Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18])C.[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24].C(OC(=O)C)C>CS(C)=O>[Br:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:4]1[C:5](=[O:20])[C:6](=[O:19])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18]
Reactant: CCOc1c(Nc2ccc([N+](=O)[O-])cc2O)c(=O)c1=O
Reactant: Nc1ccccc1Br
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=c1c(Nc2ccc([N+](=O)[O-])cc2O)c(Nc2ccccc2Br)c1=O
Temperature: 25 °C
Yield: 18.7 %

Procedure:
A solution of 3-ethoxy-4-(2-Hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione (0.39 g, 1.4 mmol) and 2-bromoaniline (0.36 g, 2.09 mmol) in 2 mL DMSO was heated at 110° C. for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added, and a precipitate formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. Titration from acetone and hexanes gave 106 mg (19%) of 3-(2-bromoanilino)-4-(2-hydroxy-4-nitroanilino)-3-cyclobutene-1,2-dione. LCMS(H+) 404
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10](O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([Cl:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(O)nn1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1cc(-c2ccc(Cl)cc2)c(Cl)nn1Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A suspension of 2-benzyl-5-(4-chlorophenyl)-6-hydroxypyridazin-3(2H)-one (8.5 g, 27.2 mmol) in phosphorus oxychloride (50 mL) was stirred at 95° C. for 1 h. Analysis by HPLC/MS indicated the starting material had been consumed. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with EtOAc. The resulting EtOAc solution was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (330 g) eluting with a gradient of EtOAc (0-40%) in hexanes to afford 6.2 g (69%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.80 min, (M+H)+=331.0. 1H NMR (CDCl3, 400 MHz): δ 7.27-7.80(m, 9H), 6.88 (s, 1H), 5.36 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18](OCC)=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.CCOCC.[NH3:31]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([NH2:31])=[O:19])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Reactant: N
Solvent: CO
Solvent: CCOCC
Product: NC(=O)Cc1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, 100 mg, 0.28 mmol) was dissolved in a 7N solution of ammonia in MeOH (40 mL) and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to afford a yellow solid. Et2O was added and the yellow precipitate was collected by filtration. DCM was added and the off white precipitate was isolated by filtration, this was repeated to yield the title compound as an off white solid (59 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.64 (d, J=1.6 Hz, 2H), 7.57-7.44 (m, 4H), 7.37 (dd, J=2.7, 9.0 Hz, 1H), 7.08-7.02 (m, 1H), 5.34 (s, 2H), 3.60 (s, 2H). [M+H]=327.2.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:9]2=[N:10][CH:11]=1.[C:16]([O:19][CH:20](OCC)OCC)(=O)[CH3:17]>>[CH2:16]([O:19][CH:20]=[C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=2)[NH:12][C:13]1=[O:15])[CH3:17]
Reactant: CCOC(OCC)OC(C)=O
Reactant: O=C1Cc2cc(-c3ccco3)cnc2N1
Product: CCOC=C1C(=O)Nc2ncc(-c3ccco3)cc21

Procedure:
This compound was synthesized from 5-(2-furyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ10.96 (s, 1H); 8.36 (s, 1H); 7.87-7.84 (m, 2H); 7.72 (s, 1H); 6.87 (d, 1H); 6.56 (m, 1H); 4.42 (m, 2H); 1.36 (m, 3H).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[C:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccccc1Oc1sccc1[N+](=O)[O-]
Temperature: 105 °C

