Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17](=O)[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].Cl.ClC1C=CC=C2C=1C(=O)OC(C1C=CC(OC3C=CC=CC=3)=CC=1)=C2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:31]([CH2:30][C:29]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:28]=3[F:27])[C:17](=[O:16])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1oc(-c2ccc(OCc3ccccc3)cc2)cc2cccc(Cl)c12
Reactant: NCc1ccc(F)cc1F
Agent: Cl
Agent: O=c1oc(-c2ccc(Oc3ccccc3)cc2)cc2cccc(Cl)c12
Solvent: Cc1ccccc1
Product: O=c1c2c(Cl)cccc2cc(-c2ccc(OCc3ccccc3)cc2)n1Cc1ccc(F)cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 3-(4-benzyloxyphenyl)-8-chloro-isochromen-1-one (1.7 g, 4.7 mmol) and 2,4-difluorobenzylamine (0.75 mL, 6.3 mmol) was prepared in toluene (25 mL) in a 100 mL round-bottomed flask under nitrogen. To the resulting suspension was added a solution of methyl aluminoxane (5.0 mL, of a 1.5 M solution in toluene, 7.5 mmol). Gas evolution was observed as the aluminoxane solution was added. The resulting suspension was then heated to reflux. As the solution came to reflux the solids dissolved to afford a brown solution. After stirring at reflux for 16 hours, an aliquot of the reaction was worked up with aqueous HCl, and analyzed by TLC. There was no visible 8-chloro-3-(4-phenoxyphenyl)-isochromen-1-one, and there were two product spots visible. Heating was discontinued and the reaction was allowed to cool to ambient temperature. The reaction was then quenched by the addition of 1N HCl (aq.) (50 mL), and diluted with EtOAc (100 mL). The layers were separated and the acidic aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (50 mL), saturated aqueous NaHCO3 (30 mL), then brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a white foam. The crude foam was purified by silica gel column chromatography eluting with a gradient from 0% to 30% EtOAc/hexane. Two product peaks were collected from the column: The first peak that eluted was concentrated to afford 3-(4-benzyloxyphenyl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one, a compound of formula (Id), (1.68 g, 73% yield); 1H-NMR (400 MHz, CDCl3): δ 7.51-7.48 (2H, m), 7.46-7.33 (6H, m), 7.11-7.07 (2H, m), 7.04-6.96 (1H, m), 6.95-6.91 (2H, m), 6.78-6.71 (1H, m), 6.66-6.59 (1H, m), 6.39 (1H, s), 5.17 (2H, s), 5.10 (2H, s); and the second peak that eluted was concentrated to afford 2-[2-(4-benzyloxyphenyl)-2-oxoethyl]-6-chloro-N-(2,4-difluorobenzyl)benzamide, a compound of formula (W) (533 mg, 22% yield); 1H-NMR (400 MHz, CDCl3): δ 7.78 (2H, d, J=8.8 Hz), 7.45-7.30 (5H, m), 7.26-7.14 (3H, m), 7.00-6.93 (3H, m), 6.71 (1H, t, J=6.3 Hz), 6.56-6.49 (1H, m), 6.45-6.37 (1H, m), 5.12 (2H, s), 4.40 (2H, d, J=6.3 Hz), 4.16 (2H, s).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:33](C)[C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:27]=2)=[CH:22][CH:21]=1)=O.O>C1COCC1>[CH3:9]/[C:8](=[CH:18]\[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:41])[CH:27]=2)=[CH:22][CH:21]=1)/[C:6]([O:5][CH2:4][CH3:3])=[O:7]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(-c2cccc(CNC(=O)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
440 mg (11 mmol) of sodium hydride (80% in oil) and 10 ml of THF are introduced into a three-necked flask under a stream of nitrogen. A solution of 2.2 ml of triethyl 2-phosphonopropionate in 10 ml of THF is added dropwise, followed by a solution of 3 g (9.1 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared in Example 1(e)), and the mixture is stirred at room temperature for 3 hours. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvents, 3 g (80%) of ethyl (E)-2-methyl-3-(3′-{[(1-phenyl-methanoyl)amino]methyl}biphenyl-4-yl)acrylate are collected in the form of an oil.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][N:8]2[CH:7]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>O>[Br:5][C:6]1[S:10][C:9]2=[N:11][C:12]([C:14]([N:17]=[N+:18]=[N-:19])=[O:16])=[CH:13][N:8]2[CH:7]=1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NC(=O)c1cn2cc(Br)sc2n1
