Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[N+:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)([O-:33])=[O:32]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([N+:31]([O-:33])=[O:32])=[CH:42][CH:41]=3)[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)cn1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
4-Phenyl-1-(indoline-5 -sulfonyl)-2-imidazolone (300 mg, 0.88 mmol) prepared in Preparation 3 was suspended in 10 m of dichloromethane. Then, pyridine (85 μ, 1.05 mmol) and 4-nitrobenzoyl chloride (163 mg, 0.88 mmol) were added thereto one after another. The resulting reaction mixture was stirred at room temperature under nitrogen atmosphere for 5 hours while the reaction being monitored by TLC. After the reaction was completed, the whole mixture was diluted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, concentrated, and finally purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1, v/v) to afford 400 mg of the title compound as a yellow solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:23]1([O:29][CH2:30][CH2:31][Br:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[Br-:32].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:31][CH2:30][O:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: BrCCOc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]

Procedure:
To a solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0550 g, 0.187 mmol) in 2 CH3CN/3CHCl3 (2.5 mL) was added 2-bromoethyl phenyl ether (0.060 g, 0.29 mmol).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[O:27]>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][S:14]([C:11]2[CH:12]=[CH:13][C:8]([C:2]3([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:9][CH:10]=2)(=[O:16])=[O:15])=[C:20]([C:26]([C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)=[O:27])[CH:21]=1
Reactant: CC1(c2ccc(S(=O)(=O)Cl)cc2)CCOCC1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Product: CC1(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)CCOCC1

Procedure:
The title compound was prepared by the reacting 4-(4-methyl-tetrahydro-pyran-4-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone according to the general procedure described for the preparation of (N-aryl-benzenesulfonamides. 1H NMR (CDCl3) δ 10.21 (s, 1H), 8.77 (d, 2H, J=6.0 Hz), 7.79 (d, 1H, J=8.8 Hz), 7.73 (m, 2H), 7.51-7.54 (m, 1H), 7.31-7.36 (m, 3H), 7.24-7.26 (m, 2H), 3.58-3.80 (m, 4H), 1.95-1.99 (m, 2H), 1.70-1.74 (m, 2H), 1.22 (s, 3H). MS: m/z 471 (M++1).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CS(N)(=O)=[O:15].C(O)(C)(C)C.[OH2:23]>>[CH3:12][N:11]1[C:7]([C@@:1]2([OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:23])=[CH:8][CH:9]=[N:10]1
Reactant: CS(N)(=O)=O
Reactant: O
Reactant: Cn1nccc1C1=CCCCC1
Solvent: CC(C)(C)O
Product: Cn1nccc1[C@@]1(O)CCCC[C@@H]1O
Yield: 99 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 102a by using the 5-(cyclohex-1-en-1-yl)-1-methyl-1H-pyrazole (2.66 g, 16.4 mmol) prepared in Example 123b, methanesulfonamide (1.56 g, 16.4 mmol), t-butanol (20 mL), water (20 mL) and AD-mixα (Sigma-Aldrich Corp.; 23.0 g), to yield the title compound (3.22 g, 99%) as a colorless solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=1.[CH3:27][NH:28][CH3:29].C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[CH3:27][N:28]([CH3:29])[C:14]([C:12]1[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[N:9]=[C:8]([Cl:7])[N:13]=1)=[O:16]
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
Oxalyl chloride (0.38 mL, 4.5 mmol) and N,N-dimethylformamide (0.03 mL) were added to a suspension of 2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylic acid (303 mg, 1.0 mmol) in dichloromethane (20 mL). The mixture was stirred at 20° C. for 3 h and then evaporated under reduced pressure. The residue was dissolved in dichloro-methane (25 mL) and the solution was stirred together with 60% aqueous dimethylamine (1.2 mL, 13.3 mmol) and saturated aqueous sodium hydrogencarbonate solution (8 mL) for 1 h at 20° C. The mixture was diluted with dichloromethane (25 mL), and the organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using heptane/0-40% ethyl acetate as eluent to give the title compound (215 mg, 65%) as a white solid. MS ISP (m/e): 330.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.24 (d, 2H), 7.99 (s, 1H), 7.80 d, 2H), 3.17 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:12]=[CH:13][C:14]=1F)[C:5]([O:7]C(C)(C)C)=[O:6].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O>O.CS(C)=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([CH:12]=[CH:13][C:14]=1[O:24][C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:25]([F:28])([F:26])[F:27])[CH:20]=1)[C:5]([OH:7])=[O:6]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.9 %

Procedure:
tert-Butyl 3-chloro-2,4-difluorobenzoate (Preparation 154, 0.249 g, 1.00 mmol), 4-chloro-3-(trifluoromethyl)phenol (0.196 g, 1.00 mmol) and potassium carbonate (210 mg, 1.5 mmol) were added to dimethyl sulfoxide (6 mL) and stirred at ambient temperature for 4 hours, then another 18 hours at 70° C. The reaction mixture was diluted with water and extracted three times with ethyl ether. The combined organic phase was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to leave a residue. The residue was purified by silica gel column chromatography eluting with 0-10% ethyl acetate in hexanes. The desired fractions were combined and the solvent removed in vacuo. The residue was dissolved in trifluoroacetic acid (0.50 mL, 6.5 mmol) and stirred for 18 hours. The solvent was removed in vacuo and the residue triturated with dichloromethane. The resulting precipitate was collected by filtration and vacuum dried to afford the title compound as a white solid (140 mg).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O1CCCC1.C(OCC)C>[CH:5]1([CH2:4][CH:3]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(CC1CCCCC1)OC
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CCC1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 131.7 %

Procedure:
To a solution of 60 gm (349 mMol) cyclohexylacetaldehyde dimethyl acetal in tetrahydrofuran (50 ml) and diethyl ether (100 ml) was added 1N hydrochloric acid (200 ml) and the resulting mixture was stirred for 2.5 hours at room temperature. The reaction mixture was then partitioned between diethyl ether and water. The ether layer was then separated, dried over magnesium sulfate and concentrated under reduced pressure to give 58 gm of crude cyclohexylacetaldehyde.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][O:24][CH2:25][CH:26]1[NH:31][CH2:30][CH2:29][N:28]([C:32]2[N:37]=[CH:36][C:35]([C:38](OC)=[O:39])=[CH:34][N:33]=2)[CH2:27]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:38]([C:35]3[CH:34]=[N:33][C:32]([N:28]4[CH2:29][CH2:30][NH:31][CH:26]([CH2:25][O:24][CH3:23])[CH2:27]4)=[N:37][CH:36]=3)=[O:39])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COCC1CN(c2ncc(C(=O)OC)cn2)CCN1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COCC1CN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CCN1
Temperature: 60 °C
Reaction time: 18 h
Yield: 56.9 %

Procedure:
Trimethylaluminium (2M in toluene, 1.596 mL, 3.19 mmol) was added dropwise to a solution of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (314 mg, 1.27 mmol) and methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (338 mg, 1.27 mmol) in toluene (6.35 mL) at 25° C. The resulting mixture was stirred at 60° C. for 18 h under nitrogen. The reaction mixture was added to methanol (100 mL) and treated with HCl (2N aqueous solution, until pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford the crude product as a yellow dry film. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (348 mg, 57%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CN(S(C)(=O)=O)C4)CC2)no1
Reaction time: 0.75 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50 mg, 0.13 mmol) and triethylamine (0.036 ml, 0.26 mmol) in dichloromethane (1.3 ml) was added methanesulfonyl chloride (0.020 ml, 0.26 mmol) at room temperature. Stirring for 45 minutes was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (37 mg, 62%) as white solid. MS m/e: 462 ([M+H]+).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[CH2:15]([N:18]([CH2:29][CH:30]=[CH2:31])[C:19]1[N:23]2[CH:24]=[C:25](F)[CH:26]=[CH:27][C:22]2=[N:21][N:20]=1)[CH:16]=[CH2:17]>CN(C=O)C>[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:25]2[CH:26]=[CH:27][C:22]3[N:23]([C:19]([N:18](/[CH:29]=[CH:30]/[CH3:31])/[CH:15]=[CH:16]/[CH3:17])=[N:20][N:21]=3)[CH:24]=2)[CH2:6][CH2:5]1
Reactant: C=CCN(CC=C)c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C/C=C/N(/C=C/C)c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
To a suspension of sodium hydride (40% in mineral oil, 690 mg, 17.31 mmol) in DMF (20 mL) was added Intermediate A (1.12 g, 6.92 mmol) and the reaction mixture was stirred for 20 min at RT. A solution of Intermediate 101b (1.34 g, 5.77 mmol) in DMF (20 mL) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched by careful addition of MeOH and then loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product containing fractions were concentrated in vacuo and the resultant residue was purified by FCC on silica, using a gradient of 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (1.33 g, 61%) as an orange gum. 1H NMR (400 MHz, CDCl3): 0.92-1.13 (1H, m), 1.39 (6H, dd, J=7.2, 1.7 Hz), 1.82-2.16 (4H, m), 2.26-2.38 (1H, m), 3.93-3.99 (1H, m), 4.99-5.10 (2H, m), 5.18 (1H, t, J=4.4 Hz), 6.10 (2H, dd, J=8.2, 2.0 Hz), 7.09 (1H, dd, J=9.9, 2.2 Hz), 7.25-7.44 (3H, m), 7.48-7.53 (1H, m), 7.57-7.66 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:6]
Reactant: Nc1ccccc1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 13.7 %