Procedure:
To a solution of 2-chloro-3-nitrothiophene (1.13 g, 6.93 mmol) in NMP (10 mL) in a pressure vessel was added 2-tert-butylphenol (1.04 g, 6.93 mmol) and K2CO3 (1.0 g, 10.1 mmol). The reaction was flushed with nitrogen, sealed and then heated to 105° C. for 48 h. The reaction was cooled to rt, diluted with EtOAc (˜150 mL) and washed twice with saturated aqueous NaCl (2×˜150 mL). The aqueous washes were then back extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated to yield the crude desired product.
Reaction SMILES: Br[C:2]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:19])[N:3]=1.[C-:20]#[N:21].[Na+].C([Sn](Cl)(CCCC)CCCC)CCC>C(#N)C.O>[C:20]([C:2]1[C:12]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([CH3:19])[N:3]=1)#[N:21]
Reactant: CCOC(=O)c1cc(NC(CC)CC)c(Br)nc1C
Reactant: [C-]#N
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc(NC(CC)CC)c(C#N)nc1C
Temperature: 88 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of ethyl 6-bromo-2-methyl-5-(pentan-3-ylamino)nicotinate (1.202 g, 3.65 mmol) in acetonitrile (30 ml) was added sodium cyanide (0.357 g, 7.3 mmol), tributyltin chloride (1.306 g, 4.015 mmol) and Pd(dpppf)3 (0.298 g, 0.365 mmol). The reaction mixture was stirred at 88° C. overnight. The reaction mixture was diluted with water (100 ml), then extracted with ethyl acetate (3×100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate and brine. After evaporation of solvent, ethyl 6-cyano-2-methyl-5-(pentan-3-ylamino)nicotinate (0.59 g, 59% yield) was obtained by column chromatography. 1H NMR (400 MHz, CDCl3): 7.56 (s, 1H), 4.50 (q, J=6.8 Hz, 2H), 4.35 (br, s, 1H), 3.40 a9m, 1H), 2.64 (s, 3H), 1.80-1.50 (m, 4H), 1.42 (t, J=6.8 Hz, 3H), 1.0 (t, 6H). MS (EI) for C15H21N3O2: 276.2 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:42]1[C:47]([O:48][CH3:49])=[C:46]([O:50][CH3:51])[CH:45]=[CH:44][C:43]=1[C:52]1[CH:53]=[C:54]2[C:58](=[CH:59][CH:60]=1)[C:57](=[O:61])[O:56][CH2:55]2>O1CCCC1.C(OCC)(=O)C>[CH3:49][O:48][C:47]1[C:46]([O:50][CH3:51])=[CH:45][CH:44]=[C:43]([C:52]2[CH:53]=[C:54]3[C:58](=[CH:59][CH:60]=2)[C:57](=[O:61])[O:56][CH2:55]3)[C:42]=1[O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: COC(=O)C(C)(C)CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)COc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OC
Temperature: 70 °C
Yield: 28.6 %

Procedure:
To a stirring solution of methyl 3-hydroxy-2,2-dimethylpropanoate (2.76 g, 20.94 mmol, in portions) in tetrahydrofuran (25 mL) was added diethylazodicarboxylate (2.43 g, 13.96 mmol), triphenylphosphine (3.59 g, 13.96 mmol) and 5-(2-hydroxy-3,4-dimethoxyphenyl)isobenzofuran-1(3H)-one (2 g, 6.98 mmol) and the resultant reaction mixture was heated to 70° C. for 6 h. The reaction mixture was diluted with ethyl acetate layer, washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash, column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford Methyl 3-(2,3-dimethoxy-6-(1-oxo-1,3-dihydroisobenzofuran-5-yl)phenoxy)-2,2-dimethylpropanoate as a solid (800 mg, 28.6%)
Reaction SMILES: [CH2:1]([N+:3]1([O-])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:4]1=[O:14])[CH3:2].C[Si]([C:20]#[N:21])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[CH2:1]([N:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:20]#[N:21])[CH:9]=2)[C:4]1=[O:14])[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CC[N+]1([O-])CCN(c2ccncc2)C1=O
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CCN1CCN(c2ccnc(C#N)c2)C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.1 %

Procedure:
1-Ethyl-3-(4-pyridyl)-2-imidazolidinone N-oxide (0.56 g, 2.7 mmol) was dissolved in nitroethane (20 ml), and trimethylsilyl cyanide (0.55 g, 5.5 mmol) and N,N-dimethylcarbamoyl chloride (0.44 g, 4.1 mmol) were added thereto. The mixture was stirred at room temperature for 20 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (5:1, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (0.17 g, 29%) as white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH:16]([N:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[N:2]1)([CH3:18])[CH3:17]
Reactant: OCCc1cc[nH]n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc(CCO)n1
Temperature: 100 °C
Yield: 25.9 %

Procedure:
To a solution of 1.0 gm (9.0 mMol) 2-(3-pyrazolyl)-1-ethanol in 36 mL dimethylformamide were added 2.38 gm (22.5 mMol) sodium carbonate followed by the dropwise addition of a solution of 0.89 mL (9.0 mMol) 2-iodopropane in 8 mL dimethylformamide. The reaction mixture was heated to 100° C. for 18 hours. The reaction mixture was then cooled to ambient and then concentrated under reduced pressure. The residue was partitioned between water and dichloromethane. The organic phase was then washed with water followed by saturated aqueous sodium chloride and was then dried over sodium sulfate. The remaining organics were concentrated under reduced pressure to give 0.36 gