Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=[O:22])[C:17]=3[CH:23]=2)[C:3]1=[O:24].[CH3:25][C:26](O)([CH2:28][C:29]([CH3:32])(O)[CH3:30])[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)C.C(OCC)(=O)C.O>[CH3:25][C:26]1[CH2:27][CH:21]([C:18]2[C:17]3[CH:23]=[C:13]([N:4]4[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[N:2]([CH3:1])[C:3]4=[O:24])[CH:14]=[CH:15][C:16]=3[S:20][N:19]=2)[O:22][C:29]([CH3:32])([CH3:30])[CH:28]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: CC(C)(O)CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=CC(C)(C)OC(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1, 2-benzisothiazole-3-carboxaldehyde(0.500 g, 0.00141 mol), 2,4-dimethyl-2,4-pentanediol (0.260 g, 0.00183 mol), p-toluenesulfonic acid (0.0100 g, 0.000071 mol) and toluene is stirred overnight at reflux with azeotropic removal of water. The mixture is cooled to room temperature, diluted with diethyl ether and ethyl acetate and washed with two prortions of water and brine. The organic layer is dried and concentrated in vacuo to a brown oil, which is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a white solid (0.200 g, 31.4%, mp 88-92° C.) which is characterized by NMR spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][OH:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:19](OC)([CH3:21])[CH3:20]>CC(C)=O.B(F)(F)F.CCOCC>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C@H:9]1[CH2:15][O:16][C:19]([CH3:21])([CH3:20])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: COC(C)(C)OC
Reactant: COC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (7.0 g, 30.0 mmol) in acetone (90 mL), there was added 2,2-dimethoxypropane (37 mL, 300 mmol) followed by BF3.Et2O (0.11 mL, 0.9 mmol). The resulting solution was stirred at rt overnight. Solvents were removed under vacuum, and the residue was redissolved in ether (100 mL), washed with sat'd NaHCO3 (20 mL). Upon concentrating under vacuum, the residue was purified by flash column chromatography to give (S)-tert-butyl 4-(2-methoxy-2-oxoethyl)-2,2-dimethyloxazolidine-3-carboxylate (7.51 g, 92%). MS m/z 296 (M+Na+).
Reaction SMILES: [CH3:1][N:2]([C:9]1[S:13][C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH3:20])[C:3](=[O:8])[CH2:4][CH2:5][S:6][CH3:7].B1([O-])OO1.[OH2:25].[OH2:26].O.O.[Na+].C([O-])(O)=O.[Na+].ClCCl>C(O)(=O)C>[CH3:7][S:6]([CH2:5][CH2:4][C:3]([N:2]([CH3:1])[C:9]1[S:13][C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][C:10]=1[CH3:20])=[O:8])(=[O:26])=[O:25]
Reactant: CSCCC(=O)N(C)c1sc(-c2cccnc2)nc1C
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc(-c2cccnc2)sc1N(C)C(=O)CCS(C)(=O)=O
Temperature: 65 °C
Yield: 52.8 %

Procedure:
To N-methyl-N-(4-methyl-2-pyridin-3-yl-thiazol-5-yl)-3-methylsulfanyl-propionamide (Compound 19, 132 mg, 0.43 mmol) in glacial acetic acid (4.0 mL) was added sodium perborate tetrahydrate (165 mg, 1.07 mmol), and the mixture was heated at 65° C. for 16 h. The reaction mixture was carefully poured into a separatory funnel containing saturated aqueous NaHCO3 resulting in gas evolution. When the gas evolution had ceased, dichloromethane was added and the layers were separated. The aqueous layer was extracted twice with dichloromethane, and all the organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 10% methanol/dichloromethane) to give the desired product as a white oil (77 mg, 65%): IR (KBr) 2927, 1675 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.10 (d, J=2.0 Hz, 1H), 8.68 (dd, J=4.9, 1.7 Hz, 1H), 8.19 (dt, J=8.2, 2.0 Hz, 1H), 7.41 (dd, J=7.9, 4.9 Hz, 1H), 3.41 (t, J=6.9 Hz, 2H), 3.28 (s, 3H), 2.96 (s, 3H), 2.77 (t, J=7.3 Hz, 2H), 2.38 (s, 3H); ESIMS m/z 340.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH2:50]3)[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3Nc3cnc(OC)c(F)c3)nc(C)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)CC3)cc2-c2cc(N)nc(C)n2)cc1F
Temperature: 80 °C
Yield: 80.7 %

