Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(C(C)C)CC)(C)C.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>C(Cl)Cl>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([N:4]([O:3][CH3:2])[CH3:5])=[O:20]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A mixture of N-methoxymethanamine hydrochloride (22.1 g, 228.5 mmol), diisopropyl ethyl amine (63.5 mL, 365.6 mmol) and CH2Cl2 was treated dropwise with 3-bromobenzoyl chloride (15 g, 68.5 mmol) in CH2Cl2, stirred at room temperature for 30 minutes, and concentrated under vacuum. The resultant residue was dispersed in water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (Biotage) using hexanes/EtOAc (2/1) as the eluting solvents to give 3-bromo-N-methoxy-N-methylbenzamide as a tan solid (15.1 g, 90% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[Li+].[F:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[N:12]=[N:13][CH:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:25])[CH:3]=2)[N:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1F
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ccncc4F)c3)n2)c(F)c1
Temperature: 80 °C
Yield: 42.2 %

Procedure:
A mixture of 5-(3-bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (from Example 8 below) (120 mg, 0.33 mmol), lithium chloride (70 mg), cuprous iodide (6.3 mg) and 3-fluoro-4-tributylstannylpyridine (120 mg, 0.31 mmol) in dry 1,4-dioxane (5 ml) was degassed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (30 mg) was added and the mixture heated under an atmosphere of nitrogen at 80° C. for 48 h. On cooling to room temperature the mixture was partitioned between dichloromethane (30 ml) and 25% aqueous ammonium hydroxide (15 ml). The organic layer was separated, solvent removed at reduced pressure, and the residue subjected to preparative thin layer chromatography on silica gel, eluent 2% methanol in dichloromethane. The product was recrystallised from hot toluene to give 3-(2,4-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-4-yl)phenyl]-[1,2,4]triazine as a solid (50 mg): δH (500 MHz, d6-DMSO) 7.35 (1H, m), 7.52 (1H, m), 7.73 (2H, m), 8.34 (1H, m), 8.63 (3H, m), 8.78 (1H, s), 10.18 (1H, s); m/z (ES+) 383.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[CH2:10][CH:9]1[C:31]([OH:33])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)#[N:45].CCN(CC)CC.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])[C:14]([O:16][CH2:17][C:18]([Cl:20])([Cl:19])[Cl:21])=[O:15])[CH2:10][CH:9]1[C:31]([N:55]1[CH2:54][CH2:53][N:52]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[C:44]#[N:45])[CH2:57][CH2:56]1)=[O:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(N(Cc2ccc(F)cc2F)C(=O)OCC(Cl)(Cl)Cl)CC1C(=O)N1CCN(c2ccccc2C#N)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 4-[(2,4-difluoro-benzyl)-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (3.5 g, 6.6 mmol), HOBt (1.4 g, 10 mmol), 1-(2-cyanophenyl)piperazine (1.5 g, 7.9 mmol) in DCM (50 ml) were added Et3N (1.8 ml, 13.2 mmol) and EDC.HCl (1.9 g, 10 mmol). The mixture was stirred overnight, then washed with 10% citric acid, Na2CO3, brine, dried and concentrated to give the title product as a colorless oil (4.5 g, 6.4 mmol). MS m/e=700.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:18][CH:17]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Oc2cncc(Cl)n2)cc1
Yield: 92 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 4-acetamidophenol (202 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (327 mg). Yield: 92%. 1H NMR (250 MHz, DMSO-d6) δ 2.12 (s, 3H, CH3—NH), 7.25 (d, 2H, Harom 3+5, J=8.9 Hz), 7.71 (d, 2H, Harom 2+6, J=8.9 Hz), 8.55 (s, 1H, HPz 5), 8.57 (s, 1H, HPz 3), 10.10 (s, 1H, NH). m/z: 264.0 [(M+H)+, calcd for C12H10ClN3O2 263.0].
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7](=[S:29])[NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1>C1(C)C=CC=CC=1>[F:25][C:24]([F:27])([F:26])[C:20]1[CH:19]=[C:18]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]2[S:29][C:7]([NH2:6])=[N:8][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NC(=S)NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: Nc1nnc(-c2ccccc2Nc2cccc(C(F)(F)F)c2)s1
Yield: 35.3 %

Procedure:
Methanesulfonic acid (260 μl, 4.01 mmoles) is added dropwise to a suspension of 2-[(3-trifluoromethylphenyl)amino]-benzoic acid, 2-(aminothioxo-methyl)hydrazide (865.9 mg, 2.44 mmoles) in 30 ml of toluene. The mixture is heated at reflux for two hours. The solvent is decanted from the bright red oil. The oil is washed with toluene and stirred with ether to yield a red solid. The solid is filtered off and suspended in 50 ml of ethyl acetate. The suspension is stirred vigorously with 10% aqueous ammonium hydroxide and the layers are separated. The ethyl acetate layer is washed with water and dried over magnesium sulfate. Filtration and concentration in vacuo gives a light brown solid that is purified by flash chromatography eluting with a gradient of hexane and ethyl acetate (1:1 to 1:3) to provide 289.5 mg (35%) of 5-[2-[(3-trifluoromethylphenyl)amino]phenyl]-1,3,4-thiadiazol-2-amine, mp 122°-123° C.
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH:25][NH2:26])[CH2:23][CH3:24]>CO>[C:1]1([CH:7]2[NH:26][N:25]([CH2:22][CH2:23][CH3:24])[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10][CH2:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Reactant: CCCNN
Solvent: CO
Product: CCCN1NC(c2ccccc2)C2=C1C(=Cc1ccccc1)CSC2
Reaction time: 0.5 h

Procedure:
A mixture of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one (5.84 g, 20 mmole) and n-propyl hydrazine (1.48 g, 20 mmole, CA 59:8724f) in MeOH (100 ml) is heated at reflux temperature for 3 hours. The initial heterogeneous mixture becomes homogeneous after about 0.5 hour. Upon cooling, crystals form and are collected and washed (MeOH) to give 5.0 g, m.p. 106°-118°. Recrystallization from MeOH gives the major product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:15][CH2:14]1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COCCN1CCN(c2cc(OC)c([N+](=O)[O-])cc2C)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCN1CCN(c2cc(OC)c(N)cc2C)CC1
Reaction time: 8 h
Yield: 366.3 %

Procedure:
1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methyloxy)ethyl]piperazine (1.44 g, 4.66 mmol) was placed in a 100 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/C (1.09 g, 0.28 mmol) was added followed quickly by a rubber septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (60 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step B (1.15 g, 17.07 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.56 (s, 1H), 6.42 (s, 1H), 4.30 (s, 2H), 3.70 (s, 3H), 3.43 (t, J=5.87 Hz, 2H), 3.23 (s, 3H), 2.71 (t, J=4.58 Hz, 4H), 2.45-2.56 (m, 6H), 2.04 (s, 3H)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][C:34]=1[CH3:35])[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][CH2:10]2)(=O)=O.[Cl-].[Li+].[CH2:40]([Sn](CCCC)(CCCC)C=C)[CH2:41]CC>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:35][C:34]1[CH:33]=[C:32]2[C:9]([CH2:10][CH2:11][C:12]3[C:13]2=[N:14][O:15][C:16]=3[C:17]2[C:21]([C:22]([F:24])([F:23])[F:25])=[C:20]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:19][N:18]=2)=[CH:8][C:7]=1[CH:40]=[CH2:41]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cc2c(cc1C)-c1noc(-c3noc(-c4ccccc4)c3C(F)(F)F)c1CC2
Temperature: 100 °C
Yield: 62.3 %

Procedure:
A mixture of 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate (Preparation 64D, 0.120 g, 0.220 mmol) and lithium chloride (0.014 mL, 0.661 mmol) in dioxane (15 mL) was degassed with nitrogen for 15 minutes. Tributyl(vinyl)stannane (0.077 g, 0.242 mmol) was added followed by the addition of tetrakis(triphenylphosphine) palladium(0) (0.025 g, 0.022 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and filtered. The brownish residue was washed with ethyl acetate (3×10 mL), and the combined filtrates were concentrated under reduce pressure. The residue was chromatographed on silica gel eluting with a mixture of 10% ethyl acetate and 90% hexane to yield 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.088 g, 0.137 mmol, 62% yield) as a tan viscous liquid. The product had an HPLC ret. time=4.58 min (condition B). LC/MS M+1=423.30.
Reaction SMILES: [C:1]1([C:11]#[C:12][CH:13]=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([Mg]Br)[CH:16]=[CH2:17]>O1CCCC1>[C:1]1([C:11]#[C:12][CH:13]([OH:14])[CH2:17][CH:16]=[CH2:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[Mg]Br
Reactant: O=CC#Cc1cccc2ccccc12
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1cccc2ccccc12
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of naphthalen-1-yl-propynal (2.50 g, 13.88 mmol) in tetrahydrofuran (50 mL) was added to a stirred solution of allylmagnesium bromide (1M in diethyl ether, 20.81 mL, 20.81 mmol, 1.5 eq.) at 0° C. over 0.5 h under an atmosphere of nitrogen. Stirring was continued for a further 2 h at 0° C. The reaction was quenched with water (50 mL) at 0° C. To the reaction mixture was added diethyl ether (100 mL) and the reaction mixture was stirred and allowed to separate. The aqueous phase was re-extracted with diethyl ether (3×100 mL) and the combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford a yellow oil. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 30%:70%) to afford the desired compound as a yellow oil (2.34 g, 76%). 1H NMR (400 MHz, CDCl3) δ ppm 2.67-2.69 (2H, m, CH2), 4.80-4.81 (1H, m, CH), 5.24-5.31 (2H, m, CH2), 5.99-6.06 (1H, m, CH), 7.40-7.64 (4H, m, Ar—H), 7.66 (1H, d, J 8.0 Hz, ArH), 7.82 (1H, d, J 8.0 Hz, ArH), 8.28 (1H, d, J 8.0 Hz, ArH).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]3=2)[CH:10]=[C:9]1[CH:23](O)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1.C1CC=CCC=1>O1CCCC1.[Pd]>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]3=2)[CH:10]=[C:9]1[CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(c3c1cc(C(C)O)n3Cc1ccccc1)CCCC2
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1cc2c(OC)cc3c(c2n1Cc1ccccc1)CCCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.1 %

Procedure:
A solution of 1-benzyl-2-(1-hydroxyethyl)-4-methoxy-6,7,8,9-tetrahydro-1H-benz[g]indole (1.0 g, 3.0 mmol) in tetrahydrofuran (5 mL) was treated with acetic anhydride (0.28 mL, 3.0 mmol), pyridine (0.53 mL, 6.6 mmol), 1,4-cyclohexadiene (3 mL), and 10% palladium-on-carbon (0.5 g) at 70° C. for 7 h. The mixture was cooled to room temperature, stirred for 18 h, heated at 80° C. for 9 h, cooled to room temperature, and stirred for 18 h. Additional portions of 10% palladium-on-carbon (0.5 g) and 1,4-cyclohexadiene (3 mL) were added and the resulting mixture stirred at 80° C. for 9 h. The mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was dissolved in 9:1 hexanes/ether and treated with 10% aqueous citric acid (3 mL). The organic layer was filtered through silica gel, which was eluted with hexanes, methylene chloride, and ether. Concentration of the appropriate fractions provided 662 mg (70%) of the title compound as an amber foam. 1H NMR (CDCl3) δ 7.22 (m, 3H), 6.83 (d, J=7 Hz, 2H), 6.42 (s, 1H), 6.25 (s, 1H), 5.54 (s, 2H), 3.95 (s, 3H), 2.96 (m, 2H), 2.85 (m, 2H), 2.55 (q, J=6 Hz, 2H), 1.70 (m, 4H), 1.28 (t, J=6 Hz, 3H); MS ES+ m/e 320 (p+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=O.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].CCCCCCC>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[N:19][S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18]
Reactant: O=C1CCOc2ccc(Br)cc21
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(C)(C)S(=O)N=C1CCOc2ccc(Br)cc21
Temperature: 60 °C
Yield: 82.6 %

Procedure:
6-Bromochroman-4-one (5.0 g, 22 mmol) and 2-methylpropane-2-sulfinamide (2.6 g, 22 mmol) were dissolved in dry THF (80 mL). Titanium ethoxide (10 g, 44 mmol) was added. The resulting mixture was heated at 60° C. for 2 days. An additional portion of titanium ethoxide (1.0 g, 8.4 mmol) was added after 12 h. The mixture was mixed with heptane and evaporated onto silica gel. Flash chromatography on silica (0-50% EtOAc in heptane) gave the title compound (6.0 g, 83% yield). 1H NMR (500 MHz, CDCl3) δ ppm 1.34 (s, 9 H) 3.26-3.32 (m, 1 H) 3.47-3.54 (m, 1 H) 4.28-4.40 (m, 2 H) 6.83 (d, 1 H) 7.46 (dd, 1 H) 8.06 (d, 1 H); MS (ES+) m/z 330 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C=O)C>[C:19]1(=[O:29])[N:23]([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(O)(CCN1C(=O)c2ccccc2C1=O)c1ccccc1-c1ccccc1

Procedure:
A mixture of 2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol, 2.04 g of potassium phthalimide and 40 ml of DMF is heated at 110° for 1.5 hours. After cooling, the mixture is worked up in the customary manner to give 1-phthalimido-3-p-biphenylyl-butan-3-ol, m.p. 153°-155°.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[N:10][N:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[C:12]2[N:11]=[N:10][N:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2c1nnn2C1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2c1nnn2C1CCCCC1
Temperature: 60 °C

Procedure:
In a 500 ml. Paar hydrogenator is placed 49.2 g. of the 4-nitro-1-cyclohexyl-1H-benzotriazole, 220 ml. ethanol and 2.5 g. 10% palladium on carbon catalyst and the mixture is heated to 45° C. Hydrogen is introduced at about 40 psi and the temperature of the reaction is maintained at 60° C. The reaction is over after 11/2 hours and the catalyst is then removed by filtration. On evaporation of the solvent, the product is isolated in quantitative yield as an oil, which solidifies on standing, m.p. 54°-60° C. Analysis Calcd. for C12H16N4 : C, 66.64; H, 7.46; N, 25.90. Found: C, 66.38; H, 7.55; N, 25.69.
Reaction SMILES: CS(O[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[N:22])=[CH:11][N:10]=1)[CH2:7][CH3:8])(=O)=O.C(N(CC)CC)C.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>C(Cl)Cl.O>[N:30]1([CH:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CCC(OS(C)(=O)=O)c1ccc(-c2ccccc2C#N)cn1
Reactant: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(c1ccc(-c2ccccc2C#N)cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.1 %

Procedure:
To solution of 1-(5-(2-cyanophenyl)pyridin-2-yl)propyl methanesulfonate (0.050 g, 0.15 mmol) in DCM was added triethyl amine (0.030 g, 0.30 mmol) followed by imidazole (0.20 g, 0.30 mmol) at room temperature. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic extracts were dried over sodium sulphate, filtered and concentrated to obtain the crude compound which was purified by preparative TLC by using 5% MeOH/DCM to give 2-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzonitrile (10 mg, 24%). 1H NMR (400 MHz DMSO-d6): δ 8.77 (s, 1H), 8.04 (dd, 1H), 7.98 (d, 1H), 7.84 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.63 (t, 1H), 7.44 (d, 1H), 7.34 (s, 1H), 6.92 (s, 1H), 5.43 (dd, 1H), 2.31-2.20 (m, 2H), 0.83 (t, 3H); LC-MS m/z calcd for [M+H]+ 289.14. found 289.5.
Reaction SMILES: C(OC(=O)[N:6]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:15]=2)[CH:9]=1)C=C.C(N(C(C)C)CC)(C)C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.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>[C:30]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: C=CCOC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
tert-Butyl-(3-{2-[2-(4-hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl}benzyl)-carbamic acid allyl ester (intermediate 118, 176 mg) was dissolved in methylene chloride (5 mL), followed by addition of diisopropylethylamine (0.11 mL), 1,3-dimethylbarbituric acid (78 mg) then Pd(PPh3)4 (50 mg). The mixture was stirred at room temperature overnight. The mixture was washed with saturated NaHCO3, brine, dried over Na2SO4, filtered and chromatographed on silica gel with methylene chloride:methanol (95:5) to afford 112 mg of product in 78% yield. LC-MS showed the product had the expected M+H+ of 377. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.1 (s, 1H) 8.0 (d, 1H) 7.5 (m, 2H) 7.1 (m, 3H) 6.7 (m, 2H) 3.8 (s, 2H) 3.6 (m, 2H) 2.8 (m, 2H) 1.2 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([CH:14]=1)[C:8]([O:10]CCC)=[O:9])=[O:2].[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:15][CH2:16][CH2:17][CH3:18])=[C:7]([CH:14]=1)[C:8]([OH:10])=[O:9])=[O:2]
Reactant: CCCOC(=O)c1cc(C=O)ccc1OCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCOc1ccc(C=O)cc1C(=O)O
Temperature: 70 °C
Yield: 94.9 %

Procedure:
To a solution of propyl 5-formyl-2-propoxybenzoate (1.0 g, 4.0 mmol) in tetrahydrofuran/methanol/water (20 mL: 20 mL: 8 mL) is added 5 N sodium hydroxide solution (2 mL, 10 mmol). The mixture is heated in a 70° C. oil bath for three hours and then allowed to cool to room temperature. While acidifying to pH 1 with concentrated hydrochloric acid, a white solid precipitated, which is collected and discarded. The filtrate is concentrated under reduced pressure, and the solid residue is collected by filtration and washed with water to give 5-formyl-2-propoxybenzoic acid as flocculent white needles (0.79 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OCC)C>O1CCCC1.CCCCCC>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:29]=[CH:30][C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:43])=[CH:3][C:4]=3[F:31])[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 21 %

Procedure:
To a solution of 3-[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (61 mg) in tetrahydrofuran (3.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.2 M, 1.70 ml) at room temperature, followed by stirring at room temperature for 9.5 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether (1 ml) and hexane (1 ml) were added to give a precipitate. The precipitate was filtered off, and dried under aeration to provide the titled compound (17.8 mg, 21%) as white powder.