Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N+:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([O-:14])=[O:13]>[Cl-].[Zn+2].[Cl-].Cl>[NH2:19][C:18]1[CH:20]=[CH:21][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][C:17]=1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(F)cc1F
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 9.5 %

Procedure:
A mixture of 2,4-difluorobenzoyl chloride (88.3 g) and 4-nitroaniline (32.9 g) was heated at 180° C. for 25 minutes. Zinc chloride (39 g) was added portionwise to the resulting mixture. The mixture was stirred for 2.5 hours at 195° C. and cooled to 130° C. To the mixture was added 3N hydrochloric acid (100 ml) and the resulting mixture was refluxed for 2 hours, then the supernatant was decanted out. 75% Sulfuric acid was added to the residue and the mixture was stirred at 130° C. for 2 hours. The reaction mixture was poured into ice and extracted with dichloromethane. The organic layer was washed with 3N hydrochloric acid (600 ml), 3N sodium hydroxide (1 l), and water successively, dried, and evaporated. The solid residue (15 g) was recrystallized from ethanol to give crystals of 2-amino-5-nitro-2',4'-difluorobenzophenone (6.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Product: O=C(CCc1ccc(Cl)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 76.4 %

Procedure:
Silica gel (5.26 g) was added to a solution of 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (0.636 g) and 3,5-bis(ethoxycarbonyl)-1,4-dihydro-2,6-dimethylpyridine (1 g) in toluene (20 ml). The slurry was stirred at 70° C. in the dark for 17 h. After removal of the solvent the residue was purified by flash chromatography on silica gel (petrol ether/ethyl acetate) to provide 3-(4-chlorophenyl)-1-phenylpropan-1-one (0.49 g) as colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:7](=[O:18])[CH2:6][CH2:5]2.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[NH:26])=[CH:11][C:10]=2[F:12])[CH2:5][CH2:6][C:7]1=[O:18]
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1C(=O)CCc2cc(N)cc(F)c21
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)CCN1C(=O)CCc2cc(NC(=N)c3cccs3)cc(F)c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
6-Amino-1-(2-(dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (312 mg, 1.24 mmol) was stirred to dissolve in ethanol (15 mL). To this solution was added methyl thiophene-2-carbimidothioate hydroiodide (708 mg, 2.48 mmol). The resulting suspension was stirred for 2 days at room temperature. When TLC analysis showed that the reaction was finished, the mixture was diluted with water and aqueous sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated and the crude product chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in ethyl acetate, then a second time using 20-80% MeCN in an aqueous buffer of ammonium carbonate and ammonium hydroxide adjusted to pH 10.6. Yield: 27 mg). 1H NMR (DMSO-d6) δ 2.14 (s, 6H), 2.44 (t, 2H, J=6.7 Hz), 2.49 (m, 2H, masked by DMSO peak), 2.80 (t, 2H, J=6.6 Hz), 3.95 (t, 2H, J=6.5 Hz), 6.61 (m, 4H), 7.09 (m, 1H), 7.62 (m, 1H), 7.75 (m, 1H). ESI-MS: 361 (MH+, 100), 316 (40), 158.6 (57), 136 (37).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].N1C=CC=CC=1>ClCCl>[C:1]([O:12][CH:11]([C:10]1[S:9][CH:8]=[N:7][C:6]=1[CH3:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1ncsc1C(O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.6 ml) was added to a solution of 1-(4-methyl-5-thiazolyl) -1-phenylmethanol (800 mg) and pyridine (0.5 ml) in dichloromethane (30 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was allowed to warm room temperature and was then stirred overnight. Evaporation and purification of the residue by flash chromatography gave the title compound.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.Br[C:37]1[CH:42]=[CH:41][C:40]([C:43](=[O:55])[CH2:44][CH:45]2[C:50](=[O:51])[O:49][C:48]([CH3:53])([CH3:52])[O:47][C:46]2=[O:54])=[CH:39][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)C>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:37]2[CH:42]=[CH:41][C:40]([C:43](=[O:55])[CH2:44][CH:45]3[C:50](=[O:51])[O:49][C:48]([CH3:53])([CH3:52])[O:47][C:46]3=[O:54])=[CH:39][CH:38]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(CC(=O)c2ccc(Br)cc2)C(=O)O1
Reactant: CC1(C)OB(c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC1(C)OC(=O)C(CC(=O)c2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2)C(=O)O1
Temperature: 80 °C
Yield: 75.6 %

