Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[NH:5][N:6]=1.CC[O-].[Na+].[C:12](OCC)(=[O:19])[CH2:13][C:14](OCC)=[O:15]>CCO>[CH3:1][C:2]1[CH:3]=[C:4]2[NH:7][C:12](=[O:19])[CH2:13][C:14](=[O:15])[N:5]2[N:6]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2n(n1)C(=O)CC(=O)N2
Temperature: 25 °C

Procedure:
(prepared in an analogous procedure to that outlined in WO 2004/026229 A2) Step A: 5-Methyl-2H-pyrazol-3-ylamine (2 g, 0.0206 mol) was dissolved in EtOH (60 ml) and NaOEt (11.58 ml of a 21% by wt. solution, 2 eq) was added, followed by diethyl malonate (3.44 ml, 1.1 eq). The mixture was heated at reflux for 3 h. After cooling to rt, the precipitate was collected by filtration, washed with additional EtOH, and dried to give 1.6 g of 2-methyl-4H-pyrazolo[1,5-a]pyrimidine-5,7-dione. Step B: The compound from step A (1.6 g) was dissolved in POCl3 (18 ml) and cooled to 0° C., N,N-dimethylaniline (3.43 ml) was added and the mixture heated at 115-120° C. overnight. After cooling to rt, the POCl3 was removed under reduced pressure, the resulting residue was taken up in CH2Cl2, and poured onto ice. Once the ice melted the mixture was neutralized with NaHCO3 (s) and the organic layer separated. The organic layer was washed with water, dried (MgSO4), concentrated under reduced pressure, and the resulting residue purified by flash chromatography (SiO2, hexane-CH2Cl2) to give 0.734 g of 5,7-dichloro-2-methylpyrazolo[1,5-a]pyrimidine. 1H NMR (CDCl3) δ 6.89 (s, 1H), 6.52 (s, 1H), 2.55 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1)=C.[O:17]=[O+][O-].CSC>CO>[CH:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:4]=1)=[O:17]
Reactant: C=Cc1cc(NC(=O)OC(C)(C)C)ncn1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(C=O)ncn1
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 6-vinylpyrimidin-4-ylcarbamate (4.4 g, 0.020 mol) in MeOH (200 mL) at −78° C. was bubbled O3 for 1 hour. N2 was bubbled through the mixture for 10 minutes and then dimethylsulfide (1.24 g, 0.020 mol) was added dropwise. After addition, the solvent was removed under reduced pressure to give the crude desired product (4.6 g, over 100% yield) which was used in the next step without purification. LCMS (ESI) m/z: 224.1 [M+H+].
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[C:8]([O:11][CH2:12][CH:13]([NH:19][C:20]([C:22]1[C:27]([I:28])=[C:26]([NH2:29])[C:25]([I:30])=[C:24]([C:31]([NH:33][CH:34]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:35][O:36][C:37](=[O:39])[CH3:38])=[O:32])[C:23]=1[I:45])=[O:21])[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:10])[CH3:9]>CC(N(C)C)=O>[C:37]([O:36][CH2:35][CH:34]([NH:33][C:31]([C:24]1[C:25]([I:30])=[C:26]([NH:29][C:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:27]([I:28])=[C:22]([C:20]([NH:19][CH:13]([CH2:12][O:11][C:8](=[O:10])[CH3:9])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:21])[C:23]=1[I:45])=[O:32])[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:39])[CH3:38]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: C=CCCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: C=CCCC(=O)Nc1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reaction time: 16 h
Yield: 89 %

Procedure:
4-Pentenoyl chloride (11.9 g, 100 mmol) was added to a stirred solution of N,N'-bis-[2-(acetyloxy)-1-[(acetyloxy)-methyl]ethyl]-5-amino-2,4,6 -triiodo-1,3-benzenedicarboxamide (47.75 g, 50 mmol) in dimethylacetamide (400 mL) at room temperature and the mixture was stirred for 16 hours. Dimethylacetamide was removed in vacuo and the residue dissolved in ethyl acetate (600 ml). The solution was washed with aqueous sodium bicarbonate (10%, 2×150 mL) and with water (2×100 mL) and brine (150 mL). The organic layer was dried and the solvent removed to obtain the crude product as an off-white solid. Further purification by crystallization from a mixture of acetone (250 mL) and hexane (75 mL) afforded the title A compound (42.5 g), m.p. 162°-64°. TLC: Rf 0.55 in ethyl acetate. Mass Spectrum: m/z 956 (M+H)+, 830, 653.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:7]1[S:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: COC(=O)c1nc(Br)sc1-c1ccccc1
Reactant: CNC
Product: CN(C)c1nc(C(=O)O)c(-c2ccccc2)s1

