Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(C(OCC)=O)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl-].[Na+].O>CS(C)=O>[CH:1]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCCc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CCCc2ccccc21
Temperature: 25 °C

Procedure:
Diethyl 3,4-dihydronaphthalene-1,1 (2H)-dicarboxylate (see J. Org. Chem., 54, 2713-18 (1989)) (5.129 g, 18.56 mmol), sodium chloride (2.17 g, 37.1 mmol) and water (1 ml) were heated in dimethyl sulfoxide (10 ml) at 180° C. for 1.5 days. After cooling to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give a crude product of ethyl 1,2,3,4-tetrahydronaphthalene-1-carboxylate as a yellow liquid. To a solution of the obtained liquid in methanol (20 ml)-tetrahydrofuran (10 ml) was added 1N aqueous sodium hydroxide solution (30 ml, 30 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, and washed with diethyl ether. The obtained aqueous solution was acidified with 1N hydrochloric acid and extracted twice with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from diethyl ether-hexane to give the objective substance.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a slurry of ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylate (1.04 g, 2.53 mmol) in THF (20 mL) was added 1.0 M of sodium hydroxide in water (20 mL). The reaction mixture was stirred at 80° C. overnight and was concentrated. The residue was diluted with 1 N HCl and a precipitate formed. The precipitate was filtered and dried to give 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (75) (0.88 g, 91%). LCMS: (FA) ES− 381.2. 1H NMR (400 MHz, d6-DMSO) δ: 13.00 (s, 1H), 7.65-7.72 (m, 2H), 7.36 (d, 1H), 3.73-3.79 (m, 4H) and 3.55-3.61 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:20]=[C:19]4[N:21]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]4=[C:17]([O:32][CH3:33])[CH:16]=3)=[CH:11][CH:10]=2)[CH2:3]1.[C:34](OC(N1C(C)CNCC1C)=O)(C)(C)C.Cl>>[CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]=[C:19]4[N:21]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[N:22]=[C:23]([CH2:24][CH3:25])[C:18]4=[C:17]([O:32][CH2:33][CH3:34])[CH:16]=3)=[CH:13][CH:14]=2)[CH2:3]1
Reactant: CCc1nn(-c2ccccc2)c2nc(-c3ccc(N4CC(C)NC(C)C4)cc3)cc(OC)c12
Reactant: CC1CNCC(C)N1C(=O)OC(C)(C)C
Agent: Cl
Product: CCOc1cc(-c2ccc(N3CC(C)NC(C)C3)cc2)nc2c1c(CC)nn2-c1ccccc1

Procedure:
The title compound was prepared according to the procedure as described in Example 98 reacting 6-(4-bromo-phenyl)-3-ethyl-4-ethoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine (according to Example 98) and 2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:16][O:17][C:18]=2/[CH:19]=C/C2C=CC=CC=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=[O:35].[Na+].C(OCC)(=O)C.O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:16][O:17][C:18]=2[CH:19]=[O:35])=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2/C=C/c2ccccc2)cn1
Agent: O=[Os](=O)(=O)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C=O)cn1
Yield: 72 %

Procedure:
A mixture of 5-[3-(4-fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (2.0 g, 4.5 mmol), osmium(VIII) oxide (28.6 mg, 0.11 mmol), sodium metaperiodate (3.85 g, 18 mmol), benzyltriethylammonium chloride (418 mg, 1.8 mmol) in dioxane (30 mL) and water (10 mL) was irradiated in the microwave for 15 min at 120° C. Extractive workup (ethyl acetate/water) was followed by drying of the organic phase over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) afforded the title compound (1.2 g, 72%) as a colourless gum. MS: m/e=371.1 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C@H:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C@H:11]1[C:17]1[CH:22]=[CH:21][C:20]2[O:23][CH2:24][O:25][C:19]=2[CH:18]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[CH3:16][N:13]1[CH2:14][CH2:15][C@H:10]2[C@H:11]([C:17]3[CH:18]=[C:19]4[O:25][CH2:24][O:23][C:20]4=[CH:21][C:22]=3[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9]2)[CH2:12]1
Reactant: CN1CC[C@H](NC(=O)c2ccccc2)[C@H](c2ccc3c(c2)OCO3)C1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CC[C@@H]2N=C(c3ccccc3)c3cc4c(cc3[C@@H]2C1)OCO4

Procedure:
7.0 g of cis-4-benzoylamino-3-(3,4-methylenedioxyphenyl)-1-methylpiperidine are heated to 90° in 75 cc of phosphorus oxychloride for 20 hours. The reaction mixture is subsequently evaporated to dryness, the residue is dissolved in 50 cc of ice water and a saturated potassium carbonate solution is added until the mixture is strongly alkaline. The reaction mixture is extracted with chloroform, and the chloroform mixture is washed with water, dried over sodium sulphate, and the solvent is evaporated. The residue is taken up in 20 cc of ethanol, and absolute hydrochloric acid in ethanol is added until an acid reaction to Congo red is obtained and precipitation is effected with ether. The precipitate, the dihydrochloride of the title compound, is recrystallized from ethanol/ether. Yellow coloured crystals having a M.P. of 248° (decomp.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]([NH:24][NH2:25])=[O:23])[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)([CH3:3])[CH3:2].[CH3:26]OC(OC)OC.CS(O)(=O)=O.CCOC(C)=O.CCCCCC>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]3[O:23][CH:26]=[N:25][N:24]=3)[N:16]=2)[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Oc1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 13.4 %

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(3-isopropoxy-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.29 g, 1.0 eq.) was dissolved in THF (7.5 mL, 26V), added trimethylorthoformate (0.095 g, 1.1 eq) and added methanesulphonic acid (0.048 g, 0.5 eq). The Reaction mixture was refluxed at 70° for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured in to ice water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic layers were washed with Brine solution. (3×15 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.28 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 35% to 40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (40 mg), Yield (13.42%). 1H NMR (400 MHz, CDCl3) δ8.46-8.54 (d, 1H), 8 (t, 2H), 7.89 (s, 1H), 7.38-7.42 (d, 1H), 7.28 (d, 1H), 7.01-7.23 (d, 1H), 4.72-4.75 (d, J=11.6 Hz, 1H), 1.59 (d, 6H): LCMS for C16H14F3N5O2 [M+1]+ 365.31 found 365.89 at 3.986 min(LCMS 95.75%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].COC1C=CC=CC=1[Mg]Br.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=O)[C:31]=3[C:40]([O:42]CC)=[O:41])=[CH:24][C:23]=2[O:22]1>C1COCC1.C1COCC1.CCOCC>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=2)[CH:31]1[C:40]([OH:42])=[O:41]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Reactant: COc1ccccc1Br
Agent: COc1ccccc1[Mg]Br
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Reaction time: 0.25 h

Procedure:
To dry magnesium turnings (81 mg, 3,4 mmol) under an argon atmosphere was added a solution of 2-bromoanisole (0.64 g, 3.4 mmol) in 5:1 THF/Et2O (3 ml). A portion of the resulting 2-methoxyphenyl magnesium bromide solution (0.45 ml, 0.51 mmol) was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (100 mg, 0.34 mmol) in THF (6 ml) under an argon atmosphere at 0° C. After stirring for 15 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 15% EtOAc/hexanes to afford the title compound. (100 mg, 68%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH3:19][O:20][C:21]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[CH:18][C:17]=1[CH:15]([OH:16])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Reactant: C1CCOC1
Product: COc1ccc(OC)c(C(O)c2cnccc2C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (110 mg, 0.52 mmol) in THF (3 mL) at −78° C. was added 1.0 M 2,5-dimethoxymagnesium bromide in THF (1.04 mL) and the reaction mixture was stirred for 15 min. The reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by chromatography of silica gel with 5% methanol in dichloromethane to yield {3-[(2,5-dimethoxy-phenyl)-hydroxy-methyl]-pyridin-4-yl}-phenyl-methanone as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30]([O:32]C)=O)=[CH:27][C:26]=3[CH:34]=2)[CH2:18][CH2:17]1)#[N:2].[NH3:35]>CO>[CH:11]1[C:3]([C:1]#[N:2])=[CH:4][C:5]2[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]5[O:29][C:28]([C:30]([NH2:35])=[O:32])=[CH:27][C:26]=5[CH:34]=4)[CH2:18][CH2:17]3)=[CH:7][NH:8][C:9]=2[CH:10]=1
Reactant: N
Reactant: COC(=O)c1cc2cc(N3CCN(CCCCc4c[nH]c5ccc(C#N)cc45)CC3)ccc2o1
Solvent: CO
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Temperature: 30 °C

Procedure:
Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate (41 g) was taken in methanol (1000 ml) under stirring at 25-35° C., followed by reacting with ammonia gas for 2 hours under pressure of 4 Kg/cm2. The separated solid was filtered and then dried to produce 32 g of vilazodone. The mother liquors were taken and the solvent was distilled off under vacuum until the solvent quantity reaches around 50 ml of the initial volume. The resulting mass was cooled to 25-30° C., followed by filtration and then drying to produce 6 g of Vilazodone (Purity by HPLC: 99.5%; Yield: 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:17]2[S:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[N:14][C:13]=2[CH3:12])=[CH:3][C:4]=1[F:11])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: CC(=O)Nc1nc(C)cs1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(C)=O)c(F)c2)s1
Temperature: 150 °C