Procedure:
A solution of 2-benzyl-3-[4′-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)phenyl]-benzofuran (500 mg, 1.22 mmol) in anhyd DMSO (5 mL) was added to a stirred suspension of 5-[2-(4-bromophenyl)-2-oxoethyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione (436 mg, 1.22 mmol) and tripotassium phosphate (1.04 g, 4.88 mmol) in anhyd DMSO (5 mL). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM complex (100 mg, 0.12 mmol) was added as a solid, and the resulting suspension was heated to 80° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether (150 mL), washed with water (2×50 mL), sat'd aq NaCl (3×50 mL), dried over anhyd MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (50-60% ethyl acetate in heptane) afforded the title compound as an off-white solid (502 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][O:8][C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.Br>C(O)C>[CH:10]1([C:9]2[O:8][N:7]=[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[C:3]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]3[CH:2]=2)[CH2:12][CH2:11]1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1c(-c2ccccc2)noc1C1CC1
Agent: Br
Solvent: CCO
Product: c1ccc(-c2noc(C3CC3)c2-c2cn3ccccc3n2)cc1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 2-bromo-1-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-ethanone (91.8mg, 0.3 mmol) and 2-aminopyridine (28.2 mg, 0.3 mmol) in ethanol (2 mL) containing hydrobromic acid (48%, 16.9 μL, 0.8 mmol) was heated under reflux under argon for 2 h. Another portion of 2-aminopyridine (28.2 mg, 0.3 mmol) was added and heating continued under reflux under argon for 1 h. After cooling to room temperature, the mixture was evaporated and poured onto saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 50:50) afforded the title compound (49 mg, 54%) which was obtained as an off-white solid. MS: m/e=302.1 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 51.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 5-amino-pentanoic acid (110 mg, 0.94 mmol) (Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (60 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. The crude product was triturated with MeOH (2 mL). Solid was collected and dried in vacuo to provide the title compound 65 mg (0.16 mmol) in 52% yield. LC-MS ESI−: 404.03 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:4][CH:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)[CH2:15][CH3:16]
Reactant: COC1=CC=C2CC(=O)CCC2C1
Reactant: CCCNCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCN(CCC)C1CCc2cc(OC)ccc2C1

Procedure:
20 g of 6-methoxytetrahydronaphthalen-2-one, 20 ml of dipropylamine and 200 mg of para-toluenesulphonic acid are introduced into 300 ml of benzene under a nitrogen atmosphere. The mixture, which has become black, is then heated under reflux for 12 hours, the water of condensation being removed by azeotropic distillation. The solution, which contains the compound (IV), is then concentrated to a volume of about 100 ml. For the hydrogenation, 150 ml of ethanol and 300 mg of PtO2 are added thereto and hydrogenation is carried out, under a pressure of about 0.3 MPa, until the absorption has stopped.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cccc(Cl)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (1.6 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (30 mL), 3-chlorophenylboronic acid (3.58 g), copper acetate (5.0 g) and pyridine (4.0 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (1.9 g, 67%) as a pale-yellow oil.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[CH3:31])[CH2:20][CH2:19]1)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[CH2:32](Br)[CH:33]=[CH2:34].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].C(OC(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:34]([O:3][CH:4]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[CH3:31])[CH2:20][CH2:19]1)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])[CH:33]=[CH2:32]
Reactant: Cc1ccc(N2CCN(CC(O)CN3C(=O)c4ccccc4C3=O)CC2)c(C)c1
Reactant: C=CCBr
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CCOC(CN1CCN(c2ccc(C)cc2C)CC1)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
55% Sodium hydride (0.65 g) was suspended in anhydrous dioxane (30 ml), followed by dropwise addition of N-[2-hydroxy-3-{4-(2,4-dimethylphenyl)piperazin-1-yl}propyl]-phthalimide (4.7 g) dissolved in dioxane (50 ml) under nitrogen gas stream and at room temperature. The resulting mixture was heated to 60° C. and stirred for 1 hour. Then, allyl bromide (1.8 g) was dropped slowly into the mixture at 40° C. and the thus formed mixture was stirred for 3 hours over a water bath at 75° C. The reaction mixture was thereafter cooled, ice water was added thereto, and it was then extracted with ether. After washing the extract twice with water, it was dried with anhydrous magnesium sulfate. The resulting mixture was filtered and the filtrate was concentrated. After washing out the mineral oil, derived from sodium hydride, with n-hexane, the residue was dissolved in ethyl acetate, followed by addition of a solution which had been obtained by dissolving oxalic acid (1.2 g) in ethyl acetate. After heating the resulting mixture, a small amount of IPE (isopropyl ether) was added. The thus obtained mixture was allowed to cool. Precipitated crystals were collected by filtration to obtain the desired compound (4.3 g; yield 69%).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:32]=[CH:31][C:12]([O:13][CH2:14][C:15]3[N:19]([CH2:20][CH2:21][O:22][CH3:23])[C:18]4[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)[CH2:4]1.C(=O)([O-])O.[Na+].Cl.[C:39](=[NH:44])(OCC)[CH3:40]>O1CCCC1.O>[ClH:1].[ClH:1].[C:39]([N:3]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3[N:19]([CH2:20][CH2:21][O:22][CH3:23])[C:18]4[CH:24]=[CH:25][C:26]([C:28]([NH2:30])=[NH:29])=[CH:27][C:17]=4[N:16]=3)=[CH:31][CH:32]=2)[CH2:4]1)(=[NH:44])[CH3:40]
Reactant: COCCn1c(COc2ccc(OC3CCNC3)cc2)nc2cc(C(=N)N)ccc21
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCn1c(COc2ccc(OC3CCN(C(C)=N)C3)cc2)nc2cc(C(=N)N)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 167.6 %

