Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])(=[O:8])=[O:7])([CH3:5])[CH3:4].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([CH3:24])=[CH:19][N:18]=1>CN(C=O)C.CS(C)=O>[Cl:16][C:17]1[N:22]=[C:21]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([CH:3]([CH3:5])[CH3:4])(=[O:8])=[O:7])[C:20]([CH3:24])=[CH:19][N:18]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 730 mg of NaH in a mixture of DMF/DMSO (25/2.5 ml) is added drop-wise at 0° C., 2.53 g (12.69 mmol) of 2-(iso-propylsulfonyl)benzenamine in DMF/DMSO (10 ml, ratio 9/1). The solution is stirred 30 minutes at 0° C. and 4.11 g (25.3 mmol, 2 eq.) of 2,4-dichloro-5-methylpyrimidine diluted in 10 ml of DMF/DMSO (ratio: 9/1) is added dropwise. The solution is warmed-up to room temperature and stirred overnight. After work-up, the crude product is directly crystallized from cold CH3CN in several batches to afford 2-chloro-N-(2-(iso-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine as pale creamy colored crystals: ESMS m/z 326.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][NH:15][CH:14]([CH3:17])[CH2:13][NH:12]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:13][CH:14]([CH3:17])[NH:15][CH2:16][CH:11]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC1CNC(C)CN1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc(Cl)cc2)C(C)CN1

Procedure:
Was synthesized in the same way as A) from 1-chloro-4-chloromethyl-benzene (1.27 g, 7.89 mmol) and 2,5-dimethyl-piperazine (1.0 g, 8.77 mmol) in DMF. Yield 701 mg, 37%.
Reaction SMILES: [CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:15]1[C:20]([CH2:21][CH3:22])=[N:19][C:18]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:17]([CH2:31][CH3:32])[N:16]=1>CS(C)=O.O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:18]1[C:17]([CH2:31][CH3:32])=[N:16][C:15]([O:11][CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[C:20]([CH2:21][CH3:22])[N:19]=1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br
Reactant: OC1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1OC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1,2,3,4-tetrahydronaphthalen-1-ol (248 mg) in DMSO (3 ml) was added to NaH (100 mg) suspended in DMSO (4 ml). The reaction mixture was stirred at r.t. for 1 hour and heated at 75° C. for 1 hour. 2-bromo-5-(2,4-dichlorophenyl)-3,6-diethylpyrazine in DMSO (3 ml) was added. After 24 h, the rxn mixture was diluted with 30 ml of H2O, extracted with CH2Cl2, washed with NaHCO3, brine, dried (MgSO4), filtered and concentrated. Flash chromatography (1:50 EtOAC:Heptane) gave the title compound: 1H NMR (CDCl3) δ 1.23, 1.95, 2.13, 2.20, 2.58, 2.83, 2.96, 6.46, 7.36; HRMS (ESI+) calcd for C24H24Cl2N2O1 (M+H)+ 427.1344, found 427.1359.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH:20]=[N:19][N:18]=[C:17]1[CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].[C:34](=[O:37])(O)[O-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:33])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:17]([CH2:21][N:22]2[C:23](=[O:32])[C:24]3=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]3[C:26]2=[O:27])=[N:18][N:19]=[C:20]1[CH2:17][N:16]1[CH2:20][CH2:34][O:37][CH2:9][CH2:10]1
Reactant: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Reactant: O=C([O-])O
Agent: [Na+]
Product: O=C(c1ccccc1Cl)c1cc(Cl)ccc1-n1c(CN2CCOCC2)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 13, 2',5-dichloro-2-[3(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is reacted with the above suspension then neutralized with sodium bicarbonate to give 2',5-dichloro-2-[3-(morpholinomethyl)-5-(phthalimidomethyl)-4H-1,2,4-triazol-4yl]-benzophenone.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[C:33][C:24]1[CH:23]=[C:22]([CH2:21][NH:20][C:15]2[C:14]([C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2NCc2ccnc(Cl)c2)cc1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)CC#Cc1cc(CNc2ncccc2C(=O)Nc2ccc(C(C)(C)C)cc2)ccn1
Temperature: 100 °C

