Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-ethanone (10 g, 0.0735 mole) in DMF (50 mL) was added K2CO3 (20.2 g, 0.147 mole) at ambient temperature. Benzyl bromide (13.83 g, 0.0808 mole) was then added and the resulting mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then quenched with iced water. The resulting precipitate was isolated by filtration and dried to afford 16.2 g (98%) of 1-(4-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 98.38%. A mixture of THF (130 mL) and NaH (60% w/w dispersion in oil) (5.28 g, 0.132 mole) was cooled to 0° C. with stirring for 5 minutes. Diethyl oxalate (12.87 g, 0.0886 mole) was added and the mixture was heated to reflux for 15 minutes. after cooling to ambient temperature 1-(4-benzyloxy-phenyl)-ethanone (10 g, 0.0442 mole) in THF (50 mL) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 70° C. for 1 hour. The reaction mixture was then quenched with cold aqueous NH4Cl solution. The resulting precipitate was isolated by filtration and dried to afford 21.2 g of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 36.5%. A solution of 4-(4-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (10 g, 0.03064 mole), acetic acid (20 mL) and hydrazine hydrate (1.685 g, 0.0337 mole) was heated to reflux for 8 hours. The reaction mixture was then poured into iced water and basified with saturated aqueous NaHCO3 solution. The product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6.3 g (64%) of 5-(4-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 95.10%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([OH:12])[CH2:7][CH2:6]2
Reactant: O=C1CCc2cc(C(F)(F)F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2cc(C(F)(F)F)ccc21
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
To a solution of 5-(trifluoromethyl)indan-1-one (0.7 g, 3 mmol) in THF (5 mL) cooled in an ice bath was added sodium borohydride (0.1 g, 3 mmol) followed by MeOH (1 mL). After being stirred for 30 min, the reaction was quenched with aqueous NaHCO3. The resulting solution was extracted with EtOAc twice. The extracts were washed with brine, dried (MgSO4), filtered and concentrated. The crude material was purified by flash chromatography on silica eluting with 20% EtOAc/hexane to afford the desired product (0.65 g, 92%) as an oil. LC/MS calculated for C10H9F3O: (M+H)+203; found 185.1 (M+H—H2O)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[Cl:26].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[C:25]([Cl:26])[CH:24]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Cl)c(Cl)c4)cc3CC[C@@H]12
Yield: 64.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 156 mg (64%) of the title compound as a foam. mp 129°-135°. FDMS: m/e=374. α[D]589 =+68.66 (c=1.03, chloroform).
Reaction SMILES: OC1C=CC([C:8]2[NH:9][C:10](=O)[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14](OC)=[CH:13][C:12]=3OC)=CC=1.C([Li])CCC>C1COCC1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:8][N:9]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)cc3)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.3 mmol) in CH2Cl2 (30 mL), oxalyl chloride (3.62 g, 28.5 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent and excess oxalyl chloride were removed at reduced pressure. The solid was dissolved in CH2Cl2 (10 mL) and methyl amine hydrochloride (1.33 g, 42.81 mmol) was added on cooling and the mixture was stirred at room temperature for 4 h. The solvent was removed and the crude product was purified by chromatography using 5% methanol in CH2Cl2, to give 1.3 g of the amide intermediate (43% yield). To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 M solution in hexane) was added slowly under nitrogen with cooling (ice-salt bath), maintaining the temperature below 20° C. The mixture was stirred for 1 h at 0° C., then cooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was added quickly. The cooling bath was removed and the mixture was stirred at room temperature for 16 h. Saturated aqueous NH4Cl solution was added with cooling, and the layers were separated. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to give the crude intermediate, which was purified by chromatography using 5% methanol in CH2Cl2, to give two products (1) 678 mg of isoquinoline in 26% yield and (2) 780 mg of quinalone product in 27% yield. To a suspension of the above quinalone product (780 mg, 1.65 mmol) in ethanol (20 mL), conc. HCl (2 mL) was added and the mixture was heated at 70° C. for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed and purified by chromatography to give 3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). Selected data: MS (ES) m/z: 297.93; MP 245-247° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].C(N(C(C)C)C(C)C)C.[NH:19]1[CH2:22][CH:21]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[O:24])[CH2:20]1>CN(C)C=O.O>[Cl:8][C:7]1[C:6]([N:19]2[CH2:22][CH:21]([C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH:35]4[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH2:40]4)(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])[CH2:20]2)=[CH:5][N:4]=[N:3][C:2]=1[Cl:1]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(NC(=O)C3CNC3)cc2)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(NC(=O)C3CN(c4cnnc(Cl)c4Cl)C3)cc2)CC1
Reaction time: 8 h

Procedure:
To 3,4,5-trichloropyridazine (1.624 g, 8.85 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.289 g, 17.71 mmol) in 50 mL N,N-dimethylformamide at 0° C. was added tert-butyl 4-(4-(azetidine-3-carboxamido)phenylsulfonyl)piperidine-1-carboxylate (2.5 g, 5.90 mmol) in 10 ml N,N-dimethylformamide, dropwise. The reaction mixture was stirred from 0° C. to room temperature overnight, diluted with water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, concentrated and purified by flash chromatography to give the title compound.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#N.[C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[Mg]>C(O)(C)C>[N:6]1[CH:7]=[CH:8][C:3]([C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:16])=[CH:4][CH:5]=1
Reactant: N#Cc1ccncc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-cyanopyridine (5.2 g, 0.05 mole) and benzophenone (9.1 g, 0.05 mole) in iso-propanol was added acetic acid (6.0 g, 0.1 mole) and magnesium metal (1.2 g, 0.05 mole). The resulting mixture was stirred at room temperature for 4 h. The precipitated product was filtered and washed with acetone, and upon analysis found to be 4-pyridyl diphenyl carbinol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:14])(=[O:15])[N:10]([CH3:27])[CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)NC3)c(F)c2)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)N(C)C3)c(F)c2)C(=O)O1
Yield: 75.1 %

Procedure:
N-[[(5S)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-1,2-thiazin-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (200 mg, 0.52 mmol), powdered potassium carbonate (85 mg, 0.62 mmol) and methyl iodide (88 mg, 0.62 mmol) were stirred under nitrogen in dry DMF (1 mL) for 24 hours. After evaporation of the solvent, the residue is partitioned between chloroform (65 mL) and water (15 mL). The chloroform is dried (MgSO4), filtered and evaporated. The residue is chromatographed over silica gel, eluting with 2-6% methanol-chloroform. The product is obtained as a white foam (156 mg, 75%). HRMS (FAB) calc'd for M+H=400.1342; Found: 400.1343.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:27]([N:29]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[N:30]2)[CH:26]=[CH:25][C:3]=1[O:4][CH:5]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].O.[OH-].[Li+].CO.C1COCC1>O>[CH3:1][C:2]1[CH:28]=[C:27]([N:29]2[CH:33]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:31]=[N:30]2)[CH:26]=[CH:25][C:3]=1[O:4][CH:5]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)NCCC(=O)O)cc1
Reaction time: 72 h
Yield: 92.9 %

Procedure:
A mixture of ethyl 3-(4-(1-(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)-benzamido)propanoate (55 mg, 0.11 mmol), lithium hydroxide monohydrate (7.2 mg, 0.3 mmol), methanol (2 ml), THF (2 ml), and water (0.3 ml) was stirred at 220 for 3 days. The mixture was concentrated, diluted with 8 ml of water and 0.35 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate, the extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain 3-(4-(1-(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)benzamido)-propanoic acid as a white solid (50 mg, 96%). 