Procedure:
prepared by reaction of 2-bromo-5-phenyl-thiazole-4-carboxylic acid methyl ester with dimethylamine. LC-MS: tR=0.81 min; [M+H]+=249.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][NH:14][C:15]([NH:17][CH2:18][C:19]#[CH:20])=[O:16].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.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.[Cu]I>[NH2:12][C:3]1[C:4]2[O:8][CH2:7][O:6][C:5]=2[C:9]([C:20]#[C:19][CH2:18][NH:17][C:15]([NH:14][CH3:13])=[O:16])=[CH:10][C:2]=1[Cl:1]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCNC(=O)NC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)NCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.4 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (500 mg, 1.68 mmol) and N-methyl-N′-prop-2-yn-1-ylurea (226 mg, 2.02 mmol) in ethyl acetate (10 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (118 mg, 10 mol %) followed by copper(I) iodide (32 mg, 10 mol %) and diisopropylamine (339 mg, 4.03 mmol). The reaction was allowed to warm to room temperature and stirred 3 hr. then filtered through Celite. The filtrate was purified by column chromatography on silica using ethyl acetate as eluent to give N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]-N′-methylurea (177 mg, 37%) as an colourless solid; NMR Spectrum:(DMSOd6) 2.55 (d, 3), 4.00 (d, 2H), 5.52 (s, 2H), 5.84 (q, 1H), 6.05 (s, 2H), 6.27 (t, 1H), 6.78 (s, 1H).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:12]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)=[N:10][C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:8][C:7]=2[S:6][C:5]=1[C:26]([O:28]CC)=[O:27]>O1CCOCC1.O>[NH2:3][C:4]1[C:12]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=3)=[N:10][C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:8][C:7]=2[S:6][C:5]=1[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)c1sc2nc(-c3ccccc3)nc(-c3cccc(N)c3)c2c1N
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cccc(-c2nc(-c3ccccc3)nc3sc(C(=O)O)c(N)c23)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Potassium hydroxide (20.0 g) was added to a solution of ethyl 5-amino-4-(3-aminophenyl)-2-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (example 31(e), 17.0 g) in a mixture of 1,4-dioxane (210 ml) and water (80 ml). After 16 h at 90° C., the mixture was cooled to 0° C. The resulting precipitate was filtered off, suspended in water (300 ml) and cooled to 0° C. The mixture was acidified to pH 3 by adding 2N aq. citric acid and stirred at 0° C. up to room temperature for 2 h. The resulting precipitate was filtered off, washed with water and dried in vacuo at 40° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].[H-].[Na+].Cl([F:33])(=O)(=O)=O.C(Cl)Cl>CN(C)C=O.Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:33])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)-isoindoline (1.0 g. 2.8 mmol) in dimethylformamide (10 mL) is added sodium hydride (112 mg, 2.8 mmol, 60%) at room temperature. After about 30 minutes, perchloryl fluoride (5 mmol) is bubbled into the mixture . The mixture is stirred with methylene chloride (10 mL) and IN hydrochloric acid (10 mL) for one hour. The organic layer is separated 30 and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)=[CH:11][CH:12]=1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(S(C)(=O)=O)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1ccc(S(C)(=O)=O)cc1
Yield: 39.91 %

Procedure:
Compound 92 was synthesized from [4-({(2Z)-2-(methoxyimino)-2-[4-(methylsulfonyl)phenyl]ethyl}oxy)phenyl]methanol (0.57 g, 1.63 mmol) and methyl 3-(4-hydroxyphenyl)propanoate (0.293 g, 1.63 mmol) by following the procedure described in scheme 5 (0.2 g, yield: 39.91%); Purity: 96.52%.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:1]([CH:4]([O:6][C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:8]=2)[CH3:5])=[O:3])[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O
Product: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)NC1CC1