Temperature: 85 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Thionyl chloride (0.33 mol) was added to 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid (13.1 mmol). The reaction mixture was stirred at 85° C. during 3 hrs. The mixture was then concentrated under vacuum and the residue was taken in acetone (40 mL). The sodium azide (14.4 mmol) in water (5.2 mL) was added in one portion at 0° C. and the mixture was stirred at 0-10° C. for 45 min. Water was added, and the solid filtered off and washed with water and then with a mixture of water/acetone (50/50). The solid was dried in vacuo to give compound 9 as a beige solid in 80% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 8.27 (s, 1H), 8.49 (s, 1H); and MS (ESI, EI+) m/z=272.05-274.07 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](B(O)O)=[CH:11][C:10]=2[CH:17]=1)[CH3:2].[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[CH:31]=[CH:30][C:29](Br)=[C:28]([N+:33]([O-:35])=[O:34])[N:27]=1)[CH3:25])([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[CH:31]=[CH:30][C:29]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:17][C:10]=3[CH:11]=2)=[C:28]([N+:33]([O-:35])=[O:34])[N:27]=1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)c([N+](=O)[O-])n1
Reactant: CCOCOc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCOc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3[N+](=O)[O-])cc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a degassed solution of 5-ethoxymethoxy-benzofuran boronic acid (4) (0.69 g, 2.63 mmol) in ethanol (17.5 mL), (5-bromo-6-nitro-pyridin-2-yl)-methyl-carbamic acid tert-butyl ester 12 (0.50 g, 1.51 mmol), Pd(PPh3)2Cl2 (0.14 g, 0.20 mmol) and Et3N (0.48 mL, 3.46 mmol) were added. The reaction mixture was stirred at 90° C. for 30 minutes. The reaction mixture was cooled to 0° C. and clear filtered. Volatiles were removed under reduced pressure. The residue was diluted with water and the mixture was extracted with ethyl acetate. The organic extract was washed with brine and concentrated under reduced pressure. The crude product was purified by flash column chromatography. Evaporation of solvent gave title compound 13 (58% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:13]([CH3:14])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: CNC
Reactant: O=C(Cl)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
5-chloropyrazine-2-carbonyl chloride (2.13 gram, 12.05 mmol) and dimethylamine HCl salt (1.06 gram, 12.7 mmol) were suspended in dichloromethane (50 mL) with stirring. Triethylamine (5.04 mL, 36.2 mmol) in dichloromethane (25 mL) was added dropwise at 0° C. to the reaction mixture. The combined solution was warmed up to ambient temperature and stirred for 4 hours. The compound was diluted with dichloromethane, washed with 1N HCl, water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient of 30 to 80% ethyl acetate in heptane) to provide desired 5-chloro-N,N-dimethylpyrazine-2-carboxamide (SM-1: 2.24 g, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.74 (d, J=1.37 Hz, 1H) 8.53 (d, J=1.37 Hz, 1H) 3.15 (s, 3H) 3.12 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7](=[O:24])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[NH:19][CH:20]=[CH:21][CH:22]=1.[CH:28]1([CH2:31]Cl)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7](=[O:24])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[CH2:15][CH2:16][C:17]1[C:18](=[O:23])[N:19]([CH2:31][CH:28]2[CH2:30][CH2:29]2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CC1CCCCN1CCc1ccc[nH]c1=O)NCc1cccc(F)c1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC1CCCCN1CCc1cccn(CC2CC2)c1=O)NCc1cccc(F)c1

Procedure:
230 mg of N1-(3-fluorobenzyl)-2-[1-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]-2-piperidyl]acetamide obtained in Example 198, 0.08 ml of cyclopropylmethyl chloride, 450 mg of potassium carbonate and 5 ml of DMF were stirred at 60° C. for 1 hour. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate. The drying agent was filtered off, and the solvent was evaporated. The residue was purified by NH-silica gel column chromatography (hexane:ethyl acetate=1:1, subsequently ethyl acetate), to give 180 mg of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].I[CH3:20]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:20])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]#[N:16])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C#N)cc2n1C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