Procedure:
To a solution of 1.0 g 2-aminobenzoic acid and 1.39 g of 4-amino-1-benzylpiperidine in 10 mL of methylene chloride was added 1.18 g of HOBT followed by 2.10 g of EDC. After stirring at rt for 6 hours, the reaction mixture was diluted with methylene chloride. The organic phase was washed with brine and dried over anhydrous MgSO4. Concentration under reduced pressure followed by flash chromatography eluting with 9% EtOAc in hexane, 50% EtOAc in hexane and 10% MeOH in EtOAc afforded 309 mg of the title compound as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].[NH3:17]>[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Ni]
Product: CC(C)(C)OC(=O)N1CCC(N)CC1

Procedure:
100.0 g (0.50 mol) of 1-tert-butoxycarbonyl-4-piperidone were subjected to reductive amination in 300 ml of ammonia-saturated methanol in the presence of 20.0 g of Raney nickel at 100° C. and a hydrogen pressure of 100 bar. After the catalyst had been removed by filtration, the mixture was concentrated. This gave 95.5 g of a brown oil (95.4% of theory).
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[N:20]#[C:21][NH2:22].O>CCCCCC.C(OCC)(=O)C>[NH2:22][C:21]1[N:1]=[C:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:20]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: N#CN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N)nc1C(C)C
Reaction time: 5 h
Yield: 22 %

Procedure:
5.00 g of methyl 2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate (18.7 mmol) were treated with 5 ml of N-N-dimethylacetamide and 15.71 g of a 50% strength aqueous cyanamide solution (187 mmol) and heated to reflux. After 5 h, the solution was poured onto 50 ml of water. The mixture was cooled in an ice bath and the deposited precipitate was isolated by means of a suction filter. After drying, 2.72 g of crude product were obtained in the form of a yellowish solid. After flash chromatography (150 g of silica gel; eluent: hexane/ethyl acetate 3:2), 1.19 g of methyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate were isolated in the form of a colourless solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[CH:15][CH:16]=1)[C:12](O)=[O:13])([O-:7])=[O:6]>C(Cl)(Cl)Cl>[OH:17][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:16]=[CH:15][C:11]=1[C:12]([Cl:3])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1O
Yield: 74.5 %

Procedure:
Thionyl chloride (1.6 mL, 22 mmol) was added slowly to a solution of 4-nitrosalicylic acid (1.0 g, 5.46 mmol) in chloroform (20 mL) at 0° C. The mixture was brought to reflux and maintained for 5 h. Excess thionyl chloride was evaporated to give 2-hydroxy-4-nitro-benzoyl chloride (0.82 g, 75%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH3:9])=[O:7])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:12]([C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[F:21])=[C:3]([CH:1]=[O:2])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Temperature: 90 °C
Yield: 100.6 %

Procedure:
To a round bottle flask, was added methyl 3-formyl-4-(trifluoromethylsulfonyloxy)benzoate (6300 mg, 20 mmol), 2-fluoro-5-methoxyphenylboronic acid (10 g, 61 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), potassium phosphate tribasic (6.6 mL, 81 mmol) (granular) and tetrakis(triphenylphosphine)palladium (2.3 g, 2.0 mmol). The flask was flushed with nitrogen, DME was added, and the mixture was heated at 90° C. for 6 hours. The reaction mixture was diluted with EtOAc and water. The organic phase was washed with water and brine and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was removed in vacuo to give a residue which was purified by chromatography to give the product as a yellow solid (5.80 g, 100%). MS ESI m/e: 289.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.F[C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:15]([C:14]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[CH:13]=1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=Cc1cccc(F)c1F
Solvent: O
Solvent: CCO
Product: O=C1CC(c2cccc(F)c2)Oc2ccc(Br)cc21
Yield: 15 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (22.6 g, 0.11 mol), 2,3-difluoro-benzaldehyde (15 g, 0.11 mol) and borax (40.2 g, 0.11 mol) in ethanol (140 mL) and H2O (234 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (5.3 g, 15%). 1H-NMR (CDCl3): 2.95 (d, 1H), 3.05 (t, 3H), 5.75 (d, 1H), 6.97 (d, 1H), 7.20 (m, 2H), 7.35 (m, 1H), 7.60 (d, 1H), 8.05 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11](SC)=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[O:3]1.OO[S:29]([O-:31])=[O:30].[K+].Cl[CH2:34]Cl>CO>[CH3:26][C:2]1([CH3:1])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:29]([CH3:34])(=[O:31])=[O:30])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[O:3]1
Reactant: O=S([O-])OO
Reactant: ClCCl
Reactant: CSc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)cc1
Agent: [K+]
Solvent: CO
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(S(C)(=O)=O)cc2)C1=O

