Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1.Br[CH2:16][CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[C:23]([Si:20]([CH3:22])([CH3:21])[O:19][CH2:18][CH2:17][CH2:16][N:9]1[CH:10]=[C:5]([C:4]([F:13])([F:3])[F:14])[C:6](=[O:12])[NH:7][C:8]1=[O:11])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a suspension of 50% NaH (0.42 g, 8.7 mmol) in DMF (5 mL), a solution of 5-trifluoromethyl-1H-pyrimidine-2,4-dione (1.2 g, 6.66 mmol) was added drop wise maintaining the temperature at 0° C. The mixture was then heated at 100° C. for 1 hour. After cooling to room temperature, (3-bromo-propoxy)-tert-butyl-dimethyl-silane (2 mL, 8.7 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and the crude was dissolved in a 25%aq solution of citric acid and extracted with Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (2-8) to give 0.87 g of 1-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-5-trifluoromethyl-1H-pyrimidine-2,4-dione (37% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1cccc(Br)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1)#N.CO.[Na]>C(O)(=O)C>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[N:8]=2)=[N:12][CH:13]=1)[CH3:18]
Reactant: CCc1ccc(C#N)nc1
Reactant: Nc1ccccc1N
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(-c2nc3ccccc3[nH]2)nc1

Procedure:
1.1 g. of o-phenylenediamine and 1.3 g. of 2-cyano-5-ethylpyridine were dissolved in 5 ml. of methanol. To the solution was added 0.05 g. of sodium in 1 ml. of methanol. The mixture was refluxed for 2 hours, then acidified with acetic acid and refluxed again for additional 4 hours. The reaction mixture was evaporated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([CH3:26])=[CH:20]4)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:27][CH3:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:28][O:27][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)[N:13]=[CH:12][N:11]=[C:10]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[CH:20]2
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCN1CCN(C)CC1
Yield: 32 %

Procedure:
A solution of 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (150 mg, 0.38 mmol), (prepared as described in Example 73), in 1-methylpiperazine (2 ml) was heated at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and aqueous 5% sodium hydrogen carbonate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on an isolute column eluting with methanol/ethyl acetate/methylene chloride (1/4/5 followed by 1/9/0) and 3M ammonia in methanol/methanol/methylene chloride (5/10/80). After removal of the solvent under vacuum, the solid was dissolved in the minimum of methylene chloride and ether/petroleum ether was added. The precipitate was collected by filtration, and dried under vacuum to give 6-methoxy-4(2-methylindol-5-yloxy)-7-(3-(4-methypiperazin-1-yl)propoxy)quinazoline (55 mg, 32%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:10]([O:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Reaction time: 8 h
Yield: 55.6 %

Procedure:
2,5-Dihydro-pyrrole-1-carboxylic acid tert-butyl ester (46 g, 65% purity) was dissolved in CH2Cl2 (500 mL). The solution was cooled to 0° C. mCPBA (122 g, 2 eq, 77% purity) was slowly added to the solution at 0° C. The reaction mixture was stirred at 0° C. to RT for overnight. The mixture was concentrated to 200 ml, and filtered. The organic phase was washed with 1 N NaOH solution (4×100 mL), dried over Na2SO4. The resulting oil was purified by column chromatography (hexane:ethyl acetate 3:1) to give 28 g of desired product as a colorless oil (87% yield). 1H-NMR (300 MHz, CDCl3): δ 1.41 (s, 9H), 3.26 (dd, 2H), 3.25-3.80 (m, 4H)
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[C:44]([O:43][C:42](=[O:48])[NH:41][C@H:38]1[CH2:37][CH2:36][C@H:35]([NH:34][C:31]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])[C:20]=2[CH3:30])=[O:33])[CH2:40][CH2:39]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c3) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][C:3]=1[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:12])[CH:4]=1
Reactant: Cc1cc(CCCO)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CCCBr)ccc1F
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Compound 44-3 (5.47 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (9.39 g) and N-bromosuccinimide (6.37 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.10 g) as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1>CO.O>[N:3]1([C:8]2[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[CH:10][N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: COC(=O)c1ccc(-n2ccnc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(-n2ccnc2)nc1
Reaction time: 15 h