Procedure:
A mixture of N-[4-(tert-butyl)phenyl](2-{[(2-chloro(4-pyridyl))methyl]amino}(3-pyridyl))carboxamide (0.15 g, 0.38 mmol, Example 139), 1-dimethylamino-2-propyne (62 mg, 0.76 mmol), PdCl2(PPh3)2 (13 mg, 0.0019 mmol) and CuI (7 mg, 0.019 mmol) in 1 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite®. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the title compound. MS (ES+): 442 (M+H)+; (ES−): 440(M−H)−. Calc'd C27H31N5O−441.58.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([O:28]CC)=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[N:36]=2)[CH:7]=1)[CH3:2].[Li+].[OH-].C1COCC1>CO.O>[CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[N:36]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CCOC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCOC)cn1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 51, 0.090 g, 0.15 mmol) and LiOH (0.092 mL, 0.18 mmol) were combined in MeOH (1 mL)/THF (1 mL) and heated to 100° C. in the microwave for 15 min The reaction mixture was cooled to room temperature, diluted with water (1.000 mL) and heated until the compound dissolved. The resulting solution was filtered and the filtrate was then concentrated under reduced pressure to remove methanol. HCl (1 N) was added and the resulting precipitate was collected by filtration, washed with water and dried overnight to yield a white solid (0.063 g).
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:19]1([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N+]=[N-])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O.CN(C)C=O>[NH2:1][CH:2]([C:4]([O:6][CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:5])[CH3:3]
Reactant: CC(N)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(N)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
9.0 g. of D,L-alanine and 19.0 g. of p-toluenesulfonic acid monohydrate are dissolved in 50 ml. of dimethylformamide. 21.1 g. of diphenyldiazomethane in 100 ml. of dimethylformamide are added dropwise at 50°. This mixture is stirred for 1 hour at 50° and then the solvent is distilled off in vacuum. The oily residue solidifies upon treatment with ether. The D,L-alanine, diphenylmethyl ester p-toluenesulfonate salt is recrystallized from acetonitrile and is obtained as white crystals, yield 13.5 g.; m.p. 170°-172°. 30 g. of this salt are dissolved in 200 ml. of water, layered over with 200 ml. of chloroform and 10 g. of sodium bicarbonate are added with frequent agitation. The organic phase is washed with 50 ml. of water, dried over sodium sulfate and evaporated. 17 g. of white crystalline D,L-alanine, diphenylmethyl ester are obtained, m.p. 60°-62°.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([CH2:13][C:14]#[N:15])=[CH:6][CH:5]=1)([O-])=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].O1CCCC1.[H][H]>[Pd].C(OCC)(=O)C>[C:14]([CH2:13][C:7]1[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[C:4]([NH:1][C:16](=[O:18])[CH3:17])=[CH:5][CH:6]=1)#[N:15]
Reactant: N#CCc1ccc([N+](=O)[O-])c2ccoc12
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CC#N)c2occc12
Yield: 67.8 %

Procedure:
Add (4-Nitrobenzofur-7-yl)acetonitrile (600 mg, 2.96 mmol), acetic anhydride (600 mg, 5.88 mmol), and 5% palladium on carbon (300 mg) to tetrahydrofuran (25 mL). Stir under 1 atmosphere of hydrogen for 45 minutes. Dilute with ethyl acetate, filter through a pad of Celite®, concentrate under reduced pressure, and chromatograph on flash silica using 75% ethyl acetate, 25% hexane to obtain the desired compound as an off-white solid (0.43 gm, 67%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[NH:13]1[C:21]2[CH:20]=[CH:19][N:18]=[C:17]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[C:16]=2[CH:15]=[CH:14]1>>[ClH:12].[N:22]1([C:17]2[C:16]3[CH:15]=[CH:14][N:13]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[C:21]=3[CH:20]=[CH:19][N:18]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Product: Cl
Product: N#Cc1ccc(S(=O)(=O)n2ccc3c(N4CCNCC4)nccc32)cc1

Procedure:
4-Cyanobenzenesulfonyl chloride (26.0 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (9.1 mg). LC/MS RT: 1.150 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 93%. MS: 369 (M+1) 1HNMR (CD3OD) δ ppm 3.50 (m, 4H) 4.08 (m, 4H) 7.29 (d, J=3.71 Hz, 2H) 7.98 (m, 4H) 8.29 (d, J=8.66 Hz, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[CH:8]=1.CN(C)[CH:17]=[O:18]>>[CH2:13]([C:9]1[CH:8]=[C:7]([CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCc1cccc(Br)c1
Agent: [Li]CCCC
Product: CCc1cccc(CO)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (34 ml of a 2.5M solution in hexanes) was added to a solution of 1-bromo-3-ethylbenzene (15 g) in tetrahydrofuiran (320 ml) at -78° C. After 1 hour dimethylformamide (15 ml) was added. The mixture was stirred at -78° C. for 1 hour and allowed to warm to room temperature. The mixture was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in methanol (250 ml) and treated with sodium borohydride (1.51 g) portionwise. The mixture was stirred at room temperature for 16 hours, quenched with 2M HCl (100 ml) and stirred for 4 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 2M HCl. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography eluting with 5-10% ethyl acetate in isohexane. Yield 7.6 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccnc(Cl)n2)CC1

