Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH2:22][F:21])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OCF)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OCF)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(fluoromethoxy)picolinic acid [CAS 1174321-03-9; J. M. Ellard et al. WO2011009898 (2011)] following General Procedure F yielded the title compound as a colorless solid. MS: m/z=445.4 [M+H]+.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([CH:10]1[CH2:18][CH2:17][C:13]2[S:14][CH:15]=[CH:16][C:12]=2[C:11]1=[O:19])[CH:8]=C.[OH2:20]>[Os](=O)(=O)(=O)=O.O1CCOCC1>[O:19]=[C:11]1[C:12]2[CH:16]=[CH:15][S:14][C:13]=2[CH2:17][CH2:18][CH:10]1[CH2:7][CH:8]=[O:20]
Reactant: O
Reactant: C=CCC1CCc2sccc2C1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=CCC1CCc2sccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 4.20 g of sodium periodate was added gradually to a mixture of 1.80 g of 5-allyl-4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene, 25 mg of osmium tetraoxide, 15 ml of water and 45 ml of dioxane, while keeping the reaction mixture at 24 to 26° C., and then the mixture was stirred at room temperature for 3 hours. After extraction of the reaction mixture with ethyl acetate, the organic layers were combined, washed with 2% sodium thiosulfate aqueous solution, water and brine in that order and then dried with anhydrous magnesium sulfate. After removal of the drying agent, the solvent was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography to give 1.33 g of (4-oxo-4,5,6,7-tetrahydrobenzo[b]thiophen-5-yl)acetaldehyde. A 1.32 g of the aldehyde compound and 1.39 g of N-acetylethylenediamine were dissolved in 50 ml of toluene. Then, 10 mg of camphorsulfonic acid was added, and the mixture was heated under reflux for 3 hours while removing the produced water. After cooling, the reaction solution was poured into ice-cooled saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layers were combined, the drying agent was removed by filtration and then the solvent was concentrated under a reduced pressure to give 1.38 g of N-(2-(4,5-dihydro-1H-thieno[2,3-g]indol-1-yl)ethyl]acetaamide. From this compound, N-[2-(1H-thieno[2,3-g]indol-1-yl)ethyl]acetamide was obtained in the similar manner as described in Reference Example 60.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([F:16])=[CH:14][N:13]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:12](=[O:35])[CH:11]=2)=[C:6]([F:36])[CH:5]=1>C(O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([F:16])=[CH:14][N:13]([CH2:17][CH2:18][C@@:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][OH:23])=[O:21])[C:12](=[O:35])[CH:11]=2)=[C:6]([F:36])[CH:5]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
Water (312 mL) and 1 N aq HCl (23.9 mL, 23.9 mmol) were added to a solution of (2R)-4-[4-(4-chloro-2-fluorophenyl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (74.7 g, 144.1 mmol) in ethanol (126 mL). The reaction was heated to 70° C. and stirred at this temperature overnight. The reaction was allowed to cool and the solid was collected via filtration and washed with water until the filtrate had a pH of −5. The solid was dried under vacuum to afford the title compound as a white solid (46.48 g, 74%). MS (LCMS) m/z 435.6 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (s, 3 H) 2.09-2.21 (m, 1 H) 2.44 (d, J=5.27 Hz, 1 H) 3.10 (s, 3 H) 3.77 (td, J=11.90, 5.07 Hz, 1 H) 4.04 (td, J=11.95, 4.98 Hz, 1 H) 6.51 (d, J=7.02 Hz, 1 H) 7.44 (dd, J=8.29, 2.05 Hz, 1 H) 7.50-7.56 (m, 1 H) 7.62 (dd, J=9.95, 1.95 Hz, 1 H) 8.04 (d, J=5.85 Hz, 1 H) 9.22 (s, 1 H) 11.05 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26].C1(C=CC(O)=CC=1)O>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:27]([CH2:24][CH2:25][CH3:26])[N:28]=[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11][CH2:10][CH:9]23)=[CH:4][CH:3]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CSCC1=Cc1ccc(Cl)cc1
Agent: Oc1ccc(O)cc1
Solvent: CC(Cl)Cl
Product: CCCN1N=C2C(=Cc3ccc(Cl)cc3)CSCC2C1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 6.0g of tetrahydro-3,5-bis-[(4-chlorophenyl)methylene]-4H-thiopyran-4-one, 1.3g of n-propyl hydrazine, and 100mg of hydroquinone in 100ml of dichloroethane is heated at reflux temperature for 2.5 hours and allowed to cool to room temperature. The reaction mixture is washed with dilute hydrochloric acid and water, and then dried over calcium chloride. After the solvent is removed in vacuo, the residue is chromatographed on a dry packed neutral alumina column (Activity I). The fractions eluted with 0-5% ethyl acetate/hexane are combined and crystallized from acetone/acetonitrile to give 2.8g of the title compound, melting point 118°-122°C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: NCC1CCOCC1
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Product: CS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (Acros Organics Ltd.) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=2)[C:17]=1[NH2:18]>>[CH2:7]([C:8]1[NH:11][C:12]2[C:13](=[O:34])[N:14]([CH2:31][CH2:32][CH3:33])[C:15](=[O:30])[N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:29])=[O:28])[CH:22]=3)[C:17]=2[N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CCCn1c(=O)c(N)c(N)n(CCc2cccc(C(=O)O)c2)c1=O
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCc2cccc(C(=O)O)c2)c1=O