Procedure:
Three g of the product of Example 65 was reacted with 1.1 g of cyclopropylamine, substantially as shown in Example 60, to obtain 2.6 g of the desired product, m.p. 175°-177°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCCc1ccc(O)c(CCC(=O)OCC)c1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCc1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Temperature: 92 °C
Reaction time: 22 h
Yield: 84 %

Procedure:
A mixture of 0.655 g (2.03 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-hydroxybenzenepentanoic acid ethyl ester from the preceding example, 2.80 g (12.2 mmol) of 1,5-dibromopentane, 1.12 g (8.12 mmol) of anhydrous granular potassium carbonate, and 35 mL of 2-butanone was stirred at 92° C. for 22 hr. After being cooled to room temperature, the mixture was filtered through anhydrous magnesium sulfate and the solids were washed thoroughly with ethyl acetate and ether. The filtrate and washes were combined and concentrated in vacuo and the crude product was purified by flash chromatography on 80 g of silica gel, eluting with hexane-ethyl acetate (4:1). There was obtained 0.804 g (83.9%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:22][NH2:23])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1
Reactant: NN
Reactant: Clc1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Solvent: CCO
Solvent: O
Product: NNc1nc(Cl)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
2,4-Dichloro-5,6-diphenylpyrimidine (2.0 g, 6.6 mmol) (synthesized according to the procedure described in example 7) was treated with hydrazine hydrate (0.73 g, 14.6 mmol) in ethanol (10 ml) under stirring for 5 hours at room temperature. The reaction mixture was poured onto ice-water mixture. The solid thus separated was extracted with diethylether. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (0.64 g, 32.5%).
Reaction SMILES: [C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3](Cl)[CH3:4].[C:17]([O-:21])(=[O:20])[CH:18]=[CH2:19].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3]([O:21][C:17](=[O:20])[CH:18]=[CH2:19])[CH3:4]
Reactant: C=CC(=O)[O-]
Reactant: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCOC(=O)OC(C)OC(=O)C=C
Yield: 89.4 %

Procedure:
1-Chloroethyl 4-acryloyloxybutyl carbonate (1.253 g, 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.28 g (89%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.58 (3 H, d, J=5 Hz, CH3 --CH), 1.80 (4 H, m, CH2 --CH2), 4.24 (4 H, m, 2 ×CH2 --O), 5.7-6.7 (6 H, m, 2×CH=CH2), 6.87 (1 H, k, J=5 Hz, CH--CH3).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]([CH:13]=O)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[CH3:15][N:16]1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:15][NH:16][CH2:13][C:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[N:4]2[CH2:3][CH2:2][CH2:1][C:5]=12
Reactant: Cc1c(C=O)n(C)c2ccccc12
Reactant: O=Cc1c2n(c3ccccc13)CCC2
Product: CNCc1c2n(c3ccccc13)CCC2
Yield: 54 %

Procedure:
According to the procedure of Preparation 40 (c), except substituting 2,3-dihydro-1H-3a-azacyclopenta[a]indene-8-carboxaldehyde (0.17 g, 0.92 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 54%) was prepared as a yellow oil: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([N+]([O-])=O)[CH:7]=[CH:6][N+:5]=1[O-:13].[CH:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][O:18][C:8]2[CH:7]=[CH:6][N+:5]([O-:13])=[C:4]([CH3:3])[CH:9]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(OCC2CC2)cc[n+]1[O-]
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To sodium hydride (55% pure) (4.4 g, 0.1 mol) (washed with petroleum ether), cyclopropyl-methanol (50 ml) was added. Then a solution of 2-methyl-4-nitropyridine-N-oxide (6.5 g, 0.042 mol) in cyclopropylmethanol (30 ml) was added during about 1 h. The dark brown mixture was heated to 90° C. and stirred at 90° C. for about 1 h. Thereafter the cyclopropylmethanol was distilled off under reduced pressure and methylene chloride (100 ml) was added to the residue. The mixture was stirred for about 30 minutes, then filtered and concentrated which gave 9.5 g of crude material.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][N:30]([CH3:52])[CH2:31][CH2:32][N:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[C:34]1=[O:51]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[C:34](=[O:51])[N:33]([CH2:32][CH2:31][N:30]([CH3:52])[CH3:29])[CH2:41]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN(C)CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CCN(C)C)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-[2-(dimethylamino)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=494.3.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH:10]=[CH:11][C:12](O)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]3[NH:22][NH:21][C:12](=[O:13])[CH2:11]3)[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc(C=CC(=O)O)cc1OC1CCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CC(=O)NN2)cc1OC1CCCC1
Yield: 60.1 %

