Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[C:17]([CH2:19][N:20]([C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32]2[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=2)[CH2:27][CH2:26]1)[S:21]([CH3:24])(=[O:23])=[O:22])#[N:18]>>[Cl:38][C:37]1[C:32]([NH:31][C@H:28]2[CH2:27][CH2:26][C@H:25]([N:20]([CH2:19][C:17]#[N:18])[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:30][CH2:29]2)=[N:33][C:34]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:35][CH:36]=1
Reactant: CS(=O)(=O)N(CC#N)[C@H]1CC[C@H](Nc2nc(Cl)ncc2Cl)CC1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@H]4CC[C@H](N(CC#N)S(C)(=O)=O)CC4)n3)cc2CC1

Procedure:
trans-N-(4-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-N-cyanomethyl-methanesulfonamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and trans-N-cyanomethyl-N-[4-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 308c. Product isolated as a white solid (60 mg, 40%). m.p.=159-162° C.; LCMS (m/e) 562 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.92 (s, 1H), 7.37 (d, 1H, J=8.0 Hz), 7.25 (s, 1H), 7.06 (d, 1H, J=8.0 Hz), 6.81 (s, 1H), 5.03 (d, 1H, J=7.2 Hz), 4.24 (s, 2H), 4.0-3.81 (m, 2H), 3.56 (t, 2H, J=5.7 Hz), 3.38 (s, 3H), 3.09 (s, 3H), 2.97-2.88 (m, 4H), 2.82-2.67 (m, 6H), 2.40-2.29 (m, 2H), 2.13-2.03 (m, 2H), 1.87-1.72 (m, 2H), 1.54-1.38 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O-:11])([O-])=O.[Na+].[Na+].[OH2:14]>ClCCl>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:8]([C:6]1[CH:5]=[CH:4][N+:3]([O-:14])=[CH:2][CH:7]=1)=[O:11]
Reactant: O
Reactant: Nc1ccccn1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccccn1)c1cc[n+]([O-])cc1
Temperature: 25 °C

Procedure:
A stirred suspension of the acid chloride in dichloromethane (50ml) at 0° was treated with 2-aminopyridine (1.823 g, 19.4 mmol), warmed to room temperature. After 3 hours the mixture was evaporated in vacuo to give a solid. The solid was dissolved in water (100 ml) and the solution basified with saturated aq. Na2CO3 solution. The precipitate was filtered and recrystallised from water to give the title compound as a three quarter hydrate (1.274 g), m.p. 232°-233° .
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH:14]([OH:17])([CH3:16])[CH3:15].[O:18]=[P:19]12OP3(OP(OP(O3)(O1)=O)(=O)[O:20]2)=O>CCCCCC>[P:19]([OH:20])([O:17][CH:14]([CH3:16])[CH3:15])([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:18]
Reactant: CC(C)O
Reactant: CCCCCCCCCCCCO
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCCCCC
Product: CCCCCCCCCCCCOP(=O)(O)OC(C)C

Procedure:
Dodecyl isopropyl hydrogen phosphate was prepared by slowly adding a mixture of 0.2 g. mole each of 1-dodecanol and isopropyl alcohol to a stirred slurry of 0.1 g. mole of P2O5 in 100 ml. hexane, holding the temperature of the reaction mixture below its boiling point by use of a water bath. After the addition was complete, stirring was continued until the mixture was clear and then the hexane was distilled off, the last portion under reduced pressure. The product was a clear, colorless liquid which crystallized slowly into a waxy, white solid. It was primarily the desired mixed ester with small amounts of the two symmetrical diesters.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:36][CH:33]2[CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CC1
Solvent: CCO
Solvent: O
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CC4)ncnc32)[C@]1(C)F
Yield: 62 %

Procedure:
To a stirred solution of ((2R,3S,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added cyclopropylamine (about 0.296 ml, 5.19 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.13 g) as a colorless gummy mass. Yield: 62%;
Reaction SMILES: [C:1]1(=[O:29])[N:5]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[C:4](=[O:24])[C:3]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]12.C(=O)([O-])[O-].[K+].[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>CN(C)C=O.ClCCCl>[C:17]1(=[O:18])[N:13]([NH:12][CH2:11][CH2:10][N:9]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:8][CH2:7][NH:6][N:5]2[C:4](=[O:24])[C:3]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:2]3[C:1]2=[O:29])[C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1NCCNCCNN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1NCCN(CCNN1C(=O)c2ccccc2C1=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