Treat a solution of 6-cyano-1H-indole-2-carboxylic acid ethyl ester (86 mg, 0.40 mmol) in THF (3 mL) with sodium hydride (60% disp. in mineral oil, 18 mg, 0.44 mmol) under N2. After stirring for 10 min, add iodomethane (68 mg, 0.48 mmol) and stir at rt for 3 h. Quench the reaction with sat. NH4Cl solution and extract several times with EtOAc. Dry the combined organic layers (Na2SO4) and concentrate to give a solid. Purify the crude product by silica gel chromatography (MeOH/DCM: 0% to 10%) to give the desired 6-cyano-1-methyl-1H-indole-2-carboxylic acid ethyl ester in 59% yield (54 mg, 0.24 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:31][CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (2.50 g, 7.80 mmol) in anhydrous DMF (20 mL) cooled to 0° C. in an ice bath was added a 60% dispersion of sodium hydride in mineral oil (0.47 g, 11.7 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. 2-tert-Butoxyethyl methanesulfonate (2.3 g, 11.7 mmol) was added and the mixture was stirred at 0° C. in an ice bath, then allowed to slowly warm to ambient temperature and stirred for 18 hours. The mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The layers were separated and washed with aqueous 1N HCl, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, 40M; 20% ethyl acetate/hexane) to afford (S)-benzyl 3-(tert-butoxycarbonyl(2-tert-butoxyethyl)amino)pyrrolidine-1-carboxylate (2.87 g, 88%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][CH:15]([SiH3])[CH:16]=C(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH:10]([OH:11])[CH2:16][CH:15]=[CH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CC(C)[SiH3]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC(O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution of the product of step b (20 mmol, 3.74 g) in 20 ml of CH2Cl2 at −78° C., 22 ml of a solution 1 M of TiCl4 in CH2Cl2 is added. After 10 min, trimethyallylsilane (22 mmol, 3.5 ml) in 20 ml of CH2Cl2 is added. After one hour the reaction is quenched with water. The organic layer is separated and extracted with CH2Cl2 (3×25 ml). The solution is anhydrified (Na2SO4) and after concentration 1.14 g of product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.C1(C)C=CC=CC=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]=[C:32]=[O:33])=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]3)=[O:33])=[CH:28][CH:29]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(Br)cc3)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 1-bromo-4-(isocyanatomethyl)benzene (0.201 g, 0.95 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.272 g, 85%). MS (ESI+) m/z 4.15 (M+H)+; MS (ESI−) m/z 413 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.95 (s, 3H), 4.36 (d, J 5.6, 2H), 7.23 (t, J 5.6, 1H), 7.33 (m, 2H), 7.56 (m, 2H), 7.76 (t, J 7.8, 1H), 7.85 (d, J 8.3, 1H), 8.41 (dd, J 1.5, 7.8, 1H), 8.82 (s, 1H), 9.06 (s, 1H), 9.35 (s, 1H); Anal. Calcd for Cl9H16BrN3O3: C, 55.09; H, 3.89; N, 10.14. Found: C, 55.06; H, 3.56; N, 9.84.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=3[CH:20]=2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To t-butyl 7-bromo-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g), 4-ethoxyphenyl borate (2.35 g), 1M potassium carbonate solution (25 ml) and ethanol (25 ml) was added toluene (100 ml), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphine palladium (0.55 g), and the mixture was refluxed under argon atmosphere overnight. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give t-butyl 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g) as yellow crystals.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reactant: NCCCCc1cccnc1
Solvent: C1CCOC1
Product: COc1cccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2cccc(OC)c2)c1
