporated over silica gel, and the resulting silica gel supported crude product was loaded onto an Analogix SuperFlash™ column. Flash chromatography (5%-35% ethyl acetate in hexanes) provided 1.96 g (23%) of 2-(benzenesulfonyl)-benzaldehyde as a clear, colorless oil which partially solidified over time.
Reaction SMILES: C(O[C:4]1[C:5](=[O:14])[C:6](=[O:13])[C:7]=1[NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])C.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:17]=1>C1COCC1>[C:9]([NH:8][C:7]1[C:6](=[O:13])[C:5](=[O:14])[C:4]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][C:18]=1[C:24]([F:27])([F:25])[F:26])([CH3:10])([CH3:11])[CH3:12]
Reactant: NCc1ccc(F)cc1C(F)(F)F
Reactant: CCOc1c(NC(C)(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1c(NCc2ccc(F)cc2C(F)(F)F)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To a room temperature solution of (0.7 g, 3.55 mmol) of 3-ethoxy-4-(tert-butylamino)-cyclobut-3-ene-1,2-dione and THF (30 mL) was added (0.73 g, 3.78 mmol) of the 4-fluoro-2-trifluoromethylbenzylamine via a syringe. The resulting mixture was stirred at room temperature for 12 hours. After concentration in vacuo, the resulting white solid was recrystallized from hot acetonitrile to give 0.55 gm (52%) of 3-tert-butylamino-4-(4-fluoro-2-trifluoromethyl-benzylamino)-cyclobut-3-ene-1,2-dione as a white solid: mp 192°-194° C.; 1H NMR (DMSO-d6) δ1.36 (s, 9H), 4.88 (d, 2H) 7.67 (m, 5H) ppm; IR (KBr) 3250, 2900, 1800, 1580, 1530 cm-1 ; MS (m/z) 345 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[CH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[OH2:18].[OH-].[Na+].OO>C1COCC1.C(OCC)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:18])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O
Reactant: C=C1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (4.48 g, 19.71 mmol) was dissolved in THF (100 mL) and the stirred solution was cooled to 0° C. Borane-dimethylsulfide complex (1.9 mL, 19.7 mmol) was added and the reaction mixture was allowed to warm to RT o/n. After 16 h, water was added dropwise until no bubbling was observed. The stirred mixture was then cooled to 0° C. Aqueous NaOH (5M in H2O, 5.3 mL, 26.6 mmol), then H2O2 (30 wt % in H2O, 6.0 mL, 58.5 mmol) were added dropwise. The reaction was then warmed to 50° C. After 30 min, the mixture was diluted with ethyl ether and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (25% to 75% EtOAc/Hex) to afford the title compound (2.08 g, 41%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16]Br)=[O:5].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C1COCC1>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[O:5])[CH3:1]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CBr)c2n1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Cl)cc(CN3CCN(C)CC3)c2[nH]1
Temperature: 40 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a solution of 0.125 g (0.30 mmol) of 7-bromomethyl-5-chloro-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in THF (1 ml) at RT, 55 mg of 1-methyl-piperazine was added. The reaction mixture was stirred at 40° C. for one hour and concentrated under vacuo. The crude was dissolved in CH2Cl2 (1 m) and at RT 0.2 ml of TFA was added and stirring was continued over night. Preparative HPLC (30% CH3CN/H2O) afforded 30 mg (29%) of 5-chloro-7-(4-methyl-piperazin-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C([Li])CCC.Br[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCO2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynyl chroman (from Example 10) in 4 ml of dry tetrahydrofuran at 0° C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0° C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0° C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0° C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 4-bromobenzoate in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and stirred at room temperature for 15 minutes, then treated by double ended needle with the solution of alkynyl zinc chloride prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was then extracted with 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to obtain the captioned compound as a white solid. PMR (CDCl3): δ 1.36 (6H), 1.42 (3H, t, J~7.3 Hz), 1.82-1.86 (2H, m), 4.21-4.25 (2H, m), 4.40 (2H, q, J~7.3 Hz), 6.79 (1H, d, J~8.1 Hz), 7.28 (1H, dd, J~8.1 Hz, 2.2 Hz), 7.50 (1H, d, J~2.2 Hz), 7.58 (2H, d, J~8.7 Hz), 8.03 (2H, d, J~8.7 Hz).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)(=O)C(C)C>>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=2)=[O:23])[CH2:17][CH2:16]1)=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CC(C)C(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(C(=O)CCC(F)(F)F)CC1
Yield: 70 %

Procedure:
4,4,4-Trifluorobutanoic acid (59 mg, 0.418 mmol) was reacted with PTU (80 mg, 0.278 mmol) as the same manner as the synthesis of 1-(1-isobutyrylpiperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (80 mg, 0.194 mmol, 70% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.80 (s, 1H), 7.58 (s, 4H), 6.38 (d, J=7.8 Hz, 1H), 4.19 (d, J=13.8 Hz, 1H), 3.79 (d, J=13.8 Hz, 1H), 3.77 (m, 1H), 3.16 (t, J=12.3 Hz, 1H), 2.84 (m, J=11.4 Hz, 1H), 2.60 (d, J=6.3 Hz, 2H), 2.59 (m, 2H), 1.85 (br, 2H), 1.30 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][CH:15]([S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([NH:38][S:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:35]=[N:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:22][N:21]([CH3:23])[S:18]([CH:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:2]([C:32]4[CH:37]=[N:36][CH:35]=[C:34]([NH:38][S:39]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)(=[O:41])=[O:40])[CH:33]=4)=[CH:3][CH:4]=3)[N:9]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CN(C)S(=O)(=O)C1CCN(c2cnc3ccc(Br)cc3n2)CC1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)C1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A slurry of 1-(7-bromo-2-quinoxalinyl)-N,N-dimethyl-4-piperidinesulfonamide (0.43 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.47 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.03 mmol) in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 18 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (5% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (102 mg, 43% yield) as a yellow solid. MS(ES)+ m/e 539.2 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([O:9][CH3:10])([O:7][CH3:8])[CH2:3][CH2:4][CH2:5][OH:6].[OH-].[K+].[CH:13]#[CH:14]>CS(C)=O>[CH:13]([O:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([O:9][CH3:10])[O:7][CH3:8])=[CH2:14]
Reactant: C#C
Reactant: CO[Si](C)(CCCO)OC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=COCCC[Si](C)(OC)OC
Yield: 95 %

Procedure:
In a similar manner to Example 1, 30 g (0.17 mol) of 3-(methyldimethoxysilyl)propanol, 3 g of KOH and 120 g of DMSO were reacted at 60° C. with acetylene. 3-(Methyldimethoxysilyl)propyl vinyl ether was obtained in 95% yield.