Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:8]=1)[NH2:7].[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH2:10][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][N:16]=2)=[C:6]([NH:7][S:26]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)(=[O:27])=[O:28])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1SCc1ncccn1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1ncccn1)c1cc2ccccc2o1
Yield: 50.7 %

Procedure:
Following General Procedure B, the title compound (243 mg, 51%) was prepared from 5-chloro-2-((pyrimidin-2-ylmethyl)thio)aniline (280 mg, 1.11 mmol) and benzofuran-2-sulfonyl chloride (240 mg, 1.11 mmol) in pyridine (3 ml).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11](=[CH:15]OCC)[C:12]([CH3:14])=O)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:14][C:12]1[C:11]([C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:21])([F:20])[F:1])=[CH:4][CH:5]=2)=[O:19])=[CH:15][NH:24][N:23]=1
Reactant: CCOC=C(C(C)=O)C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1n[nH]cc1C(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 33.6 %

Procedure:
N-[4-(Trifluoromethyl)phenyl]-2-(ethoxymethylene)-acetoacetamide (1 g) in 3 mL of ethanol is stirred overnight with 0.3 g of hydrazine hydrate. The precipitate is collected by vacuum filtration, washed with ethanol:water 2:1 and dried to give 0.3 g of 3-methyl-4-(4-(trifluoromethyl)phenylaminocarbonyl]pyrazole as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]([CH2:14][C:15]([O:17][CH2:18]C)=[O:16])#[N:13]>CO>[CH3:18][O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[CH:10][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CO
Product: COC(=O)C(C#N)=Cc1c[nH]c2ncccc12
Temperature: 0 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
7-azaindole-3-carboxaldehyde (3.36 g, 22.99 mmol) was taken in 60 ml of methanol and cooled to 0° C. Pipepridine (2.5 ml, 25.28 mmol) was added followed by ethyl cyanoacetate (2.23 ml, 25.27 mmol). The reaction was stirred at RT for 5 hrs then concentrated quenched with water and filtered to give a yellow solid product (4.07 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].C[O:22][C:23](=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:23](=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)CCCCCCc1ccc2c(n1)NCCC2
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)CCCCCCc1ccc2c(n1)NCCC2
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of diisopropylamine (5.17 mL, 36.9 mmol) in anhydrous tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium in hexanes (16.2 mL of a 2.5 M solution). After 5 minutes, t-butyl acetate (4.97 mL, 36.9 mmol) was added. After an additional 5 minutes, 7-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-heptanoic acid methyl ester 29-4 (3.4 g, 12.3 mmol) in tetrahydrofuran (30 mL) was added and the solution was warmed to −40° C. for one hour. The reaction mixture was then poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with ethyl acetate to give 29-5 as a yellowish oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][CH2:37][NH:36][C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccccn1
Product: NCCSC(=O)NCCc1ccccn1

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (500 mg) and 2-(2-aminoethyl)pyridine (375 μl) were subjected to the reactions described in References 2 and 4 to give 2-(2-pyridyl)ethylaminocarbonylthioethylamine (crude formate: 218 mg). The product (190 mg) was dissolved in anhydrous methanol (3 ml), to which were then added triethylamine (490 μl) and mitomycin A (245 mg: 1.0 molar equivalent). The reaction solution was treated in a similar manner to that described in Example 1 to obtain Compound 49 (297 mg) in the form of grayish blue powders with a yield of 78%.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1CCC([N:29]=C=NC2CCCCC2)CC1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[N:38]1([NH-:29])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C1COCCN1
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: [NH-]N1CCOCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 4.49 g of Z-(L)-Phe-OH in 190 ml of methylene chloride is cooled to 0° C. and 3.09 g of DCC are added. After stirring for 20 minutes at 0° C., a solution of 1.31 ml of morpholine in 10 ml of methylene chloride is added dropwise thereto over a period of 15 minutes. The reaction mixture is stirred for a further 24 hours at room temperature and, after the precipitated dicyclohexylurea has been filtered off, is washed in succession with methylene chloride, aqueous sodium hydrogen carbonate solution and brine. Drying over sodium sulfate and concentration yield the crude title compound which crystallises from ether. TLC Rf (C)=0.55.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:20])[CH2:15][N:16]=1)=[CH:8]2
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)N4CCOCC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.5 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (500 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (330 mg), 1-hydroxybenzotriazole (230 mg), morpholine (190 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give pale yellow crystals. The crystals were recrystallized from acetone-hexane and then recrystallized from acetone-methanol to give the title compound (250 mg, 43%) as colorless prisms. MS 531 (MH+). mp 148-149° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.ClC1C2OCCOC=2C(C(Cl)=O)=CC=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:12]([C:5]2[C:6]3[O:11][CH2:10][CH2:9][O:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:14])[CH2:36][CH2:35]1
Reactant: O=C(O)c1ccc(Cl)c2c1OCCO2
Reactant: CN1CCNCC1
Agent: O=C(Cl)c1ccc(Cl)c2c1OCCO2
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(Cl)c3c2OCCO3)CC1
Yield: 50.6 %

