Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl.[CH3:54][C:55]1([OH:59])[CH2:58][NH:57][CH2:56]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:54][C:55]1([OH:59])[CH2:58][N:57]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:56]1
Reactant: CC1(O)CNC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1(O)CN(c2ccc([N+](=O)[O-])nc2)C1
Yield: 73.3 %

Procedure:
A mixture of 5-bromo-2-nitropyridine (3.28 g, 16.3 mmol), XantPhos (1.13 g, 1.96 mmol), Pd2 dba3 (1.19 g, 1.30 mmol), 3-methylazetidin-3-ol hydrochloride (2 g, 16.3 mmol) and Cs2CO3 (15.9 g. 48.9 mmol) in 1,4-dioxane (70 mL) was heated at reflux for 2 h. After the completion of the reaction, the mixture was filtered off, and washed with MeOH (100 mL). The filtrate was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 207a (2.5 g, 71%). MS: [M+H]+ 210.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=NN=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>O1CCCC1.CO>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[N:10]=[N:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:28][C:27]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=CCc1ccccc1
Reactant: Clc1ccccc1-c1nnc(-c2ccccc2Cl)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Clc1ccccc1-c1cc(-c2ccccc2)c(-c2ccccc2Cl)nn1
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
3,6-Bis(2-chlorophenyl)-1,2,4,5-tetrazine (4.6 g) and phenylacetaldehyde (2.0 g) were dissolved in tetrahydrofuran (60 ml). A solution of potassium hydroxide in methanol (1.5 ml, 1%) was added dropwise to the solution and left to stand for 5 minutes. The solution was evaporated to 20 mls volume and was then diluted with water (50 ml). The precipitated solid was filtered, washed with water and dried to give 5.5 g of desired product, mp 176°-178° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:17])[CH2:9][O:10]COCC)[CH:2]=[CH2:3].C(=O)(O)[O-].[Na+]>C(O)C=C.Cl>[CH2:1]([O:4][C:5](=[O:27])[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:17])[CH2:9][OH:10])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)CC[C@@H](COCOCC)NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C=CCO
Product: C=CCOC(=O)CC[C@@H](CO)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound prepared in Example 3(1) (5.02 g) in allyl alcohol (15 ml), concentrated hydrochloric acid (40 drops) was added, and the mixture was stirred for 30 minutes at 50° C. The reaction mixture was cooled to room temperature, neutralized by adding sodium bicarbonate and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate to give the title compound having the following physical data.
Reaction SMILES: C([NH:4][C:5]([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[NH2:26])=[O:18])(C(OCC)=O)[C:6]([O:8]CC)=[O:7])(=O)C>Cl>[NH2:4][CH:5]([CH2:16][C:17]([C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[NH2:26])=[O:18])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CC(=O)c1cc(Cl)ccc1N)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: Nc1ccc(Cl)cc1C(=O)CC(N)C(=O)O