Procedure:
Dry, degassed DMF (25 ml) is added to 1-(4-bromo-2-fluoro-phenyl)-ethanone (WO 2003095441) (1.25 g, 5.76 mmol), N-(4-methyl-thiazol-2-yl)-acetamide (0.75 g, 4.80 mmol), Bis (tri-t-butylphosphine) palladium (0) (0.245 g, 0.48 mmol) and caesium carbonate (3.13 g, 9.60 mmol), and the reaction mixture heated to 150° C. for 4 hours. The reaction mixture is filtered through celite and the filtrate reduced in vacuo. Purification of the crude product by chromatography on silica eluting with 2:1 iso-hexane:EtOAc affords the title compound as a yellow solid. (MH+) 293.25
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:24]3[NH:34][N:35]=[CH:36][C:23]3=[CH:22][CH:21]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:39][O-].[Na+].CCOC(C)=O.O>CCO.C1CCCCC1>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:25]([O:26][C:27]=3[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[C:24]3[NH:34][N:35]=[C:36]([Cl:39])[C:23]3=[CH:22][CH:21]=4)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-]Cl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cn[nH]c54)c3=O)cc2)CCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c(Cl)n[nH]c54)c3=O)cc2)CCC1
Reaction time: 2 h
Yield: 60 %

Procedure:
To a stirred solution of {1-[4-(6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (5 mg, 0.01 mmol) in EtOH (1 mL), was added sodium hypochlorite (10% aqueous solution, 0.4 mL) at RT. After 2 h, EtOAc and water were added. The resulting biphasic mixture was separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The reaction was repeated with {1-[4-(6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (20 mg, 0.039 mmol) and aqueous sodium hypochlorite (2 mL) in EtOH (3 mL) with initial cooling in a cold water bath. After workup, the resultant residues were combined and subjected to flash chromatography (SiO2, gradient 20 to 40% EtOAc in cyclohexane) to afford the title compound (16 mg, 60%) as a white solid. LCMS (Method H): RT=4.39 min, [M+H]+=542/544.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([O:15][CH3:16])=[C:7]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:6]=1)=[O:4].C(O)CO.[CH2:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][NH2:33])[CH3:26].O>C(O)(=O)C>[CH2:25]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][NH:33][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([O:15][CH3:16])=[C:7]([S:17](=[O:19])(=[O:20])[NH2:18])[CH:6]=1)=[O:4])[CH3:26]
Reactant: CCN1CCCC1CN
Reactant: COC(=O)c1cc(S(N)(=O)=O)c(OC)c2c1OCCO2
Solvent: OCCO
Solvent: CC(=O)O
Solvent: O
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)c(OC)c2c1OCCO2
Temperature: 50 °C
Yield: 72.9 %

Procedure:
150 g of methyl-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate and 750 cm3 of ethylene glycol were introduced into a balloon flask. After dissolution, 127 g of 1-ethyl-2-aminomethylpyrrolidine was added and the mixture was heated at 50° C. The resulting solution was dissolved with 2 liters of water and acidified by means of 120 cm3 of acetic acid. The precipitated formed was dried off, washed with water and then dried. The precipitate was then redissolved in 915 cm3 of hot water. The solution was filtered and then the base was precipitated with ammonia. The precipitate was dried off, washed with water and then dried. 144 g of N-(1-ethyl-2-pyrrolidyl-methyl)-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 110°-115° C.; yield: 73%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20].CCO>C1COCC1.O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ccc(Br)c2ccccc12
Temperature: -78 °C
Reaction time: 30 h

Procedure:
A solution of 114.38 g (400 mmol) of 1,4-dibromonaphthalene and 1 l of THF (absolute) is cooled to −78° C. under protective gas, 160 ml (400 mmol) of n-butyllithium (2.5M in n-hexane) are subsequently slowly added at this temperature, and the mixture is stirred at −78° C. for a further 30 h. A mixture of 52.3 ml (400 mmol) of chlorotrimethylsilane in 200 ml of THF (absolute) is added to the solution obtained in this way, and the mixture is slowly warmed to room temperature. After addition of 150 ml of EtOH and subsequently 300 ml of water, the organic phase is separated off, dried over magnesium sulfate and evaporated. The oil obtained in this way is distilled at 115-135° C. and 1.7 mbar, giving 80 g (286 mmol) (corresponding to 88% of theory) of the product having a purity of greater than 99.0% according to HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:15](=O)[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH3:26])[C:19]=3[CH3:27])[CH2:13][O:12][CH2:11]2)=[C:5]([CH3:28])[C:4]=1[CH3:29].[NH2:30][C:31]1[S:32][CH2:33][CH2:34][N:35]=1.CCO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:35]3[CH2:34][CH2:33][S:32][C:31]3=[N:30][C:15]3[C:14](=[CH:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH3:26])[C:19]=4[CH3:27])[CH2:13][O:12][CH2:11][C:10]2=3)=[C:5]([CH3:28])[C:4]=1[CH3:29]
Reactant: COc1ccc(C=C2COCC(=Cc3ccc(OC)c(C)c3C)C2=O)c(C)c1C
Reactant: NC1=NCCS1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc(C=C2COCC3=C2N=C2SCCN2C3c2ccc(OC)c(C)c2C)c(C)c1C
Yield: 74.5 %