Procedure:
By the method of Example 2, phenylacetic acid is reacted with 5,6-diamino-1-[2-(3-carboxyphenyl)ethyl]-3-propyluracil to yield 8-benzyl-3-[2-(3-carboxyphenyl)ethyl]-1-propylxanthine. In turn, 5,6-diamino-1-[2-(3-carboxyphenyl)ethyl]-3-propyluracil is made by the synthetic methods of Example 1, starting with 3-carboxyphenethylamine.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][N:3]=1.[CH3:22][C:23](OC(C)=O)=[O:24]>C1COCC1.O>[C:23]([N:11]1[C:12]([CH:14]2[CH2:15][CH2:16]2)=[CH:13][C:9]([NH:8][C:6]2[C:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:4][N:3]=[C:2]([Br:1])[N:7]=2)=[N:10]1)(=[O:24])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Br)nc1Nc1cc(C2CC2)n(C(C)=O)n1
Reaction time: 2 h
Yield: 83 %

Procedure:
To the mixture of ethyl 2-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-5-carboxylate (495 mg, 1.41 mmol) in THF (100 mL) and water (10 mL) was added Ac2O (2.0 mL). The reaction mixture was stirred for 2 h and water was added. The mixture was filtered and the solid was washed with water and concentrated with ethanol to remove the residual water to obtain ethyl 4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-2-bromopyrimidine-5-carboxylate (460 mg, 83%). LC-MS (m/z)=394.0 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Reaction time: 4 h
Yield: 75.5 %

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (459 g, 2.63 mol), 4-bromobenzyl bromide (715 g, 2.86 mol) and milled potassium carbonate (771 g, 5.58 mol) was suspended in 2 L DMF at 0° C. with overhead stirring. The ice bath was removed and the mixture was stirred for 4 h, then diluted with 15 L of ice water. The mixture was stirred vigorously for 1 h, then the aqueous layer was decanted from the gummy solid. The solid was washed with 2×4 L of water, then was dissolved in 2.5 L toluene and dried over Na2SO4. The mixture was filtered, and the filtrate was cooled in an ice bath and treated with a stream of HCl gas for 1 h with vigourous stirring. The precipitate was filtered and washed with 3×0.5 L of cold toluene and dried under a stream of nitrogen to give 682 g of the title compound.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=2)[C:9]1=[O:21]
Reactant: CC=CCC1Cc2cc(OC)c(OC)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(=O)C(CC=O)C2
Reaction time: 0.5 h
Yield: 73 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 30 minutes through a solution, cooled to -70°, of 6.8 g of (RS)-2-(2-buten-1-yl)-5,6-dimethoxy-1-indanone in 100 ml of anhydrous dichloromethane and 20 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 250 ml of dichloromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 1.5 hours. The mixture was subsequently poured into 100 ml of water and neutralized while stirring by the spatula-wise addition of sodium hydrogen carbonate. An additional 70 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 120 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was crystallized from diethyl ether/hexane. 4.7 g (73%) of (RS)-2-(2-oxoethyl)-5,6-dimethoxy-1-indanone were obtained as a light yellow solid with m.p. 122°.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:19][C:20]([NH:23][C:24]([CH2:26][O:27]C(=O)C)=[O:25])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:43][Si](C)(C)[N-][Si](C)(C)C.[K+].CI.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([C:17]2[CH:22]=[N:21][C:20]([N:23]([C:24](=[O:25])[CH2:26][OH:27])[CH3:43])=[CH:19][C:18]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[CH3:38])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N(C)C(=O)CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of 70 mg (0.12 mmol) acetic acid (5-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4-o-tolyl-pyridin-2-ylcarbamoyl)-methyl ester in 4 ml tetrahydrofuran at room temperature under argon were added dropwise 0.13 ml (0.12 mmol) of a 1 M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirring was continued for 1 h at room temperature and 17 mg (0.12 mmol) methyl iodide were added. After stirring overnight, saturated ammonium chloride solution was added and the aqueous layer was extracted with diethyl ether. The diethyl ether layer was dried with sodium sulfate, evaporated, and the residue was purified by flash-chromatography to give 12 mg (18%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[NH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:11]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[N:13][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:10]1)(=[O:23])[CH3:22]
Reactant: COc1cccc(-c2n[nH]c(-c3ccccc3C)n2)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cccc(-c2nc(-c3ccccc3C)n(C(C)=O)n2)c1
Reaction time: 8 h

Procedure:
A solution of 0.8 g (0.003 mole) of 3-(3-methoxyphenyl)-5-(2-methylphenyl)-1H-1,2,4-triazole and 3 ml (0.00317 mole) of acetic anhydride was heated for two hours on a hot water bath. After evaporating the excess of anhydride by distillation under vacuum, the obtained residue was taken up with a mixture of diisopropyl ether and light petroleum. After standing overnight, a precipitate formed which was recovered by filtration. Yield: 0.72 g (78%) of the title compound M.p. 107°-110° C. Δδ=-0.26.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[ClH:22]>C(#N)C.[Cu]>[Cl:22][C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: Cl
Agent: [Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)c1ccc2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
In a three-necked flask fitted with a condenser, a suspension of copper II chloride (370 mg, 2.75 mmol) in acetonitrile (5 mL) was treated with tert-butyl nitrite (0.41 mL, 3.44 mmol) and stirred at rt for 10 minutes. A solution of 2-amino-6-trifluoromethylbenzthiazole (500 mg, 2.29 mmol) in acetonitrile (1 mL) was then added dropwise. The mixture was heated at 65° C. for 30 minutes, then cooled and diluted with an excess of 1 N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. An orange semi-solid (501 mg, 92%) was obtained and used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.10-8.05 (m, 2H), 7.74 (d, 1H); LC-MS m/z 238.2 (MH+), ret. time 3.76 min TLC Rf=0.50 (9:1 hexanes/ethyl acetate).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:13]([O:15]CC)=O)[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26]>CCO.CS(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([C:13]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:15])[C:7]2[CH:12]=[N:11][NH:10][C:8]=2[N:9]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
Aqueous NaOH (1.11 g, 27.88 mmol) was added to a solution of ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (5 g, 18.58 mmol) in EtOH (50 mL) and stirred at 60° C. for 1 h. After completion of the reaction, ethanol was removed under reduced pressure and it was acidified using 10% citric acid solution. Solid obtained was filtered and dried under reduced pressure to obtain corresponding acid. The crude acid (4.4 g, 18.2 mmol) was then dissolved in DMSO (20 mL) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (5.55 g, 36.51 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYB OP (14.24 g, 27.38 mmol) was added to it and stifling was continued overnight. After completion of the reaction, reaction mass was poured into ice to obtain a solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (4 g, 58.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][N:14]2[C:29](=[O:43])[CH:30]([NH:35][C:36]([O:38][C:39]([CH3:42])(C)[CH3:40])=[O:37])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4].O=C1CCC(=O)N1OC(=O)OC1C[CH:58]2[CH:56]([CH2:57]2)C1>Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][N:14]2[C:29](=[O:43])[CH:30]([NH:35][C:36]([O:38][CH:39]2[CH2:40][CH:58]3[CH:56]([CH2:57]3)[CH2:42]2)=[O:37])[C:31]([CH3:33])([CH3:32])[CH3:34])=[O:12])[CH2:7][CH:6]1[CH2:8][CH3:9])=[O:4]
Reactant: O=C(OC1CC2CC2C1)ON1C(=O)CCC1=O
Reactant: CCC1CC1(NC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: CCC1CC1(NC(=O)C1CC(OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)C(NC(=O)OC1CC2CC2C1)C(C)(C)C)C(=O)OC
Reaction time: 2 h
Yield: 92 %

Procedure:
1-{[4-(4-Bromobenzenesulfonyloxy)-1-(2-tert-butoxycarbonylamino-3,3-dimethylbutyryl)-pyrrolidine-2-carbonyl]amino}-2-ethylcyclopropanecarboxylic acid methyl ester was dissolved in 4N HCl in dioxane (300 mL) at room temperature and stirred for 2 h. It was then concentrated under vacuum, and co-evaporated with dichloromethane (2×200 mL) to dryness. The residue was dissolved in EtOAc (600 mL) and sat'd aq. NaHCO3 (1 L). It was stirred vigorously. After 10 min, carbonic acid bicyclo[3.1.0]hex-3-yl ester 2,5-dioxo-pyrrolidin-1-yl ester (41.4 g, 173.1 mmol) was added in one portion. After the resulting mixture was stirred for another 30 min, the organic layer was collect and washed with brine (500 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel with ethyl acetate/hexane to afford 94.4 g (92% yield) of 1-{[1-[2-(bicyclo[3.1.0]hex-3-yloxycarbonylamino)-3,3-dimethylbutyryl]-4-(4-bromobenzenesulfonyloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethylcyclopropanecarboxylic acid methyl ester.
Reaction SMILES: CC(C)([O-])C.[Na+].[Br:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1.[C:22](=S)([S:25][CH3:26])[S:23][CH3:24].CI>CS(C)=O>[Br:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([Br:21])=[CH:15][CH:16]=3)[C:11](=[C:22]([S:25][CH3:26])[S:23][CH3:24])[C:10]=2[CH:9]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CSC(=S)SC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CSC(SC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 0.08 h

Procedure:
Sodium tert-butoxide (1.24 g, 12.9 mmol) was added portionwise over 2 min to a solution of 2,7-dibromofluorene (2.0 g, 6.2 mmol) in DMSO (40 ml) at RT under nitrogen. To the resulting red solution was added dimethyl trithiocarbonate (0.94 g, 6.8 mmol) via a syringe. The reaction was stirred for 5 min and methyl iodide (1.8 g, 12.6 mmol) was added over 2 min. The reaction was stirred for 1 h worked up as above. Recrystallization from ethyl acetate/THF (2:1) afforded 2.4 g (91%). The sample was identical in all respects to that described above.
Reaction SMILES: [OH:1][C:2]1([CH2:7][S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:33]I>>[CH3:33][O:1][C:2]1([CH2:7][S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:31][CH2:32]2)(=[O:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)CC1(O)CCCC1)CC2
Reactant: CI
Product: COC1(CS(=O)(=O)N2CCC3(CCN(c4ccc(OC(F)(F)F)cc4)C3=O)CC2)CCCC1

Procedure:
The title compound was prepared in analogy to example 209 from 8-(1-hydroxy-cyclopentylmethanesulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 210) and methyl iodide. Off-white solid. MS (ESI): 491.2 (MH+).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:9]=[N:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH2:16][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:14][CH2:13]3)=[CH:6][CH:5]=1.F[P-](F)(F)(F)(F)F.[N:31]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:35]2[CH:36]=[CH:37][CH:38]=CC=2N=N1.O>C(Cl)Cl>[CH:35]1([N:31]2[CH2:17][CH2:16][N:15]([C:21](=[O:23])[CH2:20][N:15]3[CH2:14][CH2:13][C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:7]5[N:8]=[N:9][C:4]([CH3:3])=[CH:5][CH:6]=5)[CH:11]=4)[CH2:16]3)[CH2:14][CH2:13]2)[CH2:36][CH2:37][CH2:38]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)O)C3)nn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2ccc3c(c2)CCN(CC(=O)N2CCN(C4CCC4)CC2)C3)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of [6-(6-methyl-pyridazin-3-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid dihydrochloride (313 mg, 0.88 mmol) and 1-cyclobutyl-piperazine bistrifluoroacetate (356 mg, 0.97 mmol, 1.1 eq.) in DCM (10.0 ml) are added BOP (467 mg, 1.06 mmol, 1.2 eq.) and TEA (267 mg, 2.64 mmol, 3.0 eq.). The mixture is stirred at rt for 2 hr. Water (10.0 ml) is added to quench the reaction, and the organic layer is collected, dried over sodium sulfate, and concentrated. The residue is purified by PTLC (EtOAc/4% TEA) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.85 (1H, s), 7.78 (1H, dd), 7.72 (1H, d), 7.36 (1H, d), 7.15 (1H, d), 3.75 (2H, s), 3.65 (4H, m), 3.39 (2H, s), 2.99 (2H, t), 2.82 (2H, t), 2.74 (3H, s), 2.68 (1H, m), 2.28 (4H, m), 1.64-2.08 (6H, m); MS (+VE) m/z 406.2 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=O)=O)=CC=1>>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Product: CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1

Procedure:
4'-n-Decyloxy-4-hydroxybiphenyl was synthesized by monoalkylating commercially available 4,4'-dihydroxybiphenyl in the presence of an equivalent amount of n-decyl p-toluenesulfonate and an akali (m.p. 149° C.).