Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([CH3:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:28][CH3:29])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([CH3:27])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCN(C)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
0.15 g (1.5 mmol) of 1-methyl-piperazine in 10 ml of DMF was added to a solution of 0.45 g (1.275 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml in DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 15:1) and crystallization from EtOH yielded 0.40 g (75%) of 3-benzenesulphonyl-5-methyl-7-(4-methyl-piperazine-1-yl) -2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 209-210°.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:16]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:17]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]>CO.N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:16]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:4][O:2][CH3:3])[CH2:29][CH2:28]2)[C:17]([NH:19][C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=[O:18])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnccn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCC(CC(C(=O)Nc2cnccn2)c2ccc(S(C)(=O)=O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of methoxylamine hydrochloride (23 mg, 0.27 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 58, 80 mg, 0.18 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 35/65 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-methoxyimino-cyclohexyl)-N-pyrazin-2-yl-propionamide (68 mg, 81%) was a white foam: EI-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1364.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([CH3:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccc(C)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc2cccc(CBr)c2n1
Yield: 33.3 %

Procedure:
To a solution of 2,8-dimethylquinoline (3.00 g, 19.1 mmol) in carbon tetrachloride (50 mL) were added benzoyl peroxide (0.0139 g, 0.057 mmol) and N-bromosuccinimide (3.57 g, 20.0 mmol). The reaction mixture was heated at reflux for 18 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 8-(bromomethyl)-2-methylquinoline (1.50 g, 33.3%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:23])=[CH:5][C:6]([OH:22])=[C:7]([C:9](=[O:21])[CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:8]=1)[CH3:2].N1C=CC=C[CH:25]=1.C(OC)(OC)OC>N1CCCCC1.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[OH:23])[O:22][CH:25]=[C:10]([C:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=1)[C:9]2=[O:21])[CH3:2]
Reactant: c1ccncc1
Reactant: CCc1cc(C(=O)Cc2ccc3ccccc3c2)c(O)cc1O
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Solvent: C1CCNCC1
Product: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1O
Temperature: 120 °C

Procedure:
To 1-(5-ethyl-2,4-dihydroxy-phenyl)-2-naphthalen-2-yl-ethanone (c, 0.50 g) was added a mixture of pyridine (2 mL), trimethyl orthoformate (2 mL) and piperidine (2 drops), and the mixture was heated at 120° C. for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) then washed with 1 N HCl (100 mL). The organic layer was washed with water and dried. The oil obtained on concentration of the organic layer was crystallized in EtOAc/hexanes to give 6-ethyl-7-hydroxy-3-naphthalen-2-yl-chromen-4-one (d, 0.36 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CC(O)=O>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Ic1ccc2[nH]ccc2c1
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 5-iodoindole (0.2 g; 0.82 mmol) in AcOH (5 ml) NaBH3CN (0.2 g; 3.8 mmol) was added at −10° C. under N2. After stirring for 1 h at room temperature the solvent was removed in vacuo and the residue was diluted to 30 ml with Et2O and washed with 1N NaOH (5 ml), H2O (2×5 ml), brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure to give the title compound (0.2 g; 99%), which was used in next step without further purification. 1H-NMR (CDCl3) 7.35 (s, 1H); 7.25 (d, 1H, J=8.15 Hz); 6.43 (d, 1H, J=8.15 Hz); 5.21 (bs, 1H); 3.54 (t, 2H, J=8.36 Hz); 2.99 (t, 2H, J=8.36 Hz).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.Cl.[NH2:10][C@H:11]([C:19]([NH2:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[OH:20][C:19]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[N:21]=1
Reactant: O=C1CCCCC1=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Oc1nc2c(nc1Cc1ccccc1)CCCC2
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) under cooling below -30° C., and aqueous 12.5N NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred under -30° C. for 30 mins., whereafter cooling was removed and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (15 g) was added after 10 mins. stirring, the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (19.7 g, yield: 82.1%).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3([CH2:26][O:25][C:24]4[CH:27]=[C:28]5[C:32](=[CH:33][C:23]3=4)[CH2:31][CH2:30][O:29]5)[C:15]2=[O:34])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3([CH2:26][O:25][C:24]4[CH:27]=[C:28]5[C:32](=[CH:33][C:23]3=4)[CH2:31][CH2:30][O:29]5)[C:15]2=[O:34])=[CH:35][CH:36]=1
Reactant: O=C1N(Cc2ccc(OCc3ccccc3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1N(Cc2ccc(O)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A mixture of 1′-[4-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one (2.4 g, 5.1 mmol) and palladium on carbon (10% w/w, 0.49 g) in anhydrous methanol (10 mL) and ethyl acetate (50 mL) was hydrogenated at ambient temperature under a balloon pressure for 16 h. The mixture was filtered through a pad of diatomaceous earth The pad was washed with ethyl acetate (50 mL) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography and eluted with a 25% to 50% gradient of ethyl acetate in hexanes to afford 1′-(4-hydroxybenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (1.86 g, 94%) as a colorless solid: mp 226-227° C.; 1H NMR (300 MHz, CDCl3) δ 7.25-7.13 (m, 4H), 7.06-6.99 (m, 1H), 6.87-6.82 (m, 1H), 6.78-6.72 (m, 2H), 6.44-6.41 (m, 2H), 5.27 (s, 1H), 4.88 (ABq, J=69.0, 15.3 Hz, 2H), 4.84 (ABq, J=82.9, 9.0 Hz, 2H), 4.55-4.46 (m, 2H), 2.96-2.86 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.2, 161.8, 161.3, 155.5, 142.1, 132.8, 128.8, 128.7, 127.5, 123.9, 123.5, 120.0, 119.9, 118.8, 115.8, 109.4, 93.3, 80.5, 72.4, 70.0, 57.8, 43.7, 28.9; MS (ES+) m/z 385.9 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[CH:15][C:16](=[O:18])[CH3:17].[BH4-].[Na+]>CO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[CH:15][CH:16]([OH:18])[CH3:17]
Reactant: CC(=O)C=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)C=Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 77.3 %

