Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=[C:8]2[CH2:7][N:6]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([N+:24]([O-])=O)[CH:23]=2)[C:19]#[N:20])[C:5]1=[O:27])([CH3:3])[CH3:2].Cl>CO.[Fe]>[NH2:24][C:22]1[CH:21]=[C:18]([CH:17]=[C:16]([N:6]2[CH2:7][C:8]3[C:9](=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]2=[O:27])[CH:23]=1)[C:19]#[N:20]
Reactant: CSc1ncc2c(n1)N(C(C)C)C(=O)N(c1cc(C#N)cc([N+](=O)[O-])c1)C2
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CSc1ncc2c(n1)N(C(C)C)C(=O)N(c1cc(N)cc(C#N)c1)C2
Yield: 25.2 %

Procedure:
3-(1-Isopropyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-5-nitrobenzonitrile (1.2 g, 3.13 mmol), iron powder (1.75 g, 31 mmol) and conc HCl (0.5 ml, 6 mmol) were combined in methanol (100 mL) by the procedure of Example A10, step 4, to provide 3-amino-5-(1-isopropyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)benzonitrile (280 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1 H), 6.89 (m, 1 H), 6.86 (d, J=2.0 Hz, 1 H), 6.76 (t, J=2.0 Hz, 1 H), 5.73 (d, J=2.8 Hz, 2 H), 4.98 (m, 1 H), 4.68 (s, 2 H), 2.51 (s, 3 H), 1.48 (d, J=6.8 Hz, 6 H); MS (ESI) m/z: 355.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[N:19]=[C:20]2[O:23][CH:24]([CH3:26])[CH3:25])=[CH:15][C:14]=1[O:34][CH3:35]>C(O)(=O)C>[CH:24]([O:23][C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:34][CH3:35])=[C:13]([O:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[CH:22]=2)[CH:17]=[C:18]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[N:19]=1)([CH3:26])[CH3:25]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1F
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1OCCN1CCOCC1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
NaH (155 mg) was added to a solution of 2-Morpholin-4-yl-ethanol (2 ml) and stirred for 1 hour. (7-Fluoro-1-isopropoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was added to the mixture, and the mixture was heated at 180° C. for 1 hour under microwave irradiation. The reaction mixture was acidified to PH=7 with acetic acid and purified by preparative LC-MS to give [1-Isopropoxy-6-methoxy-7-(2-morpholin-4-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine (28 mg). LC-MS: m/e 442(MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)=[O:26])=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC1(C)OB(c2cccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c2)OC1(C)C
Yield: 98.7 %

Procedure:
To a solution of 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (100 mg, 0.46 mmol) in dichloromethane (4 mL), 1-chloro-4-isocyanato-2-trifluoromethyl-benzene (100 mg, 0.46 mmol) was added. The mixture was stirred until disappearance of the starting material. The solvent was evaporated to dryness to give 200 mg of 1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea in quantitative yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]([F:12])([F:11])[F:10])[CH:3]=1.[Li]CCCC.CCCCCC.[F:24][C:25]([F:36])([F:35])[O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#N.Cl.C([O:40]CC)C>O>[F:10][C:9]([F:12])([F:11])[O:8][C:4]1[CH:3]=[C:2]([C:30]([C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:26][C:25]([F:36])([F:35])[F:24])[CH:28]=2)=[O:40])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOCC
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: N#Cc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 1-bromo-3-(trifluoromethoxy)benzene (1.52 g, 6.3 mmol) in diethyl ether (50 mL) at −78° C. was added dropwise a solution of 1.6 M n-BuLi in hexane (4.2 mL, 6.6 mmol) and the reaction mixture was stirred at −78° C. for 30 min. A solution of 3-(trifluoromethoxy)benzonitrile (1.23 g, 6.6 mmol) in diethyl ether (5 mL) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 h. 3N HCl (40 mL) was added and the reaction was allowed to warm to rt followed by stirring at rt for 1.5 h. The reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by a silica gel ISCO cartridge with elution at gradient 10% EtOAc/hexane to give bis(3-(trifluoromethoxy)phenyl)methanone (1.99 g, 90% yield) as a white solid. LCMS: RT=2.10 min [M+H] 351.3 (2 min Phenomenex Luna C18 column, 4.6 X 30 mm eluting with 10-90% MeOH/H20 over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz IH (CDC13) ppm 7.46 (d, J=8.35 Hz 1 H), 7.54 (t, J=7.91 Hz, 1 H), 7.64 (s, 1 H), 7.70 (d, J=7.91 Hz, 1 H).
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:31][CH3:32])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([CH2:27][CH2:28][O:29][CH3:30])=[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:31][CH3:32])=[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]([CH2:27][CH2:28][O:29][CH3:30])=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: COCCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Solvent: CN(C)C=O
Product: COCCc1cc(N2CCN(C)CC2)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.9 %

Procedure:
0.5 g (5 mmol) of 1-methyl-piperazine in 3 ml of DMF was added to a solution of 0.45 g (1.13 mmol) of 3-benzenesulphonyl-7-chloro-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 3 hrs. The reaction solution was evaporated, the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (silica gel, CH2Cl2/MeOH 12:1) and crystallization from EtOH yielded 0.255 g (67%) of 3-benzenesulphonyl-5-(2-methoxy-ethyl)-7-(4-methyl-piperazin-1-yl)-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine as colorless crystals, m.p. 160-161°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7](F)=[CH:6][C:5]=1[NH:15][CH2:16][P:17]([OH:20])(=[O:19])[OH:18])([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[C:7]([O:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:6][C:5]=1[NH:15][CH2:16][P:17]([OH:20])(=[O:19])[OH:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1NCP(=O)(O)O
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Oc2ccccc2)cc1NCP(=O)(O)O
Yield: 68.6 %

Procedure:
) 3.18 g of N-(2-nitro-4-trifluoromethyl-5-fluorophenyl)-aminomethanephosphonic acid is stirred together with 3.18 g of sodium carbonate and 2.82 g of phenol in 40 ml of water for 4 hours at a bath temperature of 120° C. After acidification with 4N hydrochloric acid, the precipitated product is suctioned off. 2.69 g of N-(2-nitro-4-TRIFLUOROMETHYL-5-phenoxyphenyl)-aminomethanephosphonic acid is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30](Br)[CH3:31])=[CH:26][CH:25]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH3:31])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Br)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2)c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 83.8 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (415 mg, 1.08 mmol) in methanol (20 mL) and add potassium hydroxide (1.938 g, 34.53 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.34 g, 1.086 mmol) in anhydrous DMF (10 mL), add sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) and stir the mixture for 5 min. Add a solution of (±)-1-(4-fluorophenyl)ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) and heat the solution at 45° C. overnight. Cool to ambient temperature, add water and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (19:1 and 9:1) to give (±)-3-tert-butoxycarbonyl-7-chloro-6-[1-(4-fluorophenyl)ethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (397 mg, 84%). MS (ES+) m/z: 336 (M+H-Boc)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])=[CH:27][CH:26]=1)#[N:24]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: N#Cc1ccc(CN)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C#N)cc4)cc3)c2)o1

Procedure:
N-(4-Cyanobenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-cyanobenzylamine using method N. NMR; δH [2H6]—DMSO 9.25,(1H, t), 8.01,(2H, d), 7.90,(1H, dd), 7.81,(2H, d), 7.77,(1H, d), 7.56-7.51,(5H, m), 4.58,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.34 min, MH+ 409.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH:15]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=4)=[O:20])[CH2:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:32][CH2:33][CH2:34][CH2:35][N:36]=[C:37]=[O:38].ClC(C)CN=C=O>C(Cl)Cl>[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:19]([CH:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:37]([NH:36][CH2:35][CH2:34][CH2:33][Cl:32])=[O:38])[CH:7]=4)=[CH:10][CH:11]=3)[CH2:16]2)=[O:20])[CH:27]=[CH:26][CH:25]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C=NCCCCl
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)c1
Agent: CC(Cl)CN=C=O
Solvent: ClCCl
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)NCCCCl)c4)cc3C2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 57.3 %

Procedure:
To a solution of 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (0.965 g, 2.32 mmol) in DCM (30 mL) was added 3-chloropropyl isocyanate (0.357 mL, 3.48 mmol). The reaction mixture was allowed to stir at rt for 64 hr. Additional 2-chloropropyl isocyanate (0.300 mL, 2.92 mmol) was added, and the reaction mixture was allowed to stir at rt for 24 h. The solvent was evaporated and the residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-{[2-({[(3-chloropropyl)amino]-carbonyl}amino)pyridin-4-yl]oxy}-1,2,3,4tetrahydronaphthalene-2-carboxamide (0.710 g; 1.33 mmol, 57%) as a white solid. LCMS: (FA) ES+536.6, ES−533.5.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=5)[CH:26]=[N:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-n2ccnc2)cc1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Fc1ccc(-n2cncc2-c2ccc3ncn(-c4ccc(F)cc4)c3c2)cc1