Procedure:
50 mg of 2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-4-{4-(methylthio)-phenyl}-3(2H)-furanone (Example 72) in 10 ml dichloromethane and 2 ml methanol was stirred with 300 mg of OXONE at room temperature for 4 hours. The insoluble material was filtered off and the filtrate was washed with aqueous sodium bicarbonate. The organic layer was then concentrated under reduced pressure and was purified by column chromatography (ethylacetate) to give 45 mg of 2,2-dimethyl-4,5-di{4-(methylsulfonyl)phenyl}-3(2H)-furanone. mp: 245-257° C. NMR: δ1.60 (s, 6H), 3.08 (s, 3H), 3.10 (s, 3H), 7.50-7.53 (m, 2H), 7.79-7.82 (m, 2H), 7.94-8.00 (m, 4H). IR (cm−1): 2931, 1698, 1510, 1387, 1258, 1150, 960, 846, 770.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)(=[O:4])=[O:3].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl.[H-].[Na+]>CN(C)C=O>[O:4]=[S:2]1(=[O:3])[CH2:1][C:8](=[O:10])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]1[CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1ccccc1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1c2ccccc2C(=O)CS1(=O)=O
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
In a dry round bottom flask under a blanket of nitrogen 60% sodium hydride in mineral oil (1.05 g, 26 mmol) was washed with hexanes and then suspended in N,N-dimethylformamide (50 mL). Mixture was cooled to 0° C. A solution of methyl 2-(methylsulfonamido)benzoate (5.0 g, 22 mmol) in 10 mL N,N-dimethylformamide was added to the mixture drop-wise. Reaction was held at 0° C. with stirring for 25 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride was added to the mixture drop-wise. Reaction stirred for 2 hours slowly warming to ambient temperature. Reaction was quenched with 1N hydrochloric acid. Material was extracted twice with ethyl acetate. Material was washed successively with water and brine. Organic phase was dried (magnesium sulfate), filtered and concentrated to dryness. Residue was dissolved in N,N-dimethylformamide (5 mL) and added drop-wise to a mixture of 60% sodium hydride in mineral oil (1.02 g, 26 mmol) that had been washed with hexanes, suspended in N,N-dimethylformamide (50 mL) and cooled to 0° C. Ice bath was removed and the mixture was allowed to warm to room temperature. Reaction was held at room temperature overnight with stirring. Reaction was quenched with 1N hydrochloric acid. Material was extracted twice with ethyl acetate. Organic phase was washed successively with water and brine. Organic phase was dried (magnesium sulfate), filtered and concentrated to dryness. Silica gel chromatography (ethyl acetate-hexanes) afforded the title compound as a white solid in 72% yield. MS m/e (M−H)−=326.0.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[CH3:22].O=S(Cl)[Cl:25]>C(Cl)(Cl)Cl.CCCCCC>[ClH:25].[Cl:25][CH2:2][CH2:3][NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[CH3:22]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NCCCl
Product: Cl

Procedure:
Dissolve the N-(2-hydroxyethyl)-2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline (40.0 g, 0.12 mol) in 300 ml CHCl3. Add a solution of SOCl2 (59.5 g, 0.50) in 100 ml CHCl3. Reflux 16 hours, allow to cool, and dilute with an equal volume of hexane. Filter to give solid, m.p. 190°-196° C. (dec.), N-(2-chloroethyl)-2,6-dimethyl-4-(hexafluoro-2-hydroxy-2-propyl)aniline hydrochloride. The corresponding free base has m.p. 101°-104° C.