36.34 g (100 mmol) of 1,7-bis(phthalimido)-1,4,7-triazaheptane [produced according to J. Org. Chem. USSR, 23:3302 (1987)] is dissolved in 500 ml of dimethylformamide. Then, 16.6 g (120 mmol) of potassium carbonate as well as 20.53 g (120 mmol) of benzyl bromide are added to it and stirred overnight at 25° C. It is poured in ice water, the precipitated product is suctioned off, rewashed with water, taken up in 1,2-dichloroethane, dried on sodium sulfate and evaporated to dryness in a vacuum. The title compound is obtained as solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:16]2[CH2:15]1)=[O:13].[Br:27]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[Br:27][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:9])[F:11])[C:2]=3[Cl:1])=[O:13])[CH2:15][C:16]2=[N:22][C:21]=1[C:23]([F:26])([F:24])[F:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nc(C(F)(F)F)c2Br)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.181 g, 0.455 mmol, Example 2) was dissolved in N,N-dimethylformamide (DMF) (2 mL) and treated with N-bromosuccinimide (NBS, 0.097 g, 0.546 mmol). The solution was stirred at room temperature for 16 hr. The mixture was poured onto water (100 ml) containing 1% sodium sulfite (w/w) and extracted into ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to afford crude product (0.323 g). The crude product was purified by mass-directed automated preparative HPLC to afford 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.135 g, 0.283 mmol, 62.2% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)Cc2ccc(F)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-(4-fluorophenyl)acetyl chloride were treated using a method similar to that described in Example 4C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.04-7.94 (m, 1H), 7.95-7.86 (m, 1H), 7.45-7.36 (m, 3H), 7.23-7.13 (m, 2H), 4.47-4.41 (m, 2H), 3.66 (s, 2H), 1.37 (s, 9H); MS (ESI−) M/Z 425 (M−H)−.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([C:17]2[C:22]([CH2:23][CH3:24])=[N:21][C:20]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[C:19]([CH2:31][CH3:32])[N:18]=2)=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.CN(C=O)C.C([SiH](CC)CC)C>C(OCC)(=O)C.O.C1(PCCCPC2C=CC=CC=2)C=CC=CC=1>[CH2:31]([C:19]1[C:20]([NH:25][CH:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[N:21][C:22]([CH2:23][CH3:24])=[C:17]([C:16]2[CH:7]=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=2)[N:18]=1)[CH3:32]
Reactant: CCc1nc(-c2cc3c(cc2OS(=O)(=O)C(F)(F)F)CCCC3)c(CC)nc1NC(CC)CC
Agent: CC[SiH](CC)CC
Agent: c1ccc(PCCCPc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc(-c2ccc3c(c2)CCCC3)c(CC)nc1NC(CC)CC
Temperature: 60 °C
Yield: 75.4 %

Procedure:
A 7 mL oven dried vial was charged with 3-{3,6-diethyl-5-[(1-ethylpropyl)amino]pyrazin-2-yl}-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (100 mg 0.2 mmol), 1,3-diphenylphosphinopropane (1.65 mg, 0.004 mmol), Pd(AcO)2 (0.9 mg, 0.004 mmol), and DMF (0.5 mL). The reaction was heated to 60° C. on the orbital shaker. Triethyl silane (0.08 mL, 0.5 mmol) was added at once. A color change from yellow to dark orange was observed. The vial was re-sealed with a teflon lined cap and heated to 60° C. for 2 hours. After cooling to ambient temperature, the reaction was diluted with ethyl acetate, poured in H2O, washed once with sat. aq. NaHCO3 and once with Brine. The organic layer was dried with Na2SO4, filtered and concentrated to 120 mg of a crude oil. The crude was purified by Biotage MPLC (40 g column, toluene) to give 53 mg (76%) of 3,6-diethyl-N-(1-ethylpropyl)-5-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-amine as a clear oil. Rf 0.18 (toluene). IR (liq.) 2964, 2933, 2874, 2858, 2837, 1558, 1508, 1483, 1463, 1444, 1392, 1381, 1212, 1173, 833 cm−1. OAMS supporting ions at: ESI+352.2. Anal. Calcd for C23H33N3: C, 78.58; H, 9.46; N, 11.95. Found: C, 78.20; H, 9.25; N, 11.95.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:19](=[O:21])[CH3:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CNCC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(Br)cc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To A mixture of 7-bromo-1,2,3,4-tetrahydroisoquinoline (500 mg, 2.36 mmol) and triethylamine (715 mg, 7.08 mmol) in dichloromethane (10 mL) was added acetyl chloride (221 mg, 2.83 mmol) at 0° C., then the mixture was stirred for 2 h at 0° C. Water (5 mL) was added and the mixture extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (3×10 mL) and dried with Na2SO4. The residue was concentrated then purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=5:1) to give 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (500 mg, 83%) as yellow oil. LC-MS: [M+H]+, 254, tR=1.533 min.