Procedure:
A stirred solution of tetrahydro-3,5-bis[(4-methoxy-2,3-dimethylphenyl)methylene]-4H-pyran-4-one (3.0 g, 7.6 mmole) and 2-amino-2-thiazoline (1.0 g, 9.7 mmole) in 75 ml of CHCl3 is heated at reflux temperature for 72 hours. After cooling, the solution is filtered to remove a small amount of insoluble material. The solvent is evaporated to give an oily residue. Trituration with warm EtOH yields 2.7 g of a yellow solid, m.p. 226°-228° d. Crystallization from 15 ml of DMF gives 2.3 g (63%) of cream colored product, m.p. 235°-237°.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1C(=O)N([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][C@@H:57]2[S:61][CH2:60][C@@H:59]3[NH:62][C:63]([NH:65][C@H:58]23)=[O:64])=O)C(=O)C1.O>CN(C)C=O>[O:64]=[C:63]1[NH:62][C@H:59]2[CH2:60][S:61][C@@H:57]([CH2:56][CH2:55][CH2:54][CH2:53][C:51]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]3[N:16]4[N:15]=[C:14]([C:28]5[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=5)[C:13]([C:11]5[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[N:12]=5)=[C:17]4[CH:18]=[CH:19][CH:20]=3)=[O:50])[C@H:58]2[NH:65]1
Reactant: O=C1N[C@H]2[C@H](CS[C@H]2CCCCC(=O)ON2C(=O)CCC2=O)N1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)CCCC[C@@H]4SC[C@@H]5NC(=O)N[C@@H]54)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (33 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL) was added triethylamine (0.03 mL, 0.21 mmol) and d-biotin-N-hydroxysuccinimide ester (27 mg, 0.08 mmol). The resultant mixture was warmed to room temperature and stirred for 30 minutes. A subsequent 5 mg of d-biotin-N-hydroxysuccinimide ester was added and the mixture was stirred an additional 30 minutes. Water was added and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and then brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% to 8% methanol in dichloromethane) provided 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-pentanamide (25 mg, 51%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.80 (d, 1 H), 7.58 (d, 2 H), 7.32 (m, 1 H), 7.00 (d, 2 H), 6.60 (s,1 H), 6.39 (m, 1 H), 6.33 (d, 1 H), 6.18 (m, 1 H), 6.02 (m, 1 H), 5.72 (s, 1 H), 5.62 (broad, 1 H), 4.44–4.31 (m, 2 H), 4.19 (m, 1 H), 3.89 (s, 3 H), 3.39 (m, 2 H), 3.28 (m, 2 H), 3.06 (m, 1 H), 2.95 (m, 2 H), 2.77 (dd, 1 H), 2.58 (d, 1 H), 2.20–2.05 (m, 4 H), 1.82–1.54 (m, 12 H), 1.39 (m, 2 H); MS m/z 698 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13](=[O:24])[N:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:34])[NH:1][CH2:2][C:3]([N:5]([CH2:12][C:13](=[O:24])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:4])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)N1CCc2ccccc2C1)c1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCc3ccccc3C2)c2ccccc2)c1
Yield: 36.5 %

Procedure:
The procedure is analogous to that described in Example 106, but 2.0 g of 2-amino-N-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]-N-phenylacetamide and 0.8 g of 3-methylphenyl isocyanate are used as the starting material. The crude product is purified by chromatography on 70 g of silica (0.065-0.200 mm) contained in a column 2.5 cm in diameter [eluent: methylene chloride/methanol (98-2 by volume)], collecting 20 cm3 fractions. Fractions 12 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from ethyl acetate, 1.0 g of 2-[3-(3-methylphenyl)ureido]-N-[2-oxo-2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]-N-phenylacetamide melting at 135° C is obtained.