Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[N:10]=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:27]1[C:36]2[C:31](=[C:32](F)[C:33](F)=[C:34]([S:38]([O-])(=[O:40])=[O:39])[C:35]=2F)[C:30]([Cl:44])=[N:29][C:28]=1C1C(F)=C(F)C(F)=C(F)C=1F>C1COCC1>[Cl:44][C:30]1[C:31]2[C:36](=[CH:35][C:34]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[N:10]=[CH:11][S:12][CH:13]=3)(=[O:40])=[O:39])=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: COc1ccc(CNc2cscn2)cc1
Reactant: O=S(=O)([O-])c1c(F)c(F)c2c(Cl)nc(-c3c(F)c(F)c(F)c(F)c3F)c(F)c2c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2cscn2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-4-amine (Intermediate PPPPP; 0.085 g, 0.384 mmol) in THF (1.408 ml) was added lithium bis(trimethylsilyl)amide (0.403 ml, 0.403 mmol) drop wise over 10 min. The mixture was stirred for 15 minutes prior to the addition of a solution of perfluorophenyl-1-chloroisoquinoline-6-sulfonate (From Step 1 in Example 73; 0.15 g, 0.366 mmol) in THF (1.0 ml). After 45 minutes of stirring (ice melt) LCMS indicated that the reaction was nearly complete. The mixture was allowed to stir and slowly warm to room temperature overnight. LCMS indicated that the reaction was complete. The reaction was quenched by the addition of acetic acid (˜2 ml) and the resulting mixture was dried under reduced pressure and purified via silica gel chromatography (40 g silicycle HP column) ramping EtOAc in heptane (0-50%) providing product 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-4-yl)isoquinoline-6-sulfonamide. m/z (ESI) 446.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:35]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>O1CCCC1>[CH2:42]([N:41]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:18]([C:10]1[C:9](=[O:21])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]2[C:12]([N:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:19])[CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: O=C(O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Reactant: CCCCCCNCCCCCC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCN(CCCCCC)C(=O)c1nc2ccccc2n(Cc2ccccc2)c1=O
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
In 30 ml of tetrahydrofuran were dissolved 0.50 g of 1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxylic acid and 0.87 ml of triethylamine, and after cooling to −40° C., 0.19 ml of ethyl chlorocarbonate was added dropwise over 5 minutes. After stirring at −40° C. for 10 minutes, 0.46 ml of dihexylamine was added dropwise over 5 minutes. After stirring at −40° C. for an hour, the temperature was raised to room temperature over an hour, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue, after addition of ethyl acetate, was washed with water, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; chloroform) and recrystallized from hexane to give 0.53 g of N,N-dihexyl-1-benzyl-1,2-dihydro-2-oxoquinoxaline-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)/[CH:7]=[C:21]1\[C:22](=[O:26])[NH:23][C:24]2[C:20]\1=[CH:19][CH:18]=[C:17]([Cl:16])[CH:25]=2
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1cc(Br)ccc1OCC(F)(F)F
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cc(Br)ccc1OCC(F)(F)F
Temperature: 70 °C
Yield: 69.3 %

Procedure:
5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde prepared in Example 232a (11 g, 39 mmol) and 6-chlorooxindole (5.4 g, 32 mmol) were mixed in anhydrous methanol (50 mL) at room temperature. Then pyrrolidine (2.7 g, 39 mmol) was added dropwise. The mixture was then heated at 70° C. for 3 h. After cooled to 4° C., the mixture was filtered and resulting precipitate was collected, dried to give E/Z-3-[5-Bromo-2-(2,2,2-trifluoro-ethoxy)-benzylidene]-6-chloro-1,3-dihydro-indol-2-one as yellow solid (9.6 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NN2CCN(C)CC2)s1
Solvent: CCO
Solvent: O
Product: CN1CCN(NC(=O)c2ccc(C(=O)NN)s2)CC1
Temperature: 25 °C
Yield: 65 %

Procedure:
Methyl 5-(4-methylpiperazin-1-ylcarbamoyl)thiophene-2-carboxylate (218 mg, 0.77 mmol) in ethanol (60 mL) was refluexed with heating with hydrazine monohydrate (0.40 mL) for 6 hours and allowed to cool to room temperature, and the solvent was evaporated at 40° C. mL of diethyl ether was added to the resulting oil, and the precipitated solid was collected by filtration, washed with water and dried to give 142 mg of the desired product (yield 65%).
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 86.2 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.816 g, 7.033 mmol) in t-butyl methyl ether (16 ml), lithium hydroxide monohydrate (0.271 g, 6.46 mmol) was added and the mixture was stirred for 2.25 hours at room temperature. A solution of methyl (Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]-5-heptenate (8) (1.554 g, 3.920 mmol) in t-butyl methyl ether (4.7 ml) and water (0.75 ml) were added thereto, and the mixed solution was heat refluxed for approximately 24 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 47 g, ethyl acetate:hexane=1:4), to give methyl(Z)-7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]-5-heptenate (9) (1.787 g; 3.380 mmol; yield: 86.2%) as a pale yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:28][CH2:27]2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: Cc1cccc(CNC2CC2)c1
Product: Cc1ccc(N(CC(=O)N(Cc2cccc(C)c2)C2CC2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=3)[CH:3]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Oc1ccc2nc(-c3ccc(O)c(F)c3)cc(-c3ccc(Cl)cc3)c2c1
Yield: 87 %

Procedure:
This compound was prepared from 6b using 4-chlorophenylboronic acid according to method P. Orange powder; Yield: 87%; mp 140-147° C.; 1H-NMR (400 MHz, DMSO-d6) δ 7.03 (d, J=2.7 Hz, 1H), 7.06 (t, J=8.8 Hz, 1H), 7.32 (dd, J=9.1, 2.7 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.87 (s, 1H), 7.93-7.98 (m, 2H), 8.07 (dd, J=13.0, 2.1 Hz, 1H), 9.94 (s, 1H), 10.20 (s, 1H); MS (ESI) m/z 364/366 ([M−H]−), 366/368 ([M+H]+); Anal. Calcd for C21H13ClFNO2: C, 68.95; H, 3.58; N, 3.83. Found: C, 68.23; H, 3.54; N, 3.78.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[OH:12])=[O:3].[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=O>>[Cl:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]1[O:12][C:5]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=2[C:2](=[O:3])[CH:1]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COc1ccc(C(C)=O)c(O)c1
Product: COc1ccc2c(=O)cc(-c3ccccc3Cl)oc2c1

Procedure:
2 is prepared from 2-hydroxy-4-methoxyacetophenone and 2-chlorobenzoyl chloride by the procedure of Example 1. Material is purified by flash chromatography (gradient elution using 25% ethyl acetate in hexane and 10% ethyl acetate in chloroform; material is loaded on column in methylene chloride), yielding 2 with a melting point of 148.5°-149.5° C.
Reaction SMILES: O=C=[N:3]C1CC(C)(C)CC(C)(CN=C=O)C1.[C:17]([O:21][CH2:22][CH2:23]O)(=[O:20])[CH:18]=[CH2:19].[N-]=C=O>>[NH2:3][C:17]([O:21][CH2:22][CH3:23])=[O:20].[C:17]([O-:21])(=[O:20])[CH:18]=[CH2:19]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: C=CC(=O)OCCO
Agent: [N-]=C=O
Product: C=CC(=O)[O-]
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 2150.1 %

Procedure:
A 250 ml, 3 neck round bottom flask fitted with a mechanical stirrer and a thermometer was dried under nitrogen and charged with poly-7-FOX diol (polyfluorooxetane diol with heptafluoro group) (24.3 grams, 9.1 meq.) from Example 5. Isophorone diisocyanate (3.0 grams, 27.2 meq) and dibutyltindilaurate (12 mg) were added and the mixture was heated at 70 C. for 14 hours. The reaction mixture was cooled to room temperature and washed with heptane (2 times 100 mL each). The isocyanate-terminated poly-7-FOX prepolymer was then dissolved in tetrahydrofuran (50 mL) and treated with dibutyltin dilaurate (12 mg). The resulting solution was reacted with 2-hydroxyethyl acrylate (HEA, 1.16 gram, 10 meq) at room temperature. No observable exotherm was observed on the addition of HEA. The progress of the reaction was monitored by following the disappearance of the isocyanate band in an infrared spectroscopic spectrum (IR) at 2270 cm−1. The mixture was heated at a temperature of 60 C. for 4 hours. On completion, as indicated by the disappearance of the NCO band in the IR, the reaction mixture was precipitated into water (450 mL). The resulting solution was dried over magnesium sulfate, filtered and stripped of solvent under reduced pressure to produce 17.2 grams of a urethane-acrylate terminated poly-7-FOX.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(N[C:29](=[O:39])[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:30]1[C:29](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:38][CH:31]1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Product: CCOP(=O)(OCC)C(CC1C(=O)c2ccccc2OC1c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and tetralone (II), MS (m/e) 524, 479, 302 and 165; IR (neat) 2983, 1683, 1607, 1580, 1499, 1474, 1464 and 1257 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[H][H].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>CN(C)C=O.O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(C)(C)C)[nH]n1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3,5-di-tert-butyl-1H-pyrazole (1.00 g, 5.55 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.27 g, 6.8 mmol) under ice-cooling. After completion of hydrogen generation, methyl 4-(bromomethyl)benzoate (1.40 g, 6.11 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried to give the title compound (1.78 g, yield 98%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: Fc1cc2c(cc1Br)CCC(=S)N2
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1cc(F)c(Br)cc1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroquinoline-2(1H)-thione (122-4; 7.0 g, 0.026 mol) in n-butanol (30 mL) was added acetic hydrazide (4.81 g, 0.065 mol). Reaction mass was warmed at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.88-7.86 (d, J=7.6 Hz, 1H), 7.70-7.67 (d, J=10 Hz, 1H), 3.0-2.94 (m, 4H), 2.67 (s, 3H). MS (M+1): 284.2.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9](O)=[O:10])[C:6](=[O:12])[C:5]([NH:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1.Br.Br.[S:30]1[C:34]2[CH2:35][CH:36]([NH2:39])[CH2:37][CH2:38][C:33]=2[N:32]=[C:31]1[NH2:40]>>[NH2:40][C:31]1[S:30][C:34]2[CH2:35][CH:36]([NH:39][C:9](=[O:10])[CH2:8][N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([NH:13][S:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)(=[O:15])=[O:16])[C:6]3=[O:12])[CH2:37][CH2:38][C:33]=2[N:32]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2cccc(C(F)(F)F)c2)c(=O)n1CC(=O)O
Reactant: Nc1nc2c(s1)CC(N)CC2
Agent: Br
Product: Cc1ccc(NS(=O)(=O)Cc2cccc(C(F)(F)F)c2)c(=O)n1CC(=O)NC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[6-methyl-2-oxo-3-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)-1(2H)-pyridinyl]acetic acid and 4,5,6,7-tetrahydro-1,3-benzothiazol-2,6-diamine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a white solid compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:23][CH:22]=2)[N:3]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCC1CCc2cc(-c3ccc(O)cc3)nc(F)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cc3c(c(F)n2)C(=O)C(CCCCCCCC)CC3)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1-fluoro-3-(4-hydroxyphenyl)-7-octyl-6,7-dihydro-5H-isoquinolin-8-one are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1-fluoro-3-[4-(octyloxy)phenyl]-7-octyl-6,7-dihydro-5H-isoquinolin-8-one.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[C].[Pd]>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: OCCC=Cc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OCCCCc1ccc(O)cc1
Yield: 99 %

Procedure:
4-(4-benzyloxyphenyl)-3-buten-1-ol (1.70 g) was dissolved in a mixture of methanol-THF (1:1, 20 ml); 10% palladium carbon (0.17 g) was added, followed by vigorous stirring in a hydrogen atmosphere for 1.5 hours. The catalyst was filtered off; the filtrate was concentrated under reduced pressure to yield the titled compound (1.1 g) as a colorless crystalline powder.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:14]2[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
To a solution of p-cresol (5.76 g, 0.053 mol) and 1,3-dinitrobenzene (8.97 g, 0.053 mol) in 100 mL of dimethylsulfoxide was added cesium carbonate (43.4 g, 0.133 mol). The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature, quenched with water, and extracted with diethyl ether. The organic layers were combined, washed with 0.1 N HC1 and water, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 8.0 g (66%) of the desired 3-(4-methylphenoxy)nitrobenzene product as a yellow oil. 1H NMR (CDCl3) δ 7.83 (s, 1H), 7.64 (t, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 6.8 (d, 2H), 2.20 (s, 1H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:18])=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:19]/[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][C:28]([CH2:35][CH3:36])([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH3:30])/[C:9]1=[O:37])=O)(C)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:54])=[C:43]([CH:45]=[N:46][C:47]([O:49][Si](C)(C)C)=[CH2:48])[CH:44]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:37])[C:10]3([CH:19]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=4[O:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH2:29][CH3:30])[CH2:35][CH3:36])[CH2:48][C:47](=[O:49])[NH:46][CH:45]3[C:43]3[CH:44]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=3[CH3:54])[C:11]2=[CH:12][C:13]=1[F:18]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)c(F)cc21)C(=O)OC
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)OC
Yield: 19 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-benzylidene]-5-fluoro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.4 g, 2.5 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (8 mmol) in toluene (8 mL) to give the title compound (300 mg).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:5]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O.C(Cl)Cl>C(Cl)Cl.CO>[CH2:1]([S:3][C:4]1[N:9]2[CH:10]=[CH:11][N:12]=[C:8]2[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:21])=[O:20])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:5]=1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCSc1nc(-c2ccc(S(=O)(=O)Cl)c(OC)c2)cc2nccn12
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCSc1nc(-c2ccc(S(=O)(=O)N3CCCCC3)c(OC)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(5-Ethylsulfanyl-imidazo[1,2-c]pyrimidin-7yl)-2-methoxy-benzenesulfonylchloride (200 mg, 0.52 mmol) and piperidine (89 mg, 1.04 mmol) in CH2Cl2: MeOH (2:1, 5 ml). was stirred overnight at room temperature. Water was added to the reaction mixture and extraction was carried out with CH2Cl2. The combined organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated to give the crude product of 5-Ethylsulfanyl-7-[3-methoxy-4-(piperidine-1-sulfonyl)-phenyl]imidazo[1,2-c]pyrimidine which was purified by preparative thin layer chromatography (45 mg, 20%).
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[F:54].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:50]2[CH:51]=[CH:52][C:53]([F:54])=[C:48]([Cl:47])[CH:49]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 60 °C
Yield: 22 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (31 mg, 0.05 eq.), (R)-BINAP (76 mg, 0.05 eq.) and 3-chloro-4-fluoro-phenylboronic acid (850 mg, 2.0 eq.). 60 mL of MeOH and 6.0 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone. The reaction mixture was heated at 60° C. for 2 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 180 mg (22%) of the title product as a light yellow oil.