Procedure:
A solution of 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.200 g, 0.264 mmol) in TFA (2 mL) at RT was treated with a few drops of triflic acid. The solution was heated to 80° C. for 90 minutes. The reaction mixture was allowed to cool to RT and was then concentrated. A few ice cubes were added and then saturated NaHCO3 (aq.) was added followed by CH2Cl2. The mixture was filtered and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 0% to 3% MeOH in CH2Cl2, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.110 g, 0.213 mmol, 81% yield) as a yellow solid. m/z (ESI, +ve) 517.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.17 (br. s, 1H); 8.35 (dd, J=13.01, 2.25 Hz, 1H); 8.22 (d, J=2.15 Hz, 1H); 8.17 (d, J=2.35 Hz, 1H); 7.95-7.98 (m, 1H); 7.04 (s, 2H); 6.80 (s, 1H); 3.94 (s, 3H); 3.61 (q, J=6.78 Hz, 1H); 3.11 (t, J=4.99 Hz, 4H); 2.87 (s, 3H); 2.53-2.58 (m, 5H); 2.43-2.50 (m, 2H); 1.38 (d, J=6.85 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4].[CH3:22]I>CN(C)C=O>[CH3:1][N:2]([CH3:22])[C:3]([C:5]1[N:6]([CH3:21])[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[C:13]=1[CH:12]=[CH:11][C:10]([Cl:14])=[CH:9]2)=[O:4]
Reactant: CNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Reactant: CI
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 0 °C

Procedure:
A suspension of 9.0 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid methylamide in 120 ml. of dimethylformamide is treated under argon at 0° C. with 5.0 g. of potassium tert. butylate and then stirred in an ice-bath for 30 minutes. At 0°-5° C. there are added 8 ml. of methyl iodide in one batch, the mixture is subsequently stirred for 2 hours at room temperature and poured onto 2 liters of ice-water. After the addition of 100 g. of sodium chloride, the separated oil is extracted with methylene chloride. The organic phase is washed with a solution of sodium chloride, dried over sodium sulfate and concentrated to dryness under reduced pressure. The oily residue is dissolved in 200 ml. of hot hexane. The solution obtained is cooled in an ice-bath, colorless crystals separating, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid dimethylamide having a melting point of 86°-88° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.[NH:34]1[C:38]([NH2:39])=[N:37][N:36]=[N:35]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:39][C:38]3[NH:37][N:36]=[N:35][N:34]=3)=[O:30])=[CH:31][CH:32]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2cc(O)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(N(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)C2CCC(C(C)(C)C)CC2)nc2cc(O)ccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 15 Step B (0.02 mmol, 10 mg), 1H-tetraazol-5-amine monohydrate (0.2 mmol, 21 mg), HOBt (0.2 mmol, 31 mg) and DIEA (0.3 mmol, 52 μL) in 0.5 mL of DMF was added EDC (0.2 mmol, 38 mg). The reaction was heated to 40° C. 15 min, then allowed to stand at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in ca. 2:1 dioxane/H2O and acidified with TFA, then purified by reverse-phase chromatography (Condition B). The product was lyophilized affording the title compound as a white solid. MS (ESI): m/z 503 (M+H). HPLC A: 1.88 min.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH-].[Na+].C(OCC)C>C1COCC1.O>[CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=Cc1ccc(C(=O)O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a well-stirred solution of methyl p-vinylbenzoate (36.0 g, 0.222 mole) in THF (200 mL) was added a solution of sodium hydroxide (17.78 g, 0.444 mole) in water (200 mL) at room temperature. After stirring overnight, water (100 mL), THF (150 mL), and ethyl ether (200 mL) was added and the phases separated. The aqueous phase was acidified with a solution of concentrated hydrochloric acid (41 mL) in water (90 mL) then extracted three times with THF (500-600 mL each). The latter combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to provide 32.7 g (99.5 percent) of white solids. Proton nmr (Gemini model 300 MHz) in deuterochloroform: delta 8.08 (2H), 7.50 (2H), 6.78 (1H), 5.90 (1H), 5.41 (1H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:31]([O:35][C:36](=[O:44])[CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1)([CH3:34])([CH3:33])[CH3:32].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[C:31]([O:35][C:36](=[O:44])[CH2:37][N:38]1[CH:42]=[CH:41][C:40]([NH:43][C:8](=[O:9])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:21])([F:22])[F:23])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:39]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Reactant: CC(C)(C)OC(=O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3c(cccc3C(F)(F)F)C2=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol, prepared as in Example 1) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (prepared as in US 20080021032, Example 3, 86 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then quenched by the addition of methanol and then diluted with methylene chloride. The organic layer was then concentrated in vacuo with silica gel (2.0 g). The silica gel with absorbed material was placed in a SIM and purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford {3-[(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (151 mg, 100%) as a white foam: HR-ES(+) m/e calcd for C26H31N4O4F3 [M+H]+ 521.2370, observed 521.2368; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.49 (s, 1H), 8.08 (d, J=7.46 Hz, 1H), 7.81 (d, J=7.67 Hz, 1H), 7.63 (t, J=7.67 Hz, 1H), 7.33 (d, J=2.34 Hz, 1H), 6.73 (d, J=2.34 Hz, 1H), 5.02 (dd, J=7.03, 8.52 Hz, 1H), 4.70-4.81 (m, 1H), 4.53-4.69 (m, 3H), 1.10-2.25 (m, 20H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]=[CH2:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[CH:16]=[CH2:17])[CH3:24]
Reactant: C=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=Cc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Temperature: 55 °C
Yield: 101.3 %