Procedure:
To 200 ml of methanol was added 9.36 grams of 4-(2-fluorenyl)-3buten-2-one, then 14.9 grams of cerous chloride (heptahydrate) was added, and 1.52 grams of sodium borohydride was added thereto little by little with ice-cooling and stirring. After being stirred for 45 minutes, methanol was removed therefrom by evaporation, water was added to the residue, and extracted with chloroform. The extract was washed with water, dehydrated with magnesium sulfate, and chloroform was evaporated therefrom. The residue was recrystallized from methanol to give 7.3 grams of 4-(2-fluorenyl)-3-buten-2-ol, white crystals, melting point 153° C.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:13])[C:6]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)=O)C.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>C(O)C>[NH2:21][C:20]1[NH:22][C:4](=[O:3])[C:5]([CH3:13])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:19]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C)C(=O)c1ccco1
Agent: O=C(O)O
Solvent: CCO
Product: Cc1c(-c2ccco2)nc(N)[nH]c1=O
Temperature: 100 °C
Yield: 123.1 %

Procedure:
Following the method of Rorig and Nicholson (U.S. Pat. No. 2,710,867), a mixture of 3.00 g (15.3 mmol) (RS)-3-furan-2-yl-2-methyl-3-oxo-propionic acid ethyl ester and 1,38 g (7.65 mmol) guanidine carbonate in 20 ml ethanol was heated at 100° C. for 16 hours. The reaction mixture was then cooled to 0° C., whereupon the resulting crystals were collected by filtration and washed sequentially with water and with ice-cold ethanol to afford 1.80 g (62%) 2-amino-6-furan-2-yl-5-methyl-3H-pyrimidin-4-one as a white crystalline solid. ES-MS m/e (%): 190 ([M—H]−, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](O)=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.Cl.[CH3:29][NH:30][CH3:31].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:30]([CH3:31])[CH3:29])=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Reactant: CNC
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)N(C)C)n(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (49ε, 1.00 g, 2.47 mmol) in DMF (15 ml) was added θHOBT (0.41 g, 2.72 mmol) at room temperature, which was then followed by the addition of dimethylamine hydrochloride (0.40 g, 4.94 mmol). the reaction mixture was cooled to 0° C. and to the cooled reaction mixture was then added EDC (0.71 g, 3.70 mmol) and triethylamine (1.00 g, 1.37 ml, 9.88 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the residue so obtained. The mixture so obtained was then washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 90% ethyl acetate in hexanes as an eluent to obtain the title compound (0.94 g, 88.1%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](N(OC)C)=[O:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.F[C:27]1C=CC(COC2C=C3C(C=C(C(Cl)=O)C=N3)=CC=2)=CC=1.Cl.CNOC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:19])[CH3:27])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Reactant: O=C(Cl)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