Procedure:
A solution of diethyl acetamido-(2-amino-5-chlorophenacyl)-malonate (5.3 g, 0.01377 mol) in concentrated hydrochloric acid (60 ml) was refluxed for 7 h under stirring.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=O)[N:19]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=1)[C:18]2=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>C1COCC1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][N:19]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=1)[CH2:18]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccc(OCc3ccccc3)cc2C(=O)N1c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(N3Cc4ccc(OCc5ccccc5)cc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a stirred suspension containing LiAlH4 (0.133 g) in THF (10 mL) under nitrogen atmosphere was added 5-benzyloxy-2-(4-benzyloxyphenyl)isoindoline-1,3-dione (0.435 g) in THF (15 mL) dropwise. The reaction was stirred at room temperature for 30 min, poured into cold, saturated ammonium chloride (100 mL) and extracted with ethyl acetate (2×75 mL). The organic layer was washed with brine and dried over MgSO4. After evaporation of the solvent, the residue was dried under high vacuum yielding the title compound (0.4 g) as a brown solid. 1H NMR (DMSO-d6): 7.45-7.31 (m, 13H), 6.70 (d, 2H, J=8.5 Hz), 6.51 (d, 2H, J=8.5 Hz), 5.12 (m, 4H), 4.41 (m, 4H); MS: 408 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([OH:50])[CH:42]=1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:44]5[CH:45]=[CH:46][C:41]([F:40])=[CH:42][C:43]=5[OH:50])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1ccc(F)cc1O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5ccc(F)cc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
To (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.38 g, 0.63 mmol, 1 equiv), (4-fluoro-2-hydroxyphenyl)boronic acid (148 mg, 0.95 mmol, 1.5 equiv), and Pd(PPh3)4 (73 mg, 0.063 mmol, 0.1 equiv) was added DMF (6.3 mL that had been degassed by sparging with nitrogen for 10 min) Na2CO3 (0.63 mL of a 2 M aqueous solution, 1.27 mmol, 2 equiv) was added and the reaction was heated to 90° C. for 18 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a yellow glass (0.27 g, 68%). LCMS (M+1)=631.4.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[NH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:7]1[C:8]2[C:3](=[C:2]([NH:12][C@@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Brc1cccc2cnccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cccc3cnccc23)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
Into a 50 mL round bottom flask were added 5-bromoisoquinoline (1.12 g, 5.4 mmol), toluene (10 mL), (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.00 g, 5.4 mmol), palladium acetate (0.18 g, 0.8 mmol), rac-(±)-BINAP (0.500 g, 0.8 mmol), and cesium carbonate (2.80 g, 8.6 mmol). The vessel was evacuated, refilled with nitrogen and stirred at 80° C. for 12 h. The mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL), and the organic phase was dried over MgSO4, filtered and evaporated to afford the title compound (1.00 g, 59%). This material was of sufficient quality to be used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[CH2:13]([OH:19])[CH2:14][O:15][CH2:16]CO>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:19][CH2:13][CH2:14][O:15][CH2:16][CH2:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1
Reactant: OCCOCCO
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(OCCOCCO)c1ccc(O)c(Cl)c1
Yield: 70.1 %

Procedure:
A 500-ml eggplant type flask was charged with 50 g of 3-chloro-4-hydroxybenzoic acid methyl ester, 285 g of diethyleneglycol and further with 2.5 g of PTS (p-toluenesulfonic acid monohydrate) as a catalyst to form a mixture. The mixture was heated with stirring on an oil bath, externally regulated at a temperature of 150° C., to react the mixture for 5 hours. Thereafter, excess diethylene glycol therein was removed by means of vacuum distillation. The residue therein was poured into ice water and the precipitated crystals were recrystallized using benzene/ethanol to obtain 49 g of 3-chloro-4-hydroxybenzoic acid [2-(2-hydroxyethoxy)ethyl]-ester (melting point: 77.5° to 78° C.). To 100 ml of an acetonitrile solution containing 30 g of the 3-chloro-4-hydroxybenzoic acid [2-(2-hydroxyethoxy)ethyl]ester, 57.2 g of N-methylpyrrolidone and further 36 g of methacrylic acid chloride were added with stirring to form a solution. The solution was stirred for 8 hours at 40° C. to react the solution. Thereafter, excess methacrylic acid chloride was removed by means of vacuum distillation. The reaction mixture remaining therein was poured into ice water, and the precipitated crystals were obtained by filtration. The crystals were recrystallized with ethyl acetate/n-hexane to obtain 3-chloro-4-hydroxybenzoic acid [2-(2-methacryloyloxyethoxy)ethyl]ester (melting point: 57° to 58.5° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH:18]([NH2:27])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:29][C:30](Cl)=[O:31].[Na+].[I-].[I-].CC(C)([O-])C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]2([O:17][CH2:29][C:30](=[O:31])[NH:27][CH:18]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(Cc1ccc(F)cc1)C1(O)CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [Na+]
Product: O=C1COC2(CCN(C(=O)OCc3ccccc3)CC2)C(Cc2ccc(F)cc2)N1
Yield: 19 %

Procedure:
The title compound was prepared from aminoalcohol 103NLS28 (303 mg, 0.81 mmol) according to literature procedures (Clark et al., J. Med. Chem. 26:855-861 (1983)), by acylation of the amino function with chloroacetylchloride, followed by halogen exchange with NaI and ring closure of the iodide derivative in presence of tert-butoxide. Purification of the crude product by silica gel column chromatography, eluting with a stepwise gradient of 0-100% ethyl acetate in n-heptane, afforded the title compound (64 mg, 19% overall yield) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][C:29](=[CH2:31])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.B1C2CCCC1CCC2.[OH-:41].[Na+].OO>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:41])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-[8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazin-1-yl]-2-phenylquinoline (338 mg, 0.8 mmol) in dry THF (5 mL) was added 9-BBN (2.4 mL, 1.2 mmol, 0.5M in THF) dropwise at 0° C. under nitrogen atmosphere. The temperature was slowly warmed to rt overnight. The mixture was cooled to 0° C., and 3 mL 1N aq. NaOH and 0.6 mL 30% aq. H2O2 were added, the resulting mixture was stirred at 0° C. for 10 min, then rt for 30 min. The mixture was diluted with methylene chloride (30 mL), washed with brine (2×20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with hexanes:EtOAc=50:50→100% ethyl acetate), to obtain the title compound as a yellow solid, a mixture of cis and trans isomers in the ratio of 5:1; MS (ES+): m/z 441/443 (3/1) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 2.44-2.64 (m, 6H), 3.65-3.76 (m, 3H), 7.31, 7.33 (2×d, J=5.0 Hz, 1H, 1:5 ratio), 7.39-7.57 (m, 4H), 7.86-7.98 (m, 3H), 8.18 (m, 2H), 8.26 (d, J=8.6 Hz, 1H), 8.51, 8.53 (2×s, 1H, 5:1 ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[CH3:18][CH:19]([N:22]1[C:26](=[O:27])[N:25]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:40]4[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=4)[CH2:36][CH2:35]3)=[N:32][CH:33]=2)[CH:24]=[N:23]1)[CH2:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:18][CH:19]([N:22]1[C:26](=[O:27])[N:25]([C:28]2[CH:29]=[CH:30][C:31]([N:34]3[CH2:35][CH2:36][N:37]([C:40]4[CH:41]=[CH:42][C:43]([O:46][CH2:11][C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])([OH:10])[CH2:12][N:13]5[CH:17]=[N:16][CH:15]=[N:14]5)=[CH:44][CH:45]=4)[CH2:38][CH2:39]3)=[N:32][CH:33]=2)[CH:24]=[N:23]1)[CH2:20][CH3:21]
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Reactant: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)nc2)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC(O)(Cn5cncn5)c5ccc(Cl)cc5Cl)cc4)CC3)nc2)c1=O

Procedure:
A mixture of 2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (0.3 g, 1.1 mmole), 2-(2-butyl)-4-(2-[4-(4-hydroxyphenyl)piperazin-1-yl]pyridin-5-yl)-1,2,4-triazolin-3-one (see Preparation 5) (0.263 g, 0.67 mmole) and cesium carbonate (0.29 g, 0.89 mmole) in DMF (15 ml) was heated at 80° for 6 hours. The solvent was removed by concentration under reduced pressure and the residue was azeotroped with xylene (2×20 ml) under reduced pressure. The resulting material was partitioned between methylene chloride and water, the aqueous phase separated and re-extracted with methylene chloride. The combined organic extracts were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The residual material was purified by flash chromatography on silica gel eluting with methylene chloride (97):methanol (3):0.88 ammonia solution (1). The product obtained, after collection and evaporation of appropriate fractions, was further purified by flash chromatography on silica gel eluting with methylene chloride (94.5):methanol (5.5):0.88 ammonia solution (4.5). The resulting material obtained, after collection and evaporation of appropriate fractions, was triturated with hexane to yield the desired product, m.p. 84°-87° (0.16 g, 36%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Clc1cccc(CBr)c1Cl
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(Cl)c1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=C[CH:7]=[CH:6][C:3]=1C=O.[CH3:11][O:12][C:13]([O:16][CH3:17])(C)[CH3:14]>>[CH3:11][O:12][CH:13]([O:16][CH3:17])[C:14]1[CH:7]=[CH:6][CH:3]=[C:2]([F:1])[C:9]=1[F:10]
Reactant: O=Cc1cccc(F)c1F
Reactant: COC(C)(C)OC
Product: COC(OC)c1cccc(F)c1F