Procedure:
To a suspension of 3-cyclopentyloxy-4-methoxycinnamic acid (7.9 g, mmol) in toluene (25 ml) is added hydrazine hydrate (2.91 n-A, 60 mmol). The reaction mixture is heated to 100° (bath temperature) for 24 hours. Toluene is partially removed and ether carefully added, and the product allowed to crystallize. The solid is filtered to give crude product (6 g). A crystallization from chlorofom-hexane gives the pure product (5 g) m.p. 185°-186°. 1H NMR (CDCl3) δ 7.02 (1H, s, NH--CO), 6.88 (3H, m, arom), 4.79 (2H, m, carbinolic and benzylic), 4.28 (1H, m, NH), 3.84 (3H, s, CH3O--), 2.79 (2H, d, --CH2CO), 1.9 (5H, m, cyclopentyl C-H), 1.61 (3H, m, cyclopentyl C-H); IR(KBr),3420,3220,3160,2960,1700,1660 cm-1 ; MS m/z 276 (M)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[S:34]([CH3:33])(=[O:36])=[O:35])[CH3:29]
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)S(C)(=O)=O
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g, 0.305 mmol) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (7.5 mg, 0.062 mmol), methanesulfonyl chloride (0.05 mL, 0.61 mmol, Aldrich, St. Louis, Mo.), and Hünig's base (0.2 mL, 0.9 mmol). The reaction mixture was stirred at room 20 min and then the solvent was removed in vacuo. The crude product was purified by column chromatography (40 g of silica, 10% to 30% acetone in hexanes) to afford N-(1-methylethyl)-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide (0.110 g) as a mixture of two isomers:
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]\[C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1)=[O:6])([CH3:4])[CH3:3].[CH3:19][Li]>C1(C)C=CC=CC=1>[CH3:4][C:2]([S:5]([NH:7][C@@H:8]([C:9]1[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11][CH:10]=1)[CH3:19])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)/N=C\c1cnc(C(F)(F)F)nc1
Reactant: [Li]C
Solvent: Cc1ccccc1
Product: C[C@@H](NS(=O)C(C)(C)C)c1cnc(C(F)(F)F)nc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
To a solution of 2-methyl-N-{(1Z)-[2-(trifluoromethyl)pyrimidin-5-yl]methylene}propane-2-sulfinamide (14.3 g, 51.2 mmol) in toluene (260 mL) at −70° C. was added methyllithium (1.6 M; 35.0 mL, 56.0 mmol). The mixture was stirred at −70° C. for 15 min. The mixture was quenched with saturated aqueous ammonium chloride and the reaction was allowed to warm to ambient temperature. The mixture was extracted with dichloromethane (3×). The combined organic extracts was dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→35% hexanes/ethyl acetate then 100% ethyl acetate—94% ethyl acetate/methanol) gave the title compound (7.23 g). MS 240.0 [(M+1)−56].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][CH3:23].[CH3:24][S-:25].[Na+].O>CN(C)C=O>[CH3:24][S:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCCl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCCSC
Temperature: 80 °C
Reaction time: 1.83 h
Yield: 88.8 %

Procedure:
A suspension of 1-(5-chloropentyl)-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine (2.5 g, 7.56 mmol) in anhydrous N,N-dimethylformamide (38 mL) was heated to 80° C. to provide a light yellow solution. Sodium thiomethoxide (0.67 g of 95%, 9.07 mmol) was added in a single portion and heating was continued for 110 minutes. The resulting light brown suspension was poured into water (300 mL) with rapid stirring. A white solid precipitated. After the suspension had cooled to ambient temperature, several scoops of solid sodium carbonate were added. The suspension was chilled in an ice water bath with stirring for 1 hour. The solid was isolated by filtration, washed with cold water and then dried to provide 2.3 g of 1-[5-(methylthio)pentyl]-2-propyl-1H-imidazo[4,5-c]quinoline-4-amine as a white powder.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:29])[CH2:27][OH:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[OH:28][CH2:27][C@H:26]([NH:29][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-(−)-phenylglycinol and DIEA to give 2-((R)-2-hydroxy-1-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 376 (MH+).