7-((4-Fluorobenzyl)oxy)-N-methoxy-N-methylquinoline-3-carboxamide. To a solution of 7-((4-fluorobenzyl)oxy)quinoline-3-carbonyl chloride in DCM (14 mL) was added N,O-dimethylhydroxylamine hydrochloride (207 mg, 2.12 mmol) and DIPEA (0.739 mL, 4.23 mmol). The reaction was stirred for 15 minutes at ambient temperature before being concentrated onto silica. Purification (FCC, SiO2, 0-80%, EtOAc/hexanes) afforded the title compound as a white solid (324 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 9.18 (d, J=2.0 Hz, 1H), 8.54 (d, J=1.6 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.51-7.44 (m, 2H), 7.32 (dd, J=2.3, 9.0 Hz, 1H), 7.11 (t, J=8.8 Hz, 2H), 5.21 (s, 2H), 3.59 (s, 3H), 3.45 (d, J=0.8 Hz, 3H). [M+H]=341.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)[CH2:7][CH2:6]1.[C@@H:21]12[C:30](=O)[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[ClH:32]>N1C=CC=CC=1.C(O)C>[ClH:32].[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:1]4[C:27](=[O:28])[C@H:22]5[C@H:21]([CH2:26][CH2:25][CH2:24][CH2:23]5)[C:30]4=[O:29])[CH2:6][CH2:7]3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(3aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.01 g, 10.8 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (1.9 g, 12.3 mmol) in dry pyridine (30 ml) was heated at reflux for 16 hours. The dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was purified twice by flash chromatography over a silica gel column. The pure product thus obtained weighed 2.5 g (67%). This was converted to the hydrochloride salt by treatment with HCl in ethanol (50 ml). The cis-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-hexahydro-1 H-isoindole-1,3-dione hydrochloride crystals so obtained weighed 3.0 g, m.p.=242°-245° C.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12](/[CH:16]=[CH:17]/[CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1>CCO.[Pd]>[O:2]1[CH2:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: NC/C=C/c1cccc(OCC2CCOCC2)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCCc1cccc(OCC2CCOCC2)c1

Procedure:
Hydrogenation of Example 31 ((E)-3-(3-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)prop-2-en-1-amine hydrochloride) at 1 atm H2 pressure using Pd/C (10% wt, 0.020 g) catalyst in EtOH (absolute, degassed, 20 mL) for 1.5 hrs gave after filtration through Celite and concentration of the filtrate under reduced pressure Example 32 hydrochloride as a white solid. Yield (0.150 g, 73%); 1H NMR (400 MHz, DMSO-d6) δ 7.98 (br. s, 3H), 7.18 (t, J=7.83 Hz, 1H), 6.72-6.80 (m, 3H), 3.750-3.90 (m, 4H), 3.26-3.36 (m, 2H), 2.72 (t, J=7.24 Hz, 2H), 2.59 (t, J=7.43 Hz, 1H), 1.96 (m, 1H), 1.78-1.88 (m, 2H), 1.61-1.69 (m, 2H), 1.24-1.36 (m, 2H); MS: m/z 250.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([Sn:20]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])OC)[CH2:17][CH2:18][CH3:19]>ClCCCl>[CH2:27]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:23][CH2:24][CH2:25][CH3:26])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCC[Sn](CCCC)(CCCC)OC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Solvent: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 60 °C
Yield: 81 %