Procedure:
NaBH4 (37.82 g) is added portionwise to a suspension of the imidazolyl ester of Step 2. above (9.98 g) in methanol at about 0.° C. The reaction mixture is heated to reflux for 71/2 hours, allowed to cool and stand 15 hours. Water (75 ml) is added, and the quenched reaction mixture evaporated, affording a solid residue which is suspended in water, extracted with chloroform dried over Na2SO4, filtered and evaporated, recrystallized (CHCl3), affording the desired product as a white solid. M.P.=128.5°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N+]=[N-])=[CH:4][CH:3]=1.[CH:18]([CH:20]=[CH2:21])=[O:19]>ClCCl.CCCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:21][CH:20]2[CH:18]=[O:19])=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: [N-]=[N+]=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=CC1CC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of bis(4-fluorophenyl)diazomethane, prepared as in Example 84 from the action of activated manganese dioxide (59.7 g) on 4,4'-difluorobenzophenone hydrazone (42.81 g) in dichloromethane (195 mL), was added to a solution of acrolein (15.7 mL) in heptane (150 mL). The deep purple reaction mixture, after being stirred at 40° C. for 2 hours then at 53° C. for 30 minutes, faded to a pale amber color. Evaporation of the solvents afforded 46 g of 2,2-bis(4-fluorophenyl)cyclopropanecarboxaldehyde as an oil. The material was used without further purification in subsequent reactions.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][CH:9]([CH:11]2[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]2)[OH:10])[CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[S:21][C:22]([C:28]2[C:33]([F:34])=[CH:32][C:31]([C:35]([OH:38])([CH3:37])[CH3:36])=[CH:30][C:29]=2[F:39])=[CH:23][C:24]=1[C:25]([NH2:27])=[O:26]>>[F:39][C:29]1[CH:30]=[C:31]([C:35]([OH:38])([CH3:37])[CH3:36])[CH:32]=[C:33]([F:34])[C:28]=1[C:22]1[S:21][C:20]([NH:19][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][CH:9]([CH:11]3[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH2:12]3)[OH:10])[N:7]=2)=[C:24]([C:25]([NH2:27])=[O:26])[CH:23]=1
Reactant: O=S1(=O)CCC(C(O)Cc2cccc(Br)n2)CC1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(CC(O)C4CCS(=O)(=O)CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 2-(6-bromopyridin-2-yl)-1-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)ethanol (0.11 g, 0.32 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) as the starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)O.CC(C)=[O:19]>O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]1[C:12](=[O:19])[CH:16]=[CH:15][CH:14]1[OH:13]
Reactant: CC(C)=O
Reactant: Cc1cc(C)c(C(O)c2ccco2)c(C)c1
Solvent: O
Product: Cc1cc(C)c(C2C(=O)C=CC2O)c(C)c1
Temperature: 55 °C
Reaction time: 7 h

Procedure:
A solution of (2,4,6-trimethylphenyl)furan-2-ylmethanol (27.8 g, 129 mmol) in acetone (730 ml) and water (100 ml) is heated to 55° C. and polyphosphoric acid (2 g) is added. The mixture is stirred at 55° C. for 7 hours, then cooled to room temperature overnight. The reaction mixture is concentrated under reduced pressure to remove most of the acetone then ethyl acetate (500 ml) is added, and the reaction mixture is partitioned. The aqueous phase is extracted into ethyl acetate and the organic solutions are combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(2,4,6-trimethylphenyl)-4-hydroxycyclopent-2-enone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][S:29][CH2:28][CH2:27]3)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)N3CCSCC3)c2)=C(C)C1=O
Yield: 46.9 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and thiomorpholine (0.018 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (32 mg, 0.075 mmol, yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:13][CH2:14][CH3:15])[C:10]([NH2:12])=[S:11].C(N(CC)CC)C.Br[CH:24]([CH3:35])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=O>C(O)C>[Cl:34][C:28]1[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:27]=1[C:25]1[N:12]=[C:10]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:14][CH3:15])[S:11][C:24]=1[CH3:35]
Reactant: CCCN(C(N)=S)c1ccc(Cl)cc1Cl
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)c1ccc(Cl)cc1Cl
Temperature: 78 °C