Procedure:
The title compound b.p. 58°-62° C. (1 mm Hg) was prepared from 2,3-difluorobenzaldehyde and 2,2-dimethoxypropane by an analogous procedure to that described in Example X19.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].CN(C=O)C.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:14][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A cold (ice-bath) suspension of sodium hydride (0.55 mole, hexane washed) in 100 mL of dry THF was stirred under a nitrogen atmosphere while a solution of 2-oxazolidinone in 500 mL of 10:1 THF:DMF was added dropwise. The resulting gray suspension was warmed to room temperature and stirred for 24 hour. Benzyl bromide (66 mL, 0.056 mole) was added to the resulting white suspension and stirred at ambient temperature 24 hour. The reaction was quenched by careful addition of 26 mL water and the resulting mixture was concentrated and poured into 500 mL of water. After extraction with methylene chloride, the combined extracts were washed with water and brine and dried over magnesium sulfate. Concentration in vacuo afforded 104 g of a yellow oil which was purified by Kugelrohr distillation (bp 100°/0.1 mm) to give 81 g (92% yield) of the product as a colorless liquid which solidified on standing at room temperature to a colorless solid, m.p. 76°-78°.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([N:12]2[C:17]3[N:18]=[C:19](S(C)(=O)=O)[N:20]=[CH:21][C:16]=3[CH:15]=[C:14]([C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[C:13]2=[O:34])[CH2:11][CH2:10][CH2:9][CH2:8]1.[N:35]1[S:36][N:37]=[C:38]2[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][C:39]=12>CS(C)=O.O.C(OCC)(=O)C>[N:35]1[S:36][N:37]=[C:38]2[CH:43]=[C:42]([NH:44][C:19]3[N:20]=[CH:21][C:16]4[CH:15]=[C:14]([C:26]5[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=5[Cl:33])[C:13](=[O:34])[N:12]([CH:7]5[CH2:11][CH2:10][CH2:9][CH2:8]5)[C:17]=4[N:18]=3)[CH:41]=[CH:40][C:39]=12
Reactant: CS(=O)(=O)c1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C3CCCC3)c2n1
Reactant: Nc1ccc2nsnc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc4nsnc4c3)nc2n1C1CCCC1

Procedure:
202 mg of potassium tert-butoxide are added in 3 installments, at ambient temperature under argon, to 500 mg of compound of formula (II), 8-cyclopentyl-6-(2,6-dichlorophenyl)-2-methylsulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one, and 249 mg of the compound of formula (III), 2,1,3-benzothiadiazol-5-ylamine, in suspension in 18 ml of DMSO. After a contact time of 45 min, the reaction medium is diluted with a mixture of water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are then washed with water and then with a saturated NaCl solution. After drying over sodium sulfate and filtering, the residue is chromatographed on silica (gradient: heptane 100 to heptane/ethyl acetate 60:40) and precipitated from diethyl ether to give 283 mg of the expected product in the form of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33])[CH:26]=[CH:25]2>>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([N:38]2[CH2:37][CH2:36][N:35]([S:32]([C:27]3[CH:26]=[CH:25][C:24]4[C:29](=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=4)[CH:28]=3)(=[O:34])=[O:33])[CH2:40][CH2:39]2)=[O:16])=[CH:18][CH:19]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1

Procedure:
In a similar manner to Referential Example 48 except for the use of methyl 4-(N-tert-butoxycarbonylaminomethyl)benzoate and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8](=[CH:11]N(C)C)[C:9]#[N:10])=O)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:8]([C:9]#[N:10])=[CH:11][N:42]=[C:40]([NH:39][C:29]3[CH:30]=[CH:31][C:32]([N:33]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]4)=[C:27]([O:26][CH3:25])[CH:28]=3)[N:41]=2)=[CH:15][CH:16]=1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Cl)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc(C#N)c(-c3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 2-(4-chloro-benzoyl)-3-dimethylamino-acrylonitrile (50 mg, 0.21 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (66 mg, 0.18 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (10 mg, 14%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.