Procedure:
According to the method described in Example 33, 20 g of 8-chloro-1,4-benzodioxane-5-carboxylic acid were treated with thionyl chloride and the resulting 8-chloro-1,4-benzodioxane-5-carbonyl chloride (M.P.: 83° C.) was treated with 10.5 g of methylpiperazine. 14 g of 5-[(4-methyl-1-piperazinyl)-carbonyl]-8-chloro-1,4-benzodioxane were obtained (M.P.: 260° C. with decomposition; yield: 50.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].O[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>[OH-].[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]1[CH2:11][C:12](=[O:13])[C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:6]1
Reactant: Cc1cccc(C=O)c1
Reactant: O=C(CO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C2CC(=O)c3ccccc3O2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 86 %

Procedure:
A mixture of 3-methylbenzaldehyde (12 g, 0.1 mol), 2-hydroxyacetophenone (13.6 g, 0.1 mol), and 2 liters of 0.1 N NaOH was stirred at room temperature for 4 days. The reaction was extracted with ether and the ether dried and evaporated to give 20.5 g of 3'-methyl flavanone as an oil. The oil, not further purified but used directly, was converted in a similar manner as described in Example 1 into 8.2 g of the hydrochloride salt of 3'-methyl-3-dimethylaminomethyl flavanone, as a solid, m.p. 156°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C.O1CCOCC1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Temperature: 60 °C