Yield: 89.2 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (32.36 g) and 3-pyridinebutanamine (11.4 g) in tetrahydrofuran (120 mL) was stirred for 18 hours at room temperature and was worked up in the usual manner. The crude material was purified by HPLC (ethyl acetate) and then triturated with ether-hexane to furnish 29.6 g of (E)-5,5-bis (3-methoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 84°-86° C. Crystallization of the product from ethyl acetate-ether provided 29.0 g of amide, mp 86°-88° C.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:10]([O:11][CH3:12])[C@H:9]([CH3:13])[O:8][C@@H:7]([O:14][C:15](=[O:42])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)[C@@H:6]1[O:43][CH3:44])[CH2:2][CH3:3].I[CH2:46][CH3:47]>>[CH2:1]([O:4][C@@H:5]1[C@@H:10]([O:11][CH3:12])[C@H:9]([CH3:13])[O:8][C@@H:7]([O:14][C:15](=[O:42])[N:16]([CH2:46][CH3:47])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]([F:41])([F:40])[C:36]([F:38])([F:37])[F:39])=[CH:30][CH:29]=4)[N:24]=3)=[CH:19][CH:18]=2)[C@@H:6]1[O:43][CH3:44])[CH2:2][CH3:3]
Reactant: CCCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Reactant: CCI
Product: CCCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)N(CC)c2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)[C@@H]1OC

Procedure:
Compound 207 was N-ethylated as in Example 82, using iodoethane instead of iodomethane, to give Compound 253. 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.22 (d, J=68 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.39 (d, J=8.6 Hz, 2H), 6.17 (s, 1H), 3.8 (q, J=7.5 Hz, 2H), 3.60-3.30 (m, 11H), 3.10 (br s, 1H), 1.38 (d, J=6.0 Hz, 3H), 1.20 (t, J=7.5 Hz, 3H); MS 659.12 ([M+H]30).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[CH:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:37]=[C:38]=O)(=O)=O.CN(C)C=O.Cl>ClCCl>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:32])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:38]#[N:37])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2)c1Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]pyrrole (1.20 g) in anhydrous dichloromethane (12 ml) was added a solution of chlorosulfonyl isocyanate (0.28 ml) in anhydrous dichloromethane (2.8 ml) dropwise in a dry ice-carbon tetrachloride bath. The mixture was stirred at the same temperature for 30 minutes and then at ambient temperature for additional 1 hour. Anhydrous dimethylformamide (0.4 ml) was added to this mixture dropwise in a dry ice-carbon tetrachloride bath. After stirring at the same temperature for 30 minutes and at ambient temperature for additional 1 hour, the reaction mixture was treated with 4N-hydrochloric acid under ice-water cooling for 30 minutes. The organic layer was isolated and the aqueous layer was extracted with chloroform twice. The combined organic phases were washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluted with n-hexane-ethyl acetate to give 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-cyanopyrrole (930 mg) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Cl:11][C:4]1[CH:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)c3c(n2)CCC3)CC1
Yield: 19.2 %

Procedure:
Following general procedure B1, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with tert-butyl piperazine-1-carboxylate (0.223 g, 1.2 mmol) to afford the title compound (0.052 g, 19%) as a yellow solid. MW=337.84. 1H NMR (CDCl3, 500 MHz) δ 6.39 (s, 1H), 3.56-3.50 (m, 4H), 3.49-3.44 (m, 4H), 2.92 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.08 (quin, J=7.5 Hz, 2H), 1.48 (s, 9H); APCI MS m/z 338[M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[NH:11][N:10]=1.Cl[CH2:16][C:17](=[O:19])[CH3:18]>O1CCOCC1>[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[N:11]([CH2:16][C:17](=[O:19])[CH3:18])[N:10]=1
Reactant: COc1n[nH]c(=O)s1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1nn(CC(C)=O)c(=O)s1
Reaction time: 20 h

Procedure:
69 g of potassium carbonate are added to a solution of 33 g of 5-methoxy-3H-[1,3,4]thiadiazol-2-one in 400 ml of dioxane and the reaction mixture is heated to 60°. Then 21 g of chloroacetone are added dropwise within a short period of time and the reaction mixture is stirred at 70° for 20 hours and then, at 20°, is filtered over Celite. The filtrate is concentrated by evaporation. The residue is stirred with diisopropyl ether and filtered with suction. 45 g of crystals of the title compound having a melting point of 66-67° are thus obtained.