Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20](=[CH2:22])[CH3:21])[CH3:15].Cl>>[CH2:14]([O:16][C:17](=[O:28])[C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:19][C:20]([C:10]1[CH:11]=[C:6]([Br:5])[CH:7]=[CH:8][C:9]=1[O:12][CH3:13])([CH3:22])[CH3:21])[CH3:15]
Reactant: COc1ccc(Br)cc1
Reactant: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(O)(CC(C)(C)c1cc(Br)ccc1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
34.45 g (258.91 mmol) of aluminum trichloride is introduced into 354.35 g (237.02 mmol) of 4-bromoanisole. 38.95 g (172.19 mmol) of 2-hydroxy-4-methylene-2-(trifluoromethyl)pentanoic acid ethyl ester is added in drops to this mixture within one hour. After stirring overnight at room temperature, the batch is added to ice water and made acidic with 10% hydrochloric acid. After being extracted three times with ethyl acetate, the combined organic extracts are washed with 1N hydrochloric acid and brine. After drying on magnesium sulfate, the solvent is spun off. Most of the excess 4-bromoanisole is distilled off (10 mbar; bath temperature 110° C.). After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 36.87 g (51.8%) of the desired compound is obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([Si:9]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17](OC)=[O:18])[CH:14]=1)[CH3:8]>O1CCCC1>[CH2:23]([Si:9]([CH2:7][CH3:8])([CH2:21][CH3:22])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][CH2:16][CH2:17][OH:18])[CH:14]=1)[CH3:24]
Reactant: CC[Si](CC)(CC)c1cc(CCC(=O)OC)co1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(CCCO)co1
Reaction time: 0.33 h

Procedure:
Lithium aluminium hydride (a 1M solution in tetrahydrofuran; 5.17 ml, 5.17 mmol) was added dropwise to a solution of methyl 3-(2-triethylsilyl-4-furyl)propionate (1.38 g, 5.17 mmol) in tetrahydrofuran (5 ml) at 0 degrees under argon. After 20 minutes, the mixture was quenched with water and extracted with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave the desired alcohol, which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[F:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccccc1F
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1F

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-fluorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-fluorobenzoyl chloride in a similar manner as described above to give a yellow solid (57% yield). 1H-NMR (CDCl3): δ 8.91 (s, 1H), 8.15 (m, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.23 (dd, 1H), 7.18 (d, 1H), 7.12 (m, 2H), 5.35 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 387 (M−1).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH3:10][C:8]1([CH3:11])[O:9][CH:5]([CH2:4][NH2:1])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(CN=[N+]=[N-])O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(CN)O1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
5-(Azidomethyl)-2,2-dimethyltetrahydrofuran (22 g, 142 mmol) in THF (500 ml) was treated with Triphenylphosphine (39.0 g, 149 mmol) and t stirred for 5 mins. Water (50.0 ml) was added and the reaction mixture was heated at 80° C. for 4 hrs. The mixture was passed through Isolute® SCX-2 resin (200 g 0.67 mmol/g) eluting with MeOH (500 ml), DMSO (100 ml), 20% MeOH:DCM (500 ml), MeOH (500 ml) followed 7M ammonia in MeOH (500 ml). The ammonia layer was evaporated to dryness to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1O)=[CH:10][C:9]([NH:14][C:15](=[O:17])[CH3:16])=[C:8]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:25])=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:25][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1cc2ncc(C#N)c(O)c2cc1NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COCCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Temperature: 82.5 °C
Yield: 70.1 %

Procedure:
A stirred mixture of N-(3-cyano-4-hydroxy-7-(2-methoxyethoxy)quinolin-6-yl)acetamide (8.8 g, 0.029 mol, 1.00 equiv) in phosphorus oxychloride (70 mL, 0.765 mol, 26.4 equiv) was heated to 80-85° C. for 4 hours. The reaction mixture was cooled and filtrated. The filtrates were added to a cooled (0-10° C.) solution of potassium carbonate (270 g, 1.95 mol) in 470 ml water. The resulting yellow mixture was stirred for at least 12 hours. The mixture was filtered and washed with hot water. The collected solids were dried to give product 6.5 g. MS (ESI) m/z: 319 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([O:13]C)=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2cccc(Cl)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cnc(Cl)c2cccc(Cl)c12
Yield: 62.2 %