1H NMR (500 MHz, CDCl3) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.73 (d, J=8.29 Hz, 2H), 7.43 (d, J=2.68 Hz, 1H), 7.39 (d, J=8.29 Hz, 2H), 7.18 (dd, J=2.68, 8.78 Hz, 1H), 6.84-6.90 (m, 1H), 6.59 (d, J=8.78 Hz, 1H), 5.20 (dd, J=5.12, 7.56 Hz, 1H), 3.71 (q, J=5.94 Hz, 2H), 2.69 (t, J=5.85 Hz, 2H), 2.39 (s, 3H), 1.99-2.09 (m, 1H), 1.80-1.89 (m, 1H), 1.51-1.61 (m, 1H), 1.42-1.50 (m, 1H), 0.98 (t, J=7.32 Hz, 3H). MS (M+1): 4902.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC.Br[C:20]1[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])=[C:22]([O:32][CH3:33])[CH:21]=1.[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][NH:45][C:44](=[O:48])[CH:43]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCOCC1.[Cu]I>[CH2:34]([O:41][C:42]1[CH:47]=[CH:46][N:45]([C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([OH:28])([CH3:29])[CH3:27])=[C:22]([O:32][CH3:33])[CH:21]=2)[C:44](=[O:48])[CH:43]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: COc1cc(Br)ccc1OCC(C)(C)O
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(-n2ccc(OCc3ccccc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A mixture of potassium phosphate tribasic (633 mg, 2.98 mmol), N1,N2-dimethylcyclohexane-1,2-diamine (141 mg, 0.99 mmol), copper(i) iodide (189 mg, 0.99 mmol), 1-(4-bromo-2-methoxyphenoxy)-2-methylpropan-2-ol (328 mg, 1.19 mmol) Part A and commercially available 4-(benzyloxy)pyridin-2(1H)-one (200 mg, 0.99 mmol) in dioxane (1.0 mL) was stirred in a sealed tube at 110° C. for 60 min. After removal of the solids by filtration and concentration of the filtrate, the crude product was subjected to flash chromatography (silica gel/CH2Cl2-10% MeOH/CH2Cl2 100:0 to 0:100 gradient employing LC-MS to identify fractions containing the desired product). The semi-pure product thus obtained was further purified by prep-HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) to obtain 4-(benzyloxy)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one D-1 (298 mg, 74.3% yield) as a white foam. LC/MS 396 (M+H)+, tR 0.87 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ ppm 7.34-7.47 (5H, m), 718 (1H, d, J=7.78 Hz), 6.96 (1H, d, J=8.53 Hz), 6.80-6.90 (2H, m), 6.28 (1H, d, J=2.51 Hz), 6.16 (1H, dd, J=7.65, 2.64 Hz), 5.08 (2H, s), 3.85 (5H, s), 1.35 (6H, s).
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:5]=2[CH2:4][CH2:3]1.Cl[C:16]1[N:21]=[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:19]([Cl:34])=[CH:18][N:17]=1.C(O)(C)C.Cl.O1CCOCC1>>[Cl:34][C:19]1[C:20]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[N:21][C:16]([NH:13][C:10]2[CH:11]=[CH:12][C:5]3[CH2:4][CH2:3][C:2]([F:14])([F:1])[CH2:8][CH2:7][C:6]=3[CH:9]=2)=[N:17][CH:18]=1
Reactant: Nc1ccc2c(c1)CCC(F)(F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(F)(F)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Into a microwave vial was placed 7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (79 mg, 0.00040 mol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (100 mg, 0.0003 mol) in isopropyl alcohol (4 mL, 0.05 mol) with 4N HCl-dioxane (0.04 g, 0.0003 mol). The reaction was subjected to microwaves at 120° C. for 10 min. HPLC and LCMS indicated trace starting material remaining. The reaction mixture was resubjected to microwaves for an additional 10 min. A tan solid had precipitated out of solution and was collected by filtration. The solid was redissolved in methylene chloride (5 mL) and washed with sat. sodium bicarbonate (1×5 mL) and water (2×5 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give N-{(1R,2R)-2-[5-Chloro-2-(7,7-difluoro-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a brown solid (75 mg, 40%). MP: 118-128° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.93 (s, 1H), 7.62 (s, 1H), 7.46 (d, 1H, J=8 Hz), 7.18 (d, 1H, J=8 Hz), 7.07 (d, 1H, J=8 Hz), 6.71 (d, 1H, J=8 Hz), 3.84 (m, 1H), 2.94 (s, 3H), 2.70 (m, 4H), 1.99-2.09 (m, 6H), 1.71 (m, 2H), 1.18-1.39 (m, 5H); MS (m/e) 500 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[CH:26]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1)[CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1>O1CCOCC1>[CH3:49][O:48][C:46]([C:43]1[CH:42]=[CH:41][C:40]([CH2:39][CH:26](/[CH:25]=[CH:24]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:45][CH:44]=1)=[O:47]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Reactant: O=C1CCCN1CCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