Procedure:
12.6 g of 4'-chloro-3'-chlorosulfonylacetophenone were introduced, while stirring, in a mixture of 5.6 g of aniline, 7.5 g of triethyl amine and 100 ml of dioxane. The mixture was allowed to dwell over night at 20° C., it was heated to 60° C. during 30 minutes while stirring and the separated triethylamine-hydrochloride was separated. The filtrate was concentrated under reduced pressure and the residue was crystallized under water. Colorless crystals (from isopropanol/active charcoal), melting point: 142° C.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>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>[OH:17][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)c1ccc(C#CCCCO)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Methyl 4-iodobenzoate (13.1 g, 60 mmol), PdCl2(PPh3)2 (2.0 g, 3 mmol), and CuI (855 mg, 4.5 mmol) were added to TEA (60 mL). The mixture is degassed while stirring by bubbling N2 vigorously into the solution. Pent-4-yn-1-ol (5.5 g, 66 mmol) was added by syringe. The mixture was heated at 90° C. overnight. After cooling, the crude mixture was concentrated by rotary evaporation and pumped on the high vacuum for 1 h. The oil was dissolved in DCM and adsorbed onto Celite followed by purification by chromatography (gradient 10-100% EtOAc/Hexanes) to give the title compound as a light yellow powder (9 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, 2H, J=9.0, 1.5 Hz), 7.44 (dd, 2H, J=9.0, 1.5 Hz), 3.90 (s, 3H), 3.85 (m, 2H), 2.57 (t, 2H, J=5.5 Hz), 1.87 (m, 2H), 1.42 (t, 1H, J=5.5 Hz); ES/MS calcd. for C13H15O3+ 219.1. found m/z=219 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:16]=3[CH:15]=2)[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]=[CH2:36].O>CN(C)C=O>[CH3:1][N:2]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:6](=[O:7])[N:5]([C:14]2[CH:26]=[CH:25][C:17]3[N:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[N:20]([CH2:36][CH:35]=[CH2:34])[C:16]=3[CH:15]=2)[C:3]1=[O:4]
Reactant: C=CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3nc(C(F)(F)F)[nH]c3c2)c1=O
Agent: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3[nH]c(C(F)(F)F)nc3c2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(C(F)(F)F)nc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 1.3 grams (0.003 mole) of a tautomeric mixture of 1-methyl-3-(2-trifluoromethylbenzimidazol-5-yl)-6-trifluoromethyluracil and 1-methyl-3-(2-trifluoromethylbenzimidazol-6-yl)-6-trifluoromethyluracil (prepared in Example 4) in 15 mL of N,N-dimethylformamide was stirred, and 0.9 gram (0.007 mole) of potassium carbonate was added. The reaction mixture was then stirred at ambient temperature for one hour, and 0.5 gram (0.004 mole) of 3-bromopropene was added in one portion. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for an additional two hours. The reaction mixture was then poured into water, and the resultant solid precipitate was collected by filtration. The solid was washed with water and then with diethyl ether. Thin layer chromatographic analysis of the solid indicated it to be a 1:1 mixture of the proposed products. The solid was subjected to high pressure liquid chromatography, with 5% 1-methylethanol in hexane as the eluant. The appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 1-methyl-3-[1-(2-propen-1-yl)-2-trifluoromethylbenzimidazol-6-yl]-6-trifluoromethyluracil, mp 171°-173° C. (compound 9). Other appropriate product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of 1-methyl-3-[1-(2-propen-1-yl)-2-trifluoromethylbenzimidazol-5-yl]-6-trifluoromethyluracil, mp 185°-187° C. The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([SH:12])[N:6]=[C:5]2[OH:13].CI.[O-][CH2:17]C.[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:12][CH3:17])[N:6]=[C:5]2[OH:13]
Reactant: CC[O-]
Reactant: Oc1nc(S)nc2ccc(Br)cc12
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc(O)c2cc(Br)ccc2n1

Procedure:
A solution of 6-bromo-2-mercapto-quinazolin-4-ol (0.32 g, 1.26 mmol), methyl iodide and sodium ethoxide in DMF (5 mL) was stirred at room temperature for 3 hours. HCl (1N, 3 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated to provide 0.31 g of crude product which was used without further purification. The product was characterized as follows: MS (m/z) 271 [M+H]+; HPLC retention time (Rt)=1.87 minutes (Method B).
Reaction SMILES: O.[C:2](Cl)(Cl)=[S:3].[NH2:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(Cl)Cl>[C:9]([C:8]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=1[N:6]=[C:2]=[S:3])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S