Procedure:
4-Benzyloxy-2-vinylphenol (0.40 g, 1,77 mmol) was dissolved in anhydrous DMF (4 mL), followed by the addition of ethyl bromoacetate (0.29 mL, 2.65 mmol), and cesium carbonate (0.75 g, 2.30 mmol). The mixture was then heated for 18 h (55° C.). The reaction mixture was then cooled and concentrated in vacuo. The crude residue was partitioned between EtOAc (70 mL) and water (40 mL). The organic layer was washed with brine, dried (Na2SO4), and removed in vacuo to give 0.56 g (100%) of a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.44-7.31 (m, 4H), 7.13 (d, J=2.9 Hz, 1H), 7.10-7.06 (m, 1H), 6.82 (dd, J=8.8, 2.9 Hz, 1H), 6.73 (d, J=9.3 Hz, 1H), 5.76 (dd, J=17.1 Hz, 1.5 Hz, 1H), 5.30 (dd, J=11.2, 1.5 Hz, 1H), 5.03 (s, 2H), 4.58 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H); MS (FIA) m/e 313 (M+1).
Reaction SMILES: [H-].[Na+].CC1C=CC(S(O[CH:14]2[C:18](F)([F:19])[CH:17]([C:21]3[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:16][CH2:15]2)(=O)=O)=CC=1.C1OCCOCCOCCOCCOC1.[Cl-].[NH4+]>O1CCCC1>[F:27][C:22]1[C:21]([C:17]2[NH:16][CH:15]=[CH:14][C:18]=2[F:19])=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CNC(c3cccnc3F)C2(F)F)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Fc1cc[nH]c1-c1cccnc1F
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate (18.0 g) in tetrahydrofuran (180 mL) was added sodium borohydride (3.68 g) under ice-cooling, methanol (90 mL) was further added, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate. To a suspension of sodium hydride (9.74 g) in tetrahydrofuran (100 mL) was added dropwise a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate in tetrahydrofuran (100 mL) under ice-cooling, 15-crown-5 (32.2 g) was added, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1) to give the title compound as a colorless solid (yield 6.35 g, 72%).
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[Cl:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[C:15](=[CH:26][NH:27][C:28]=3[CH3:29])[CH2:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:12]=2[CH:11]=1.C(Br)C#C.O>O1CCCC1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:31]=[CH:30][C:13]2[C:14]3[C:15](=[C:26]([CH2:3][C:1]#[CH:2])[NH:27][C:28]=3[CH3:29])[CH2:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:12]=2[CH:11]=1
Reactant: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: CC(C)[N-]C(C)C
Agent: C#CCBr
Agent: [Li+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCc1[nH]c(C)c2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
By means of a syringe 7 ml (4.2 mmole) of a 0.62 M tetrahydrofuran solution of lithium diisopropylamide was added dropwise to a solution of 1.3 g (4.0 mmole) of 8-chloro-6-(2-fluorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine in 30 ml of dry tetrahydrofuran which was cooled to -20° C. The solution was stirred at -20° C. for 5 minutes followed by the addition of 2.4 ml (25 mmole) of 80% propargyl bromide in toluene. The mixture was allowed to warm to room temperature and stirred for 2 hours. Water was added and the mixture was extracted with ether. The ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give an amber foam. Purification by column chromatography (silica gel, 20 g; eluent 5% ether in methylene chloride) gave a foam. Crystallization from a mixture of ether and petroleum ether gave cream prisms, (mp 179°-180°).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(OC)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-iodo 4-methoxy-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.94 (d, 1H), 7.49 (d, 1H), 7.26-7.38 (m, 8H), 7.06 (m, 1H), 6.94 (m, 2H), 6.63-6.70 (m, 3H), 4.97 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][C:9]([CH3:14])=[C:10]([CH2:11][CH:12]=[O:13])[C:6]=2[C:5](=[O:15])[N:4]([CH3:16])[C:3]1=[O:17].S(=O)(=O)([OH:20])N.Cl([O-])=O.[Na+]>CC(C)=O.O>[CH3:1][N:2]1[C:7]2[S:8][C:9]([CH3:14])=[C:10]([CH2:11][C:12]([OH:20])=[O:13])[C:6]=2[C:5](=[O:15])[N:4]([CH3:16])[C:3]1=[O:17]
Reactant: NS(=O)(=O)O
Reactant: Cc1sc2c(c1CC=O)c(=O)n(C)c(=O)n2C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1sc2c(c1CC(=O)O)c(=O)n(C)c(=O)n2C
Reaction time: 2 h