2.33 g (14.4 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No. 91152-30-6] and 4.69 g (14.4 mmol) of anhydrous cesium carbonate are added to a solution of 3.2 g (7.2 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (enantiomer 1, Example 19A) in 50 ml of dry dioxane, and the mixture is then stirred at 60° C. for 12 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→2:1→1:1). This gives 2.98 g (5.23 mmol, 72% of theory) of a colorless oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[CH:25][C:26]([OH:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.C(Cl)(=O)OCC.Cl.[NH2:47][CH2:48][CH2:49]Cl>O.O1CCCC1.C(N(CC)CC)C>[O:28]1[CH2:49][CH2:48][N:47]=[C:26]1/[CH:25]=[CH:24]/[C:23]1[C:19]([O:18][CH2:17][C:16]2[CH:35]=[CH:36][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:39])=[C:14]([O:37][CH3:38])[CH:15]=2)=[N:20][N:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:22]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: NCCCl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C2=NCCO2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 0.67 h
Yield: 35 %

Procedure:
To a mixture of (2E)-{3-{3-[(4-([2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.60 g), triethylamine (0.14 g) and tetrahydrofuran (30 mL) was added ethyl chlorocarbonate (0.15 g) at −30° C. The reaction mixture was stirred at the same temperature for 40 min and added to a mixture of 1-amino-2-chloroethane hydrochloride (0.66 g), triethylamine (0.58 g) and tetrahydrofuran (20 mL) at −30° C. After stirring the reaction mixture at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, potassium carbonate (0.19 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-({4-[({4-[(E)-2-(4,5-dihydro-1,3-oxazol-2-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-2-(2-furyl)-5-methyl-1,3-oxazole as pale-yellow crystals (0.22 g, yield 35%) from a fraction eluted with ethyl acetate-methanol (50:1, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 162-163° C.
Reaction SMILES: C(Cl)(Cl)Cl.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)=[CH:8][CH:7]=1.S(Cl)(Cl)(=O)=O.O>CC(O)C>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2ccc(Br)cc2)SC1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CC(=O)c1csc(-c2ccc(Br)cc2)c1O
Temperature: -20 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A chloroform (249 mL) solution of 2-(4-bromophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (24.9 g, 64.6 mmol, purity: 78%) was cooled to −23° C., and a chloroform (50 mL) solution of sulfuryl chloride (5.45 mL, 1.05 equivalent amounts) was dropwise added over a period of 27 minutes, followed by stirring at −20° C. for 1 hour. The temperature of the solution was raised to −5° C., and water (50 mL) was dropwise added over a period of 3 minutes, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to obtain a crude product. To the obtained crude product, 2-propanol (374 mL) was added, followed by stirring at 0° C. for 40 minutes. The formed crystals were removed by filtration to give the desired product as a yellow solid (15.7 g, yield: 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][NH:6][CH2:7][CH:8]([O:10][CH3:11])[CH3:9])[CH3:2].C(N(CC)CC)C.[N:20]#[N:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[C:29]([S:36]([NH:39][C@H:40]([C:48](Cl)=[O:49])[CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:47])[NH2:46])(=[O:38])=[O:37])[CH:28]=[CH:27]2>C(Cl)(Cl)Cl>[N:20]#[N:21].[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]([C:48](=[O:49])[C@H:40]([CH2:41][CH2:42][CH2:43][NH:44][C:45](=[NH:46])[NH2:47])[NH:39][S:36]([C:29]1[CH:28]=[CH:27][C:26]2[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=2)[CH:30]=1)(=[O:38])=[O:37])[CH2:7][CH:8]([O:10][CH3:11])[CH3:9])[CH3:2]
Reactant: CCOC(=O)CNCC(C)OC
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2cc1OC
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(CC(C)OC)C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1.3 g of N-(2-methoxypropyl)glycine ethyl ester and 1.7 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6, 7-dimethoxy-2-naphthylsulfonyl)-L-arginyl chloride which was obtained in Example 3. The reaction mixture was stirred overnight at room temperature. At the end of this period, 50 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ether to give 2.4 g of powdery N2 -(6, 7-dimethoxy-2-naphthylsulfonyl)-L-arginyl-N-(2-methoxypropyl)glycine ethyl ester.