Reaction SMILES: [Cl-].Cl[C:3]1C(C)=C(C(C)=CC=1C)C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH2:33][CH2:34][CH3:35].C1OC1CC>>[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[CH:45]=[CH2:3])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Agent: CCC1CO1
Agent: [Cl-]
Product: C=CC(C)=CC=CC(C)=CC(=O)OCCCC

Procedure:
16 g of 3-chloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride and 10 g of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester are heated to boiling with stirring after the addition of 40 g of 1,2-butylene oxide. The 1,2-butylene oxide is slowly distilled off. The reaction mixture is stirred for 30 minutes at 80°-82° C., then cooled and thoroughly extracted with hexane. The hexane extract is shaken out 5 times with 50 ml of methanol/water 70:30 parts by volume each time, then dried over sodium sulphate and evaporated under reduced pressure to produce 9-(3-chloro-2,4,6-trimethyl-phenyl), 3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester as a residue.
Reaction SMILES: [OH:1]O.[F:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[C:6](=[O:15])C(=O)[NH:8]2.[OH-].[Na+].Cl>>[NH2:8][C:9]1[CH:10]=[C:11]([F:13])[CH:12]=[C:4]([F:3])[C:5]=1[C:6]([OH:15])=[O:1]
Reactant: OO
Reactant: O=C1Nc2cc(F)cc(F)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(F)cc(F)c1C(=O)O
Temperature: 70 °C

Procedure:
Hydrogen peroxide (35% solution in water, 23 ml) was added dropwise to a stirred solution of 4,6-difluoro-2,3-dioxoindoline (14 g) in a concentrated aqueous sodium hydroxide solution (33%, 115 ml) that was heated to 70° C. The mixture was heated to 70° C. for 15 minutes. The resultant mixture was cooled to 0° C. and the the mixture was acidified to pH4 by the addition of concentrated aqueous hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to give 2-amino-4,6-difluorobenzoic acid (12 g); NMR Spectrum: (DMSOd6) 6.25 (m, 1H), 6.38 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].C(O)C.C[O-].[Na+].Br[CH2:17][C:18]([OH:20])=[O:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)CBr
Reactant: Sc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: O=C(O)CSc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-dichlorothiophenol, 50 gm, was added to 250 ml of ethanol. 63.8 ml of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 3 hours. Afterwards, 20 ml of bromoacetic acid was added and the system then heated to reflux. The system was continued at reflux for 16 hours. The reaction was then stopped and the solvent removed by stripping. The resulting material was dissolved with basic aqueous solution and then washed with methylene chloride. Concentrated HCl was next added to the aqueous solution to acidify it. The product was extracted with methylene chloride. The methylene chloride solution was stripped and triturated with hexane. The product was then filtered, washed with water and air dried to yield 55.3 gm of the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[Cl:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][C:34]=1[S:39]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:41])=[O:40]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1cnccc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cnccc1Cl)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 20 mL resealable vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.26 g, 0.64 mmol, Example 91, Step 1), DCM (6 mL), triethylamine (0.44 mL, 3.2 mmol) and 4-chloro-3-pyridinesulfonyl chloride (0.16 g, 0.76 mmol). The mixture was stirred at room temperature for 15 min. To the reaction mixture was added saturated aqueous NaHCO3. The mixture was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was concentrated and purified by silica gel chromatography (0 to 70% EtOAc/hexane) to afford 2-(4-(4-((4-chloro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol as a white solid.
Reaction SMILES: O.[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[C:10](/[CH3:26])=[CH:11]/[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20]C)[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24]C)(=[O:4])[CH3:3].CCOC(C)=O>C(C#N)(C)=O>[C:2]([O:5][CH2:6][CH2:7][CH2:8][CH2:9]/[C:10](/[CH3:26])=[CH:11]/[CH2:12][C:13]1[C:14](=[O:24])[C:15]([CH3:23])=[C:16]([CH3:22])[C:17](=[O:20])[C:18]=1[CH3:19])(=[O:4])[CH3:3]
Reactant: COc1c(C)c(C)c(OC)c(C/C=C(\C)CCCCOC(C)=O)c1C
Agent: CC(=O)C#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCC/C(C)=C/CC1=C(C)C(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
Ceric ammonium nitrate (270 mg, 0.498 mmol) was dissolved into H2O (0.75 mL) and AcCN (1.5 mL) and the solution chilled to 0° C. 77.9 mg of (E)-7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-5-methylhept-5-enyl acetate (0.223 mmol) in AcCN (1.5 mL) was added over 2 minutes and the dark orange solution stirred for 0.5 h. H2O (3 mL) and EtOAc (3 mL) were then added, the layers separated and the organics washed 2×2 mL H2O. The combined aqueous phase was back extracted 3×5 mL EtOAc and the combined organics washed 2×5 mL saturated NaCl solution and dried over anhydrous Na2SO4. The resulting yellow liquid was concentrated to a yellow oil and subjected to flash chromatography, which yielded 25.8 mg of (E)-5-methyl-7-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)hept-5-enyl acetate as a bright yellow oil (36.2%). 1H NMR (400 MHz, CDCl3) d 4.95 (t, J=6.4 Hz, 1H), 4.02 (t, J=6.8 Hz, 2H), 3.19 (d, J=6.8 Hz, 2H), 2.01 (m, 11H), 1.73 (s, 3H), 1.55 (m, 2H) 1.42 (m, 2H). 13C NMR (100 MHz, CDCl3) d 187.9, 187.0, 171.1, 143.0, 140.4, 140.3, 136.7, 119.9, 64.4, 39.1, 28.1, 25.6, 24.1, 20.9, 16.1, 12.3, 12.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](Cl)=[C:7]([Cl:13])[N:6]=1)=[O:4].[CH3:14][O:15][C:16]([C:18]1[C:23]([NH2:24])=[N:22][C:21](Cl)=[C:20]([Br:26])[N:19]=1)=[O:17].[CH3:27][O:28][CH2:29][CH2:30][NH2:31].CCN(CC)CC>CN(C=O)C.O>[CH3:14][O:15][C:16]([C:18]1[C:23]([NH2:24])=[N:22][C:21]([NH:6][CH2:5][CH2:3][O:2][CH3:1])=[C:20]([Br:26])[N:19]=1)=[O:17].[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Reactant: COCCN
Reactant: COC(=O)c1nc(Br)c(Cl)nc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCNc1nc(N)c(C(=O)OC)nc1Br
Product: COCCNc1nc(N)c(C(=O)OC)nc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 3-amino-5,6-dichloro-pyrazine-2-carboxylic acid methyl ester [CAS 1458-18-0] and 3-amino-6-bromo-5-chloro-pyrazine-2-carboxylic acid methyl ester [CAS 14340-25-1] (799 mg, 3 mmol) in DMF was added 2-methoxy-ethylamine (0.31 ml, 3.6 mmol) and NEt3 (2.09 ml, 15 mmol) and the mixture was stirred at r.t. for 3.5 h. The reaction mixture was poured into water (150 ml) and extracted with toluene (2×150 ml). The organic layers were washed with half-saturated aq. sodium chloride, combined, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane/EtOAc 100:0 to 0:100%) to provide the title compound together with 3-amino-6-chloro-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acid methyl ester (about 1:1) as colorless solid. This mixture was used for the next step.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[OH:39])[OH:31]>>[OH:39][C:33]1[CH:34]=[C:35]([OH:38])[CH:36]=[CH:37][C:32]=1[CH:30]([OH:31])[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NCC(O)c1ccc(O)cc1O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)cc4O)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 2-amino-1-(2,4-dihydroxy-phenyl)-ethanol according to the procedure of Example 255 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 1.95–2.15 (m, 2 H), 2.08 (s, 3 H), 2.50–3.20 (m, 5 H), 3.60–3.70 (m, 2 H), 5.04–5.10 (m, 1 H), 6.65–6.75 (m, 1 H), 6.24 (dd, J=8.1, 2.1 Hz, 1 H), 6.32 (d, J=2.1 Hz, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 7.12 (d, J=8.1 Hz, 1 H), 7.59 (d, J=9.0 Hz, 2 H), 7.70 (d, J=9.0 Hz, 2 H), 9.26 (s, 1 H), 9.71 (brs, 1 H), 10.44 (s, 1 H); MS (ES) m/z: 541.4 (MH+); HRMS Calcd. for C27H33N4O6S (MH+): 541.2121. Found: 541.2084.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](SC)[N:8]=2)=[CH:5][N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.O[O:19][S:20]([O-:22])=O.[K+].[CH3:24]CCCCC.CCOC(C)=O>C1COCC1.O>[I:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:20]([CH3:24])(=[O:22])=[O:19])[N:8]=2)=[CH:5][N:4]([CH:15]([CH3:16])[CH3:17])[N:3]=1
Reactant: CSc1nccc(-c2cn(C(C)C)nc2I)n1
Reactant: CCCCCC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1cc(-c2ccnc(S(C)(=O)=O)n2)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine B-1-1 (15.5 g, 43 mmol) in THF (350 mL) and water (350 mL) was added oxone (39.6 g, 64.6 mmol) at 0-5° C. After the addition, the mixture was stirred at rt overnight. TLC (hexane:EtOAc=5:1) showed the reaction was complete, EtOAc (500 mL) was added. The organic layer was separated, washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated to give 4-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine B-1-2 (16 g, 94.9%).
Reaction SMILES: [CH3:1][S-:2].[Br:3][C:4]1[CH:9]=[C:8]([CH2:10]Br)[C:7]([F:12])=[CH:6][C:5]=1[O:13][CH3:14].O.C(OCC)(=O)C>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([CH2:10][S:2][CH3:1])[C:7]([F:12])=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: C[S-]
Reactant: COc1cc(F)c(CBr)cc1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)c(CSC)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
Thiomethoxide (1.19 g, 17.0 mmol) was added to a solution of 1-bromo-5-(bromomethyl)-4-fluoro-2-methoxybenzene (4.9 g, 16.4 mmol) in anhydrous DMF (25 mL) at 0° C. The mixture was stirred at room temperature for 5 h, and then poured into water (40 mL). Extractive work up with ethyl acetate gave the title compound (4.3 g, 99.0%) as colorless oil which was carried on without purification. 1H NMR (CDCl3, 400 MHz) δ 7.50 (d, J=8.0 Hz, 1H), 6.64 (d, J=11.2 Hz, 1H), 3.88 (s, 3H), 3.63 (s, 2H), 2.04 (s, 3H).