Procedure:
To a solution of 2-[4-(pyrrolidin-3-yloxy)phenoxymethyl]-1-(2-methoxyethyl)benzimidazole-5-carboxamidine dihydrochloride (44 mg) in a mixture of tetrahydrofuran (2 ml) and water (0.6 ml) were added sodium hydrogencarbonate (38 mg), and ethyl acetoimidate hydrochloride (33 mg), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, insoluble material was removed and the solvent was evaporated. The obtained residue was separated by HPLC (50% methanol-water, 0.05% trifluoroacetic acid). To the obtained residue was added dil. hydrochloric acid and the solvent was evaporated and dried under reduced pressure to give the title compound (40 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([C:21]3[CH:33]=[CH:32][C:24]4[O:25]C(C)(C)[O:27][C:28](=[O:29])[C:23]=4[CH:22]=3)=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([C:21]3[CH:33]=[CH:32][C:24]([OH:25])=[C:23]([CH:22]=3)[C:28]([OH:29])=[O:27])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc(O)c(C(=O)O)c1
Yield: 88.9 %

Procedure:
A solution of N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-hexyl-2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carboxamide (108 mg, 0.20 mmol) and lithium hydroxide (120 mg, 2.9 mmol) in THF (1 mL) and water (1 mL) was heated at 70° C. overnight. The solvents were removed under reduced pressure. The residue was taken up in EtOAc and washed with an aqueous solution of HCl (1N) and brine, dried over MgSO4 and the solvent was removed under reduced pressure to give 91 mg (91%) of hte title compound. HPLC, Rt: 5.72 min (purity: 98.9%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([CH:11]([CH3:13])[CH3:12])[CH:3]=1.[ClH:14].N#N>CO.[OH-].[OH-].[Pd+2]>[ClH:14].[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[CH:11]([CH3:12])[CH3:13]
Reactant: Cc1cc(C(C)C)c(C#N)c(=O)[nH]1
Agent: [Pd+2]
Agent: Cl
Agent: N#N
Solvent: CO
Product: Cc1cc(C(C)C)c(CN)c(=O)[nH]1
Temperature: 23 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of 6-methyl-2-oxo-4-(propan-2-yl)-1,2-dihydropyridine-3-carbonitrile (5.00 g, 28.4 mmol) and in MeOH (400 ml) and HCl (8.8 ml, 12 M) was added 10% Pd(OH)2 (5.17 g, 3.68 mmol) under N2 atmosphere. The N2 gas was displaced by H2 gas and the mixture was stirred for 24 h at 23° C. under hydrogen. The H2 gas was displaced by N2 gas and the mixture was filtered through celite, washed with MeOH and concentrated. The residue was triturated with EtOH-TBME, the solid was collected with Buchner funnel and dried in vacuo to give the titled compound (6.15 g, 100%). 1H NMR (400 MHz, DMSO-d6): δ ppm 11.9 (br-s, 1H), 8.03 (br-s, 2H), 6.12 (s, 1H), 3.82-3.84 (m, 2H), 3.08-3.12 (m, 1H), 2.19 (s, 3H), 1.12 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=O)[CH2:11][CH2:10]1.C(N(CC)CC)C.O=C1N(N(N2CCOC2=O)P(Cl)(Cl)=O)CCO1.[CH3:51][NH:52][CH2:53][C:54]#[CH:55].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]([N:52]([CH3:51])[CH2:53][C:54]#[CH:55])=[O:20])[CH2:13][CH2:14]1
Reactant: C#CCNC
Reactant: COc1ccccc1N1CCN(CCC(C(=O)O)c2ccccc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: O=C1OCCN1N(N1CCOC1=O)P(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN(C)C(=O)C(CCN1CCN(c2ccccc2OC)CC1)c1ccccc1
Yield: 93.7 %