Procedure:
A five liter, 3-necked, round-bottom flask equipped with a condenser plus scrubber, mechanical stirrer, and dropping funnel was used as the reaction vessel. The reaction vessel was cooled in an ice bath after charging with 1.2 liters of water. After the water had cooled, 126 ml (1.65 moles) of thiophosgene was added. The mixture was stirred vigorously while a solution containing 352 grams (1.52 moles) of 2-amino-5-chlorobenzophenone in about 1 liter of methylene chloride was added over a period of 20 to 25 minutes. After addition was complete the funnel was rinsed with about 150 ml of methylene chloride and the reaction mixture was stirred for about one hour with the ice bath in place. Then the ice bath was removed and the reaction mixture was stirred for one additional hour. The organic phase was separated, dried with magnesium sulfate, and concentrated in vacuo. The 2-benzoyl-4-chlorophenylisothiocyanate remained behind as a brown oil which solidified on cooling. The product was recrystallized from hexane to yield tan crystals.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccc(Br)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Br)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-bromophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.72 (1H, s), 7.30-7.32 (2H, m), 7.41 (1H, d, J=0.8 Hz, J=5.2 Hz), 7.52-7.54 (2H, m), 7.56 (1H, d, J=0.8 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.0 Hz). [M+H] Calc'd for C16H11BrN4O, 355. Found, 355.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:10][CH2:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[O:22])[N:20]=2)[CH:17]=1
Reactant: NCc1c(F)cccc1F
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1c(F)cccc1F)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (2,6-difluorophenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]2[C:18]3[N:26]=[C:25](Cl)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[OH:45].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([CH:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]2[C:18]3[N:26]=[C:25]([C:34]4[CH:33]=[CH:32][C:31]([OH:45])=[C:30]([O:29][CH3:28])[CH:35]=4)[CH:24]=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(Cl)c1)C1CNCCN1c1ncnc2ccc(Cl)nc12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccc3ncnc(N4CCNCC4C(=O)Nc4cccc(Cl)c4)c3n2)ccc1O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
To a solution of 4-[(N-3-chloro-phenylcarbamoyl)-piperazin-1-yl]-6-chloro-pyrido[3,2-d]pyrimidine (0.51 mmole) in 1,4-dioxane (15 ml) and water (5 ml) was added 2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.51 mmole), potassium carbonate (1.53 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.02 mmole). The reaction mixture was refluxed for two hours, cooled down to room temperature and the solvents were evaporated in vacuo. The residue was purified by silica gel column chromatography (the mobile phase being an acetone/dichloromethane mixture in a ratio of 20:80), affording the title compound as a pure white powder (135 mg, yield 54%) which was characterized by its mass spectrum as follows: MS (m/z): 492 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cn1
Reactant: CN1CCC(NC(=O)c2cc(Cl)ccn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CN1CCC(NC(=O)c2cc(Oc3ccc(N)nc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.557 g, 5.06 mmol) in DMA (8.5 mL) was treated with potassium tert-butoxide (0.639 g, 5.69 mmol), stirred at RT for 1 h, treated with a solution of 4-chloro-N-(1-methylpiperidin-4-yl)picolinamide (1.07 g, 4.22 mmol) in DMA (8.5 mL) and stirred at RT for 20 h. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM/NH4OH) to afford 4-((6-aminopyridin-3-yl)oxy)-N-(1-methylpiperidin-4-yl)picolinamide (0.654 g, 47%). 1H NMR (400 MHz, DMSO-d6): δ 8.49-8.48 (m, 2H), 7.81 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 6.52 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 3.69 (d, J=9.9 Hz, 1H), 2.69 (d, J=11.1 Hz, 2H), 2.13 (s, 3H), 1.93 (t, J=11.2 Hz, 2H), 1.68-1.62 (m, 4H); MS (ESI) m/z: 328.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CN([CH:22]=[O:23])C>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:22]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N
Reactant: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1c(=O)[nH]c2ccccc21
Yield: 56 %

Procedure:
A mixture of [2-(2-aminophenylamino)ethyl]carbamic acid t-butyl ester (3.85 g, 15.3 mmol) and 1,1-carbonyldiimidazole (CDI) (2.73 g, 16.8 mmol) in DMF are heated at 110°-120° C. until reaction is complete by TLC, cooled and extracted with EtOAc. The combined extracts are washed with water, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (silica gel, 1:1 CH2Cl2: EtOAc as eluent) to give the title compound as a brown solid, 2.4 g (56% yield), identified by HPLC and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][O:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)O)ccc32)cc1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: COc1ccc(Cn2ccc3cc(/C(C)=C/C(=O)Nc4ccccc4OCCCC(=O)O)ccc32)cc1

Procedure:
270 mg of compound 35 was obtained in a similar manner to those described in the Examples 1 and 2 using 615 mg of ethyl 4-(2-aminophenoxy)butyrate and 443 mg of 3-[1-(4-methoxybenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.