Procedure:
A mixture of 2,4-dichloro-pyrimidine (4.0 g, 26.85 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.45 g, 32.22 mmol, 1.2 equiv) in anhydrous DMF (100 mL) was stirred at rt for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.2 g (38%) of the title compound. 1H NMR (400 MHz, CDCl3): δ1.35-1.45 (m, 2H), 1.47 (s, 9H), 1.99-2.03 (m, 2H), 2.91-2.97 (m, 2H), 3.81-3.90 (m, 1H), 4.04-4.07 (br d, 2H), 5.33 (d, J=8.0 Hz, 1H), 6.25 (d, J=4.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 28.05, 30.94, 42.04, 46.69, 78.64, 105.13, 153.86, 155.57, 159.81, 162.72. MS (ISP): 313.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[NH2:4].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][C:3]=1[N:4]1[C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15]1=[O:20]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1cc(OC2CCCC2)ccc1F
Solvent: O
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)ccc1F
Temperature: 25 °C
Yield: 34 %

Procedure:
2-Fluoro-5-cyclopentyloxyaniline (330 mg, 1.69 mmol), 3,4,5,6-tetrahydrophthalic anhydride (258 mg, 1.70 mmol) and acetic acid (10 ml) as a solvent were placed in a round bottom flask (50 cc) followed by heating under refluxing for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate (20 ml×3 portions). The organic layers were combined, and, after washing with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate. After removing the drying agent, the solvent was distilled off under reduced pressure. The resulting dark red oily substance (345 mg) was isolated and purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=4/1) to obtain the derired N-(2-fluoro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a light yellow oily substance (171 mg, 0.575 mmol, 34% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl.Cl[CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:35])[C:24]([NH:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)C(=O)NCCc4ccccc4)cc3F)ccnc2cc1OCCCN1CCOCC1
Yield: 73.7 %

Procedure:
A solution of N-{3-fluoro-4-[(7-hydroxy-6-methoxyquinolin-4-yl)oxy]phenyl}-N′-(2-phenylethyl)ethanediamide (25.6 g, 54 mmol), N-(3-chloropropyl)morpholine hydrochloride (11.7 g, 592 mmol) and potassium carbonate (16.6 g, 120 mmol) in DMF (300 mL) was heated to 80° C. overnight. Upon cooling, a majority of the DMF (250 mL) was removed on a rotary evaporator, 5% aqueous LiCl (300 mL) was added and the mixture was sonicated at room temperature. The solid was filtered, suspended in 1N HCl and washed with ethyl acetate (2×300 mL). The solution was adjusted to pH 14 using 2N sodium hydroxide and subsequently extracted with dichloromethane (3×200 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to give N-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N′-(2-phenylethyl)ethanediamide as a yellow solid (24 g, 74%). 1H NMR (400 MHz, CDCl3): δ 9.37 (s, 1H), 8.46 (d, 1H), 7.81 (dd, 1H), 7.57 (t, 1H), 7.53 (s, 1H), 7.42 (s, 2H), 7.34-7.20 (m, 6H), 6.39 (d, 1H), 4.27 (t, 2H), 4.03 (s, 3H), 3.71 (m, 4H), 3.65 (q, 2H), 2.91 (t, 2H), 2.56 (br s, 4H), 2.13 (m, 2H); 13C NMR (100 MHz, d6-DMSO): δ160.1, 160.0, 159.5, 155.2, 152.7, 152.6, 150.2, 149.5, 147.1, 139.7, 137.3, 137.1, 129.3, 129.1, 126.9, 124.8, 117.9, 115.1, 109.2, 102.7, 99.6, 67.4, 66.9, 56.5, 55.5, 54.1, 41.3, 35.2, 26.4; IR (cm−1): 1655, 1506, 1483, 1431, 1350, 1302, 1248, 1221, 1176, 1119, 864, 843, 804, 741, 700; LC/MS (M+H=603).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH3:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: Cc1ccc(C(=O)O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)NC(Cc2ccc(C(F)(F)F)cc2)C(O)c2ccc(F)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (30 ml) were added 4-methyl-1-naphthalenecarboxylic acid (268 mg, 1.44 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (413 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (220 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1) and recrystallized from ethyl acetate-hexane to give the title compound (487 mg, 70%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](N3CCNCC3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].ClCP(=O)(C)C.O>CN(C)C=O>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: CP(C)(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-n2ncc3ccccc32)cc1
Temperature: 90 °C