Procedure:
To a solution of Step 7 intermediate (900 mg, 3.57 mmol) and sulphamic acid (693 mg, 7.142 mmol) in acetone (17.8 ml) was added sodium chlorite (484 mg, 5.357 mmol) in water (5.35 ml) and reaction mixture was stirred for 2 h. The solvent was evaporated, diluted with water and acidified with 1N HCl. Solid obtained was filtered and dried to give 375 mg of title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 3.20 (s, 3H), 3.42 (s, 3H), 3.80 (s, 2H), 12.19 (br s, 1H); MS (m/z) 249.10 (M+H)+.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=O>O1CCCC1>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]/[CH:39]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCCCCCCBr
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCC/C=C\CCCCCCCCCBr
Yield: 64.6 %

Procedure:
60 g (0.13 mol) of (5-carboxypentyl)triphenylphosphonium bromide were suspended in 250 ml of tetrahydrofuran. 30 g (0.26 mol) of potassium t-butylate in 20 ml of tetrahydrofuran were then added. Subsequently, 26 g (0/11 mol) of 10-bromodecanal were added. After usual work up 28 g (65%) of crude 6Z-16-bromohexadec-6-enoic acid were obtained having the following characteristics: Z/E=93/7;
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: COC(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C
Yield: 85.8 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.500 g, 1.35 mmol), (2-methoxycarbonylphenyl)boronic acid (0.290 g, 1.62 mmol), sodium carbonate (0.857 g, 8.10 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.088 g, 0.135 mmol) in DME (10 mL) and H2O (2.5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.494 g, 86%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[NH:30][CH2:29][CH:26]([N:27]([C:10]3[C:11]([F:13])=[C:12]4[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:15])[CH2:28]1)[CH2:25][CH2:24][CH2:23]2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CC2CNC(C1)CN2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4)c(F)c21
Temperature: 25 °C

Procedure:
A solution of 0.81 g (3.0 mmol) of -ethyl-6, 7, 8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.66 g (3.3 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 1.35 ml (9.0 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile was heated under reflux for 3 hr. After cooling to room temperature the solid was collected by filtration to give 0.52 g {of the title compound, mp 245°-250° .