Procedure:
The title compound, light brown solid (26 mg, 20%), MS (ISP) m/z=373.5 [(M+H)+], mp 247° C., was prepared in accordance with the general method of example 28 from 6-bromo-1-(4-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate G) (204 mg, 0.7 mmol) and commercially available 1-(4-fluoro-phenyl)-1H-imidazole (56.8 mg, 0.35 mmol).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[NH:22][NH2:23].C(N=C=NCCCN(C)C)C>ClCCl>[C:26]([O:25][C:21]([N:22]([C:7](=[O:9])[C:6]1[CH:10]=[C:11]([F:15])[C:12]([F:14])=[CH:13][C:5]=1[NH:4][C:3]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:2]=1[F:1])[NH2:23])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(N)C(=O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution of 2-(2,4-difluoroanilino)-4,5-difluorobenzoic acid (Example 5, 2.18 g, 7.6 mmol) and tert-butyl carbazate (1.57 g, 11.8 mmol) in dichloromethane (30 mL) is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (2.25 g, 11.77 mmol). After stirring for 16 hours at room temperature, the reaction mixture is diluted with dichloromethane and then washed with saturated NaHCO3, water, and brine. The organic layer is dried over Na2SO4, concentrated under vacuum, and purified via column chromatography (1:3 ethyl acetate/hexanes) to afford [2-(2,4-difluoroanilino)-4,5-difluorobenzoyl]-hydrazinecarboxylic acid tert-butyl ester as a solid (2.20 g). MS EI: m/z 400 (M+).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][C:1]([N:29]1[CH2:30][CH2:31][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1)=[O:2]
Reactant: CN(C)CCCN
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
To a solution of 5.7 g (0.035 mole) of 1,1'-carbonyldiimidazole in 75 ml of tetrahydrofuran (THF) was added a solution of 3.5 g (0.034 mole) of 3-dimethylaminopropylamine in 75 ml of THF and the reaction mixture was stirred at ambient temperature for 1.5 hr. A solution of 4.9 g (0.03 mole) of 1-phenylpiperazine in 50 ml of THF was added and the reaction mixture was heated at reflux for 20 hr. The solution was concentrated under reduced pressure and the residue was dissolved in 150 ml of benzene. The solution was washed thrice with 50 ml portions of water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil as residue which crystallized upon standing. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration and recrystallized from cyclohexane to yield 5.0 g (57%) of title compound as a white solid, m.p. 91°-95° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C-:17]#[N:18].[K+]>C(#N)C>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][C:17]#[N:18])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: ClCc1c2ccccc2cc2ccccc12
Agent: [K+]
Solvent: CC#N
Product: N#CCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 9-chloromethyl-anthracene (10.0 g, 44.11 mmol) and potassium cyanide (28.72 g, 441.1 mmol) in acetonitrile (1.6 L) was heated to reflux for 2 hours. The mixture was cooled to room temperature, filtered and concentrated. The residue was dissolved in CH2Cl2, washed with water, dried over MgSO4 and concentrated to give anthracen-9-yl-acetonitrile as yellow crystals (9.40 g, 98% yield). 1H NMR (CDCl3) δ 8.53 (1H, s), 8.18 (2H, d), 8.07 (2H, d), 7.65 (2H, dd), 7.54 (2H, dd), 4.60 (2H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17][CH:16]=1>>[C:9]1([C:6]2[N:5]=[CH:4][C:3]([CH2:2][C:19]3[CH:20]=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:8][N:7]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1cnc(-c2ccccc2)nc1
Reactant: OB(O)c1cncnc1
Product: c1ccc(-c2ncc(Cc3cncnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 64a (102 mg, 0.41 mmol) and pyrimidine-5-boronic acid (76 mg, 0.61 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:2) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. White solid. Yield: 41 mg, 40%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.00 (s, 2H), 7.46-7.55 (m, 3H), 8.39-8.47 (m, 2H), 8.63-8.71 (m, 4H), 9.15 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=31.1, 128.1, 128.6, 129.1, 130.9, 132.2, 137.0, 156.9, 157.2, 157.6, 163.7; (ESI): m/z=248.83 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]2[S:13][C:14]([C:23]3[N:27]=[CH:26][N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:24]=3)=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)=[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][N:4]2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][C:46]([F:50])([F:49])[CH2:45][CH2:44]1>>[F:49][C:46]1([F:50])[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:10][C:7]2[CH:8]=[CH:9][N:4]3[N:3]=[C:2]([CH3:1])[C:11]([C:12]4[S:13][C:14]([C:23]5[N:27]=[CH:26][N:25]([CH:28]6[CH2:33][CH2:32][CH2:31][CH2:30][O:29]6)[N:24]=5)=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[N:16]=4)=[C:5]3[CH:6]=2)[CH2:44][CH2:45]1
Reactant: FC1(F)CCN(CCCl)CC1
Reactant: Cc1nn2ccc(O)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nn2ccc(OCCN3CCC(F)(F)CC3)cc2c1-c1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Yield: 90.9 %