Procedure:
A stirred mixture of 4.3 g of 1-phenyl-3-(1-piperazinyl)-1H-indazole (prepared as in Example 2), 2.3 g of potassium carbonate, and 2.3 g of chloromethyldimethylphosphine oxide in 75 ml of dimethylformamide was heated at 90°, under nitrogen, for 16 hrs. Additional chloromethyldimethylphosphine oxide (0.6 g) was added, and the reaction mixture heated at 90° C. for 24 hrs. The reaction mixture was poured into water and the aqueous solution extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to an oil. Flash chromatography of the oil on silica gel, eluting with dichloromethane/methanol (10%) followed by concentration of the appropriate fractions and trituration with diethyl ether gave 2.5 g (45%) of 3-[4-(dimethylphosphinylmethyl)-1-piperazinyl)]-1-phenyl-1H-indazole.
Reaction SMILES: O.[NH2:2][NH2:3].Cl.[CH3:5][C:6]1[C:7]([O:9][C:10](=O)[C:11]=1[CH3:12])=[O:8]>O>[OH:8][C:7]1[N:2]=[N:3][C:10]([OH:9])=[C:11]([CH3:12])[C:6]=1[CH3:5]
Reactant: NN
Reactant: CC1=C(C)C(=O)OC1=O
Agent: Cl
Solvent: O
Product: Cc1c(O)nnc(O)c1C

Procedure:
50 ml of purified water was added to 3.4 ml(0.07 mol) of hydrazine monohydrate and then 14 ml(0.14 mol) of conc. hydrochloric acid was added dropwise thereto. Then, the reaction solution was warmed to boil. When the reaction mixture begins to reflux, 8.83 g(0.07 mol) of 2,3-dimethylmaleic acid anhydride was added thereto. The reaction solution was continuously refluxed for 3 hours and then cooled. The precipitated white crystal was filtered, washed with purified water, dissolved in boiling purified water to remove insoluble material and then recrystallized to obtain the title compound as an amorphous white crystal.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][N:4]=1)[NH2:2].[C:13](=S)=[S:14].C(N(CC)CC)C.S>N1C=CC=CC=1>[N:1]1[N:2]=[C:13]([SH:14])[N:4]2[N:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]=12
Reactant: NNc1nncc2ccccc12
Reactant: S=C=S
Agent: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Sc1nnc2c3ccccc3cnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
In pyridine, was dissolved 25 g of 1-hydrazinophthalazine. Thereto, 13 g of carbon disulfide was added dropwise at a temperature of 0° C. The stirring was continued for 30 minutes and then, the temperature of the reaction mixture was raised to 50° C., and the stirring was continued for additional 1 hour. Thereafter, the temperature was lowered to 0° C. again. Upon the addition of excess triethylamine to the resulting solution, hydrogen sulfide gas began to evolve. The temperature of the reaction system was raised and the refluxing was continued for 3 hours. Thereupon, the evolution of the gas ceased, and the reaction system was cooled. Upon cooling, crystals separated out. The crystals were filtered off, and recrystallized from ethanol. Yield 23 g, Melting Point 270°-280° C.
Reaction SMILES: [CH3:1][N:2]([CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=1.Br[C:35]1[N:36]=[C:37]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)[C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH2:51]([N:48]1[CH2:47][CH2:46][N:45]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[C:35]([C:7]3[CH:6]=[CH:5][C:4]([C:3](=[O:23])[N:2]([CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH3:1])=[CH:9][CH:8]=3)[N:36]=2)[CH2:50][CH2:49]1)[CH3:52]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)N(C)CCOCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(C(=O)N(C)CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 46.7 %

Procedure:
N-Methyl-N-(2-benzyloxyethyl)-4-tributylstannylbenzamide (1.93 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.93 g) were heated under reflux overnight in the presence of tetrakistriphenylphosphinepalladium(0) (0.13 g) in xylene in nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate and adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, which was then extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)-N-methylcarbamoyl]phenyl}isoquinoline (0.69 g) as a pale yellow viscous oil.