Procedure:
The title compound was prepared from 4-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylbutanoic acid (1.77 g, 5 mmole), triethylamine (1.518 g, 15 mmole), N,N-bis(2-oxo-3-oxazolidinyl)phosphoramidic chloride (1.527 g, 6 mmole), N-methylpropargylamine (0.415 g, 6 mmole) and methylene chloride (80 mL) in the manner described in Example 1, to yield 1.9 g of the title compound as the dihydrochloride, m.p. 197°-8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.B(Cl)(C1C(C)C2C(C)(C)C(C2)C1)C1C(C)C2C(C)(C)C(C2)C1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH:12]([OH:13])[N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C(CCCC(=O)N1CCOCC1)c1ccc(F)cc1
Agent: CC1C(B(Cl)C2CC3CC(C2C)C3(C)C)CC2CC1C2(C)C
Solvent: Cc1ccccc1
Product: O=C(CCCC(O)N1CCOCC1)c1ccc(F)cc1
Reaction time: 6 h
Yield: 54.6 %

Procedure:
10 gms of 1-(4-Fluoro-phenyl)-5-morpholin-4-yl-pentane-1,5-dione was taken in 62 ml of toluene to this 46 ml of (−)-Diisopinocampheyl chloroborane (DIP chloride) solution was added at 0-5° C. Stirred the reaction mass for about 6 hours and quenched the reaction mass with 750 ml of 10% NaOH. To the reaction mass was washed with brine solution. Washed the obtained organic layer with ammonium chloride solution and dried over sodium sulphate. Distilled the solvent and isolated through column chromatography to get 5.5 gms of 1-(4-Fluoro-phenyl)-5-hydroxy-5-morpholin-4-yl-pentan-1-one.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[CH:25]3)=[O:21])[CH2:13]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:19][C:20]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][N:26]=[CH:25]3)=[O:21])[CH2:13]1
Reactant: O=C(NC1CCCCN(Cc2ccccc2)C1)c1ccc2[nH]ncc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(NC1CCCCNC1)c1ccc2[nH]ncc2c1
Yield: 72.8 %

Procedure:
Ammonium formate (716 mg, 11.4 mmol) and 10% palladium carbon (containing 50% water, 100 mg) were added to a solution of the N-(1-benzylazepan-3-yl)-1H-indazole-5-carboxamide (494 mg, 1.42 mmol) obtained in Example 147 in ethanol (28 ml) at room temperature, and the resulting mixture was stirred with heating under reflux for 5 hours. The reaction mixture was filtered to remove the catalyst and the solvent of the filtrate was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/methanol/aqueous ammonia=10/1/0.1) to obtain N-azepan-3-yl-1H-indazole-5-carboxamide (267 mg, 73%).
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O-:23].[Na+].O.Cl>CN(C)C=O.CO>[CH3:22][O:23][C:2]1[C:7]([Br:8])=[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Clc1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br
Temperature: 80 °C

Procedure:
2.21 g (6.04 mmol) of 2-chloro-3-bromo-4-(cis-4-phenylcyclohexylamino)pyridine in 30 ml of dimethylformamide are treated with 4.31 ml of 30% strength solution of sodium methoxide in methanol and the mixture is heated at 80° C. for 1 hour. After cooling, water is added, the mixture is adjusted to pH 8 using 1/2 conc. hydrochloric acid and the reaction product is extracted with ethyl acetate. For purification it is chromatographed. Yield: 1.72 g (79%); Rf =0.4 (diisopropyl ether)
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=1.CCN(C(C)C)C(C)C.O=[CH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]1([CH3:24])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:2]=1
Reactant: CCOC(=O)CCCCCC=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2cccc(C)c2)CCCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3cccc(C)c3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-m-Tolyl-3-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate FB)(61 mg, 0.193 mmol) in dry DCE (1 ml) at RT was treated with DIPEA (0.037 ml, 0.213 mmol) followed by ethyl 7-oxoheptanoate (66.6 mg, 0.387 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (205 mg, 0.967 mmol) was added. The resulting mixture was stirred at 60° C. overnight. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3×). The combined organic extracts were passed through a phase separating column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-5% EtOAc/iso-hexane to afford the title compound; LCMS Rt 1.61 mins MS m/z 473.4 [M+H]+; Method 2minLC_v003