Procedure:
A solution of 1,5-dichloro-4-methoxyisoquinoline (1.2 g, 5.26 mmol) in DCM (15 ml) was added BBr3 (9.23 g, 34.8 mmol) at 0° C. drop wise. The reaction mass was refluxed for 5 h. The residue was cooled and quenched with methanol. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (0.7 g, 62.2%) as light brown color solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.28-8.25 (d, J=12 Hz, 1H), 7.85-7.82 (m, 2H), 7.68-7.64 (m, 1H); MS: MS m/z 214.0 (M++1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[N:10]([CH3:12])[C:9]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:22]1(C(OCC)=O)[CH2:26][CH2:25][CH2:24][C:23]1=O)#[N:2].C(O)(=[O:35])C.OS(O)(=O)=O>O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[NH:13][C:9]1[N:10]([CH3:12])[C:11]2[C:3]3[C:1](=[O:35])[NH:2][C:26]4[CH2:25][CH2:24][CH2:23][C:22]=4[C:4]=3[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CCOC(=O)C1(c2ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c3c2C#N)CCCC1=O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2ccc3c4c([nH]c(=O)c3c21)CCC4
Temperature: 100 °C
Yield: 43 %

Procedure:
A solution of the above benzimidazole (195 mg, 0.41 mmol) in a 1:1:1 mixture of water, acetic acid and H2SO4 (1.5 mL) was heated at 100° C. for 3 h. The reaction mixture was cooled and diluted with water. The precipitate was collected and washed with water. The collected yellow solid was purified by chromatography on SiO2 in CH2Cl2 /MeOH (20:1) to give the title compound (70 mg, 43%) as a light yellow solid. Mp>300° C. (dec.), MS (CI) m/z 399 (M++H).
Reaction SMILES: [CH2:1]([CH:19]1[CH2:33][NH:32][C:31](=O)[CH2:30][N:29](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][CH2:27][N:26](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24][N:23](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][C:21](=O)[NH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[CH2:1]([CH:19]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCC1CNC(=O)CN(S(=O)(=O)c2ccc(C)cc2)CCN(S(=O)(=O)c2ccc(C)cc2)CCN(S(=O)(=O)c2ccc(C)cc2)CC(=O)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC1CNCCNCCNCCNCCN1
Reaction time: 1 h
Yield: 62 %

Procedure:
To a slurry of 5-octadecyl-1,10,13-tris(p-toluenesulfonyl)-1,4,7,10,13-pentaazacylopentadecane-3,8-dione prepared as in Example 28H (4.00 g, 4.18 mmol) in anhydrous THF (100 ml) under a dry argon atmosphere was added a solution of lithium aluminum hydride in anhydrous THF (105 ml-1.0M, 105 mmol). The resulting solution was refluxed for 40 h. The mixture was quenched by the dropwise addition at 0° C. of H2O (3.25 ml), then 15% NaOH (3.25 ml) and finally H2O (9.60 ml). The resulting slurry was stirred for 1 h, THF (200 ml) was added and the white solid was filtered. The solid was washed with THF (200 ml) and then hot THF (300 ml). The filtrate and washings were combined and the solvent was removed in vacuo. The crude product was purified by recrystallization from THF--ethyl ether and then hexanes to give 1.21 g (62% yield) of the product as a white crystalline solid: mp 99°-100° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.7 Hz, 3H), 1.25 (m, 33H), 1.52 (m, 1H), 1.66 (br s, 5H), 2.34 (m, 1H), 2.72 (m, 18H); Exact mass (M+H)+ : calcd., 468.5005; found, 468.5034 (C28H62N5).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2.Cl[CH2:23][C:24]([CH3:26])=[CH2:25].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[CH3:25][C:24](=[CH2:23])[CH2:26][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:5]2
Reactant: O=C1c2ccc(O)cc2CCN1CCCc1ccccc1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=C(C)COc1ccc2c(c1)CCN(CCCc1ccccc1)C2=O
Temperature: 25 °C

Procedure:
To a solution of 6-hydroxy-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline (1.5 g, 5.34 mmol) in acetone (80 ml) is added 3-chloro-2-methylpropene (8 ml, 8.01 mmol), Cs2CO3 and a catalytic amount of KI. The reaction is then refluxed for 24 hours. After this time the reaction mixture is cooled to ambient temperature and filtered. The filter cake is washed with acetone (3×50 ml) and the combined organics concentrated in vacuo. The residue is chromatographed (silica gel, 1:4 EtOAc/hexane) to give 6-(2-methyl-2-propenyloxy)-2-(3-phenylpropyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[CH2:10]([C:12]1[NH:13][CH:14]=[C:15]([CH3:17])[N:16]=1)[CH3:11]>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:13]2[CH:14]=[C:15]([CH3:17])[N:16]=[C:12]2[CH2:10][CH3:11])(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: CCc1nc(C)c[nH]1
Solvent: C1CCOC1
Product: CCc1nc(C)cn1S(=O)(=O)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A dry round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 8.35 g of imidazole-4-sulfonylchloride and 180 ml of THF. The stirred solution was treated with 11.10 g of 2-ethyl-4-methylimidazole in one portion and stirred at room temperature overnight. The resulting precipitate was filtered off and the filtrate concentrated at reduced pressure to a foam. The foam was dissolved in ethyl acetate and the filtered solids partitioned between water and ethyl acetate. The combined organic layers were washed with water, dried with Na2SO4 and concentrated to give a waxy solid. Recrystallization was carried out using ethyl acetate and a small amount of hexane to give 8.13 g of 1-(4-imidazolylsulfonyl)-2-ethyl- 4-methylimidazole, mp 147°-8°, which recrystallized to mp 149°-50°, λmaxnujol 3.26 (NH), 7.30 (SO2N) and 8.68 μ (SO2N). NMR (DMSO, d6) 466 Hz, d, J = 2 Hz, 1H; 450 Hz, d, J = 2 Hz, 1H; 403 Hz, q, J = Hz, 1H; 170 Hz, q, J ~ 7.5 Hz, 2H; 116 Hz, d, J = 1 Hz, 3H; 66 Hz, t, J ~ 7.5 Hz, 3H.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1>>[CH:18]1([N:13]2[C:12]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccsc1
Product: c1cc(-c2c3c(nn2C2CC2)CCNCC3)cs1
Yield: 109.9 %

Procedure:
The title compound (134 mg) was prepared according to Example 281 using 200 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 281, Step C) and 84 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C14H17N3S, 259.11; found, m/z 260.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.64-7.63 (m, 2H), 7.31-7.29 (m, 1H), 4.65 (br s, 1H), 3.70-3.60 (br s, 1H), 3.57-3.52 (m, 1H), 3.40-3.38 (m, 1H), 3.19 (br s, 1H), 3.13-3.11 (m, 1H), 2.99-2.96 (m, 1H), 2.91-2.89 (m, 1H), 0.93-0.88 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]([Br:13])=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:15]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:13][C:9]1[C:10]([Cl:12])=[CH:11][C:2]2[NH:1][N:15]=[CH:14][C:3]=2[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c(N)cc(Cl)c1Br
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(Br)c(Cl)cc2[nH]ncc12
Reaction time: 24 h
Yield: 76.4 %

Procedure:
To a solution of methyl 3-amino-6-bromo-5-chloro-2-methylbenzoate (500 mg, 1.80 mmol) in acetic acid (9 mL) was added a solution of sodium nitrite (137 mg, 1.99 mmol) in water (0.9 mL) at room temperature, and the mixture was stirred for 24 hr. The organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (398 mg, yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([C:12](=[C:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])#[N:11]>C(OCC)C.[Cu]I>[C:10]([CH:12]([C:17]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])#[N:11]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)C(C#N)=C1CCOCC1
Agent: [Cu]I
Solvent: CCOCC
Product: COC(=O)C(C#N)C1(c2ccc(F)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A round bottom flask was equipped with a condenser, addition funnel and rubber septum with nitrogen inlet was charged with a solution of p-fluorophenylmagnesium bromide (2.0 M in diethyl ether, 1.99 ml, 3.97 mmol) and CuI (63 mg, 0.331 mmol) in 10 ml dry diethyl ether (10 ml). Methyl 2-cyano-2-(oxan-4-ylidene)acetate (600 mg, 3.31 mmol) in diethyl ether (10 ml) was added drop-wise over 30 min while cooling the reaction flask in an ice bath. The mixture was then stirred for 3 h. The reaction mixture was poured into a 50 g ice/1 N HCl (25 ml) mixture. The product was extracted with Et2O (3×50 ml), washed with brine (50 ml), dried (NA2SO4) and concentrated. Purified by normal phase SiO2 chromatography (7% to 60% EtOAc/hexanes) to give methyl 2-cyano-2-[4-(4-fluorophenyl)oxan-4-yl]acetate as a white solid (730 mg, 80%, m/z: 277.1 [M+Na]+ observed).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]3=[N:27][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: Nc1ncccc1-c1ccc(Oc2cccc(Cl)c2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4cccc(Cl)c4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 202 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.319 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(3-chlorophenoxy)phenyl)pyridin-2-amine (300 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. carefully. Water was added to form precipitates which were washed with water, hexane and collected. The precipitate was sonicated in EtOAc and the insoluble material was collected to give the title compound (248 mg) as an off-white solid. This was crystallized from THF-MeOH/IPE to give colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][C:30](=[O:36])[NH:31]2>>[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[CH:15][C:12]1[NH:11][C:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=3[C:13]=1[CH3:14])[C:30](=[O:36])[NH:31]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 61.6 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-dimethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (45 mg, 61.6%) as a yellow solid.
Reaction SMILES: [C:1]([C:4](=[C:9](OC)[CH3:10])[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].Cl.[C:14]([NH2:22])(=[NH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:23][C:24]([CH3:27])([O-:26])[CH3:25].[K+:28].Cl>C1COCC1.CO.CC(C)=O>[CH3:23][C:24]([CH3:27])([O-:26])[CH3:25].[K+:28].[CH3:2][C:1]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:9]([CH3:10])[N:22]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:21]=1
Reactant: N=C(N)c1ccccc1
Reactant: COC(=O)C(C(C)=O)=C(C)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nc(-c2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-acetyl-3-methoxy-2-butenoate (34.4 g, 0.2 mole), benzamidine hydrochloride (37.4 g), acetone (136 ml) and methyl alcohol (100 ml) were charged into a 1 L 3-necked, flask (fitted with addition funnel, condenser, agitator and nitrogen inlet). The reaction was blanketed with nitrogen, the agitator started and the batch cooled to between −5 and 0°C. While the batch was cooling, a solution of potassium t-butoxide was prepared (27 g in THF, 100 ml) under nitrogen. When the batch had reached the correct temperature, the potassium t-butoxide solution was charged slowly, keeping the temperature below 5° C. The batch was allowed to warm to about 25° C. The reaction was complete after about 1.5 hours. Concentrated hydrochloric acid was charged dropwise to bring the pH to 7. The batch was concentrated under vacuum until no more volatiles were collected. Methyl t-butylether (300 ml), 150 ml ethyl acetate and water (200 ml) were charged. The batch was agitated for 10 minutes, a small amount of solid was filtered off, and the layers were then separated. The organic layer was concentrated under vacuum to afford a solid residue of methyl 4,6-dimethyl-2-phenylpyrimidine-5-carboxylate, 48.7 g. m. p. 54–55° C., 1H NMR (CDCl3): δ2.58 (6H, s, CH3), δ3.89 (3H, s, OCH3), δ7.42 (3H, s, ArH), δ8.40 (2H, s, ArH). 13H CMR (CDCl3): δ168.78, δ165.24, δ164.11, δ137.57, δ131.34, δ128.93, δ128.92, δ124.12, δ52.86, δ23.65. HR-MS; Calculated for C14H15N2O2, m/z=243.1134. Found 243.1134.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][CH:3]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([N:14]=[C:10]1[N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][S:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCSC2=NCc2ccccc2)cn1
Temperature: 90 °C
Yield: 68.3 %

Procedure:
Then, a mixture of 228 mg (1 mmol) of 3-(6-chloro-3-pyridyl)methyl-2-iminothiazolidine, 180 mg (1.05 mmol) of benzylbromide and 276 mg (2 mmol) of anhydrous potassium carbonate in 10 ml of acetonitrile was heated for 3 hours at 90° C. under refluxing. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure. The resulting residue was mixed with dichloromethane and saturated sodium hydrogen carbonate aqueous solution, and the organic layer was separated. The water layer was extracted with dichloromethane, and combined organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by aminopropyl-coated silica gel (Chromatorex NH-type; Fuji Silysia Chemical Ltd.) column chromatography (eluent; hexane:ethyl acetate=2:1) to give 217 mg (yield; 68.3%) of 2-benzylimino-3-(6-chloro-3-pyridyl)methylthiazolidine as colorless oil. This product was dissolved in methanol and to this solution was added 79 mg (0.681 mmol) of fumaric acid, and the mixture was concentrated under reduced pressure. The resulting residue was treated with acetonitrile to give crystalline. The crystalline was collected by filtration and dried in vacuum to give 271 mg of fumarate of the title Compound 14.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].I[CH3:26]>>[CH3:26][O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CI
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Product: COc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 80.5 %

Procedure:
In a similar maser to Example 10(b), by reaction of 2 g (6.2 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde with 425 μl (6.8 mmol) of iodomethane, 1.68 g (88%) of the expected product are obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[F:14])=[O:5])#[N:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:1]([C:3](=[CH:17][N:18]([CH3:20])[CH3:19])[C:4]([NH:6][C:7]1[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=1[F:13])=[O:5])#[N:2]
Reactant: N#CCC(=O)Nc1c(F)cccc1F
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1c(F)cccc1F

Procedure:
As for Example 1, 2-cyano-2',6'-difluoroacetanilide as colorless crystals, m.p. 180°-181° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to yield 2-cyano-3-dimethylamino-2', 6'-difluoroacrylanilide as colorless crystals, m.p. 158°-159.5° C.