Procedure:
The title compound has been prepared according to the similar manner described in 85-B (ii) using 2-methyl-3-{4-phenyl-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}pyrazolo[1,5-a]pyridin-5-ol (100 mg, 0.218 mmol) obtained in Example 31-B-(i), potassium carbonate (75.3 mg, 0.545 mmol) and 1-(2-chloroethyl)-4,4-difluoropiperidine (80.0 mg, 0.436 mmol) obtained above. The crude product was purified by basic silica gel column chromatography (EtOAc/hexane=20/80→50/50) to give pure title compound (120 mg, 91%) as a colorless solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[C:13](=[O:16])[CH2:14][CH3:15])CC1.Br[C:18]1C=C(C=CC=1C)C(O)=O.BrC1C=C(C=CC=1C1CC1)C(O)=O.C([Mg]Br)CC>>[C:13]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH3:1])[C:8]([OH:10])=[O:9])(=[O:16])[CH2:14][CH2:15][CH3:18]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CCC(=O)c1cc(C(=O)O)ccc1C1CC1
Agent: CCC[Mg]Br
Agent: O=C(O)c1ccc(C2CC2)c(Br)c1
Product: CCCC(=O)c1cc(C(=O)O)ccc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 10.6, except 3-bromo-4-methylbenzoic acid was used in place of 3-bromo-4-cyclopropylbenzoic acid (compound 10.3) and propylmagnesium bromide was used in place of ethylmagnesium bromide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:40])[O:28][N:27]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:30]4[C:26]([CH3:25])=[N:27][O:28][C:29]=4[CH3:40])[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: Cc1noc(C)c1-c1ccc2c(c1)OCCc1sc(C(=O)N(CCO)C(C)C)nc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole to give 291. MS: (ESI+)=428.1
Reaction SMILES: CC1(C)O[O:3]1.[CH2:6]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O>[CH2:14]([N:13]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OO1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CC(C)=O
Product: ON(Cc1ccccc1)Cc1ccccc1
Yield: 98 %

Procedure:
A solution of 0.051 M dimethyldioxirane in acetone (32.9 ml, 1.67 mmol) was added to a cold stirred solution of N,N-dibenzylamine (Aldrich; 0.331 g, 1.67 mmol) in acetone (5 ml). The mixture was stirred for fifteen minutes in an ice bath. Evaporation of the solvent on the rotary evaporator gave a white crystalline solid. The solid was dissolved in acetone and the solution dried with anhydrous Na2SO4. The solvent was removed to give a chromatographically homogeneous white solid (0.352 g, 98% yield). Measured mp was 121-122; reported mp is 122-123 (DeLaMare et al 1963).
Reaction SMILES: [BH4-].[Na+].[I-].[C:4]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N+:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1)(=[O:6])[CH3:5]>CO>[C:4]([NH:7][CH2:8][C:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH:10]=1)(=[O:6])[CH3:5]
Reactant: CC[n+]1ccc(CNC(C)=O)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCN1CC=C(CNC(C)=O)CC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
Sodium borohydride (21.96 g) was added portionwise to a solution of 4-acetylaminomethyl-1-ethylpyridinium iodide (44.43 g) in methanol (400 ml) below 20° C. and the mixture was stirred at 75° C. for 3 hours. The mixture was evaporated in vacuo and the residue was poured into 0.7N aqueous solution of sodium hydroxide (115 ml). The mixture was extracted with methylene chloride. The extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by vacuum distillation to give 4-acetylaminomethyl-1-ethyl-1,2,3,6-tetrahydropyridine (23.38 g).