Procedure:
In a 50 ml dry three-neck-flask 1.5 g (7.6 mmol) of 4-hydroxy-benzophenone are suspended in 25 ml of 1,2-dichloroethane and heated to reflux under argon flow. 2.7 g (8.4 mmol) of tri-n-butylmethoxy tin are added to the solution in the course of 0.5 h. The conversion is complete according to the 1H-NMR-spectrum. The solution is concentrated and dried in high vacuum. 4.1 g of an orange oil crystallize. The crude product is dissolved at 90° C. in 20 ml of heptane. The solution is cooled and at about 60° C. brown crystals begin to form. After filtration, further cooling and freezing, the formation of crystals continues. The crystals are filtered, dried and analyzed. The structure is confirmed by 1H-NMR and 13C-NMR spectra. 3.0 g of the title product are obtained, melting at 76-82° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C([Sn](CCCC)(CCCC)/[CH:59]=[CH:60]\[O:61][CH2:62][CH3:63])CCC.C(N(CC)CC)C>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].CN(C=O)C>[CH2:62]([O:61]/[CH:60]=[CH:59]\[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:63]
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 84.5 %

Procedure:
A flask was charged with 7-bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Steps A-B; 100 mg, 0.21 mmol), tri-O-tolylphosphine (12.8 mg, 0.042 mmol) and tris(dibenzylideneacetone)dipalladium (19.3 mg, 0.021 mmol). To the flask was added DMF (3 mL), followed by (Z)-tributyl(2-ethoxyvinyl)stannane (114 mg, 0.316 mmol) and triethylamine (0.04 mL, 0.30 mmol). The reaction mixture was degassed under nitrogen, and stirred at 100° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH/DCM as eluent to afford 82.8 mg of product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]1[N:15]=[N:14][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)=[CH:12][CH:11]=1)[CH2:6]2.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>ClCCl>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]1[N:15]=[N:14][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:23]=3)=[CH:12][CH:11]=1)[CH2:6]2
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C2CCC1CN(c1ccc(C#Cc3ccc(N)cc3)nn1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1C2CCC1CN(c1ccc(C#Cc3ccc(NC(=O)c4ccccc4)cc3)nn1)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 4-[6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-ylethynyl]-phenylamine (0.53 g, 1.66 mmol) and dichloromethane (20 ml) was added: benzoylchloride (0.35 g, 2.5 mmol) solved in dichloromethane (20 ml). The mixture was stirred at 0° C. for 2 hours and was then allowed to stir at room temperature for 15 hours. Aqueous sodium hydroxide (20 ml, 1 M) was added and the mixture was extracted with dichloromethane (3×30 ml). The mixture was dried and evaporated. Mp 88-96° C. LC-ESI-HRMS of [M+H]+ shows 424.2145 Da. Calc. 424.213735 Da, dev. 1.8 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][NH:15][C:14](=[O:23])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(C)C=CC=CC=1.IC.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:24]([O:26][CH3:27])=[O:25])=[N:11][N:12]2[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][N:15]([CH3:28])[C:14](=[O:23])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CNC(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C1CN(C)C(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 3-benzyloxy-7-ethoxycarbonyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (4.0 g, 10.71 mmol) was azeotroped from toluene and dissolved in anhydrous DMF (20 mL), and iodomethane (700 μL, 11.25 mmol) was passed through a plug of activated basic alumina and added to the solution. After being cooled to 0° C., the solution was treated with sodium hydride (270 mg, 11.25 mmol, 95% dispersion in oil) and stirred for 1 hour. The reaction was quenched with acetic acid, and the solvent removed in vacuo. The resulting residue was triturated with diethyl ether to afford a solid which was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted into EtOAc three times more, and the combined organic extracts were dried over Na2SO4 and concentrated to afford the title product as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.44 (m, 2H), 7.39-7.32 (m, 3H), 5.29-5.15 (m, 2H), 4.23-4.13 (m, 3H), 4.00-3.80 (m, 1H), 3.79 (s, 3H), 3.41-3.36 (m, 1H), 3.00 (s, 3H), 1.20-1.11 (m, 3H); ES MS (M+H)=388.