Procedure:
To 1.07 g of N-(2,4-dichlorophenyl)-N-propylthiourea (Compound 10-1) in 6 ml of ethanol, there is added 1 ml of triethylamine followed, dropwise, by 1.3 g of 2-bromo-1-(2,4-dichlorophenyl)propan-1-one (Compound 1-1). The reaction mixture is heated for 3 hours at 78° C., it is evaporated to dryness and then the residue is taken up in dichloromethane. The organic phase is washed with water, dried over sodium sulphate and evaporated to dryness under vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[SiH](CC)(CC)CC>C[N+]([O-])=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C1CCCCC1
Agent: CC[SiH](CC)CC
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC(CCOC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 112 h

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (229 mg, 1.0 mmol) and cyclohexanone (86 μL, 0.83 mmol) in MeNO2 (2 mL), followed by Et3SiH (160 μL, 1.0 mmol) were added successively to a suspension of FeCl3 (35 mg, 0.20 mmol) in MeNO2 (3 mL) at room temperature under Ar protection. After the mixture was stirred at rt for 112 h, the reaction was quenched by addition of phosphate buffer (pH 7). The mixture was extracted with CH2Cl2, and the organic layer was dried over Na2SO4. After evaporation, the residue was purified by CC (SiO2, hexane/EtOAc 10:1 to 6:1) to afford 1-(tert-butoxycarbonyl)-4-[2-(cyclohexyloxy)ethyl]piperidine together with a with by-product (182 mg total) as a colorless oil. This mixture was used in the following step without further purification.
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:28]([O:33][CH3:34])(=[O:32])[C:29]([CH3:31])=[O:30]>C1COCC1>[OH:30][C:29]([CH3:31])([CH:16]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:28]([O:33][CH3:34])=[O:32]
Reactant: COc1ccc(S(=O)(=O)CCCCCc2ccccc2)cc1
Reactant: COC(=O)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)(O)C(CCCCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 33.7 %

Procedure:
A solution of n-butyl lithium in hexanes (1.9 mL, 4.4 mmol) is added dropwise to a solution of 1-(5-phenylpentane-1-sulfonyl)-4-methoxybenzene (1.35 g, 4.24 mmol) in THF (15 mL) at -78° C. The reaction is stirred at -78° C. for 15 minutes, raised to -30° C. for 15 minutes and then returned to -78° C. This solution is then cannulated into a solution of methyl pyruvate (0.82 g, 7.2 mmol) in THF (5 mL) precooled to -78° C. After 15 minutes the reaction is slowly warmed to -30° C. and stirred 15 minutes before quenching with a solution of NH4Cl (15 mL). The reaction is partitioned between ether (150 mL) and water (50 mL), and the layers are separated. The ether layer is washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The crude product is purified by gradient elution chromatography (silica, CH2Cl2 to 1% MeOH in CH2Cl2) to yield a diastereomeric mixture (2:3 ratio) of methyl 2-hydroxy-3-(4-methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoate products (0.60 g, 35%). An analytical sample of each isomer is obtained by additional chromatography using identical conditions; upper isomer, methyl 2-hydroxy-3-(4-methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoate: 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=8.7 Hz, 2H), 7.28-7.23 (m, 2H), 7.19-7.14 (m, 1H), 7.06 (d, J=7.6 Hz, 2H), 6.99-6.94 (m, 2H), 4.0-3.7 (br,1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.34-3.30 (m, 1H), 2.45 (t, J=7.5 Hz, 2H), 1.98-1.75 (m, 2H), 1.61 (s, 3H), 1.48-1.38 (m, 2H), 1.29-1.10 (m, 2H); MS (FAB) m/e 421 (M+H)+ ; lower isomer methyl 2-hydroxy-3-(4-methoxybenzenesulfonyl)-2-methyl-7-phenylheptanoate: 1H NMR (300 MHz, CDCl3) δ 7.77-7.74 (m, 2H), 7.28-7.23 (m, 2H), 7.20-7.15 (m, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.99-6.94 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.64 (bs, 1H), 3.52 (t, J=6.5 Hz, 1H), 2.51 (t, J=7.5 Hz, 2H), 1.92-1.86 (m, 2H), 1.52-1.33 (m, 4H), 1.41 (s, 3H); MS (FAB) m/e 421 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=[O:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]([CH:19]([CH3:21])[CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+].O>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:15])=[C:12]([CH:16]([CH3:17])[CH3:18])[N:11]([CH:19]([CH3:21])[CH3:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC(C)c1c(C=O)c(OCc2ccccc2)nn1C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1c(C(O)c2ccccc2)c(OCc2ccccc2)nn1C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-benzyloxy-4-formyl-1,5-diisopropyl-1H-pyrazole (0.21 g) in tetrahydrofuran (10 mL) was added a solution of phenylmagnesium bromide in tetrahydrofuran (1 mol/L, 1.5 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. A saturated ammonium chloride aqueous solution and water were added to the reaction mixture, and the mixture was purified by column chromatography on aminopropylated silica gel (eluent:tetrahydrofuran). Further purification by column chromatography on silica gel (eluent:hexane/ethyl acetate=10/1-2/1) to give the adduct material, [3-benzyloxy-1,5-diisopropyl-1H-pyrazole-4-yl] phenyl methanol. The obtained adduct material was dissolved in ethanol, and a catalytic amount of 10% palladium-carbon powder was added to the solution. The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:15]C)=[C:12](Br)[CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.C[O:23][B:24](OC)[O:25]C.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([B:24]([OH:25])[OH:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Temperature: -78 °C
Yield: 73 %

Procedure:
5-(4-chlorophenyl)-2-ethyl-1-bromobenzene (10 g, 0.03 mol) is dissolved in THF (250 ml), and the temperature is brought to −78° C. n-Butyllithium (1.33 molar solution in hexanes, 34.6 ml,) is added dropwise over 30 minutes, maintaining the temperature at around −78° C. The reaction mixture is stirred for one and half hours, then trimethylborate (4.9 g, 0.05 mol) is added dropwise and the reaction mixture stirred for two hours. A solution of 2N aqueous hydrochloric acid (100 ml) is added dropwise, and once the addition is complete the mixture is stirred for two hours. The mixture is concentrated to remove most of the tetrahydrofuran, then diluted with water and extracted with diethyl ether. The organic extracts are washed with water and brine, combined, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by flash column chromatography on silica gel, eluting with 7% ethyl acetate in hexane to give 5-(4-chloro-phenyl)-2-methylphenylboronic acid (5.4 g).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][N:6]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][NH:2][C:3](=[O:4])[O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([N:6]([CH3:5])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH:8]=[CH:9]2
Reactant: CN=C=O
Reactant: CN(c1ccncc1)n1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(ccn2N(C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Methyl isocyanate (0.72 g) was added to a solution of 1-(methyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 75 mL tetrahydrofuran containing milled potassium carbonate (2 g). After stirring three hours at ambient temperature the mixture was filtered and concentrated. The residue was eluted through silica with ethyl acetate via flash column chromatography to yield a solid 3.1 g. This was eluted through silica with 5% methanol in dichloromethane via HPLC to yield 2.6 g solid, m.p. 186°-188° C. This was recrystallized from 20% methanol in ether to yield 1.6 g of product, m.p. 186°-188° C.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)OCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
The crude 7-tert-butyl-chroman-4-ol from step B was dissolved in 50 ml dichloromethane. Pyridinium chlorochromate (4.31 g, 20 mmol) was added and the reaction mixture was stirred at ambient temperature for 3 hours, diluted with hexanes and filtered through a pad of celite. Solvent was removed from the filtrate under reduced pressure and the residue filtered through a pad of silica gel, eluting with 20% ethyl acetate:hexanes. Removal of solvent gave 2.37 g of crude product, which was chromatographed on silica gel with an eluent of 10% ethyl acetate:hexanes to give 1.50 g of the title compound (73% for 3 steps). 1H NMR (300 MHz, CDCl3) δ 7.83 (d, 1H, J=8.1 Hz), 7.07 (dd, 1H, J=8.3 and 1.9 Hz), 6.97 (d, 1H, J=1.7 Hz), 4.62 (m, 2H), 2.78 (m, 2H), 1.31 (s, 9H). MS (DCI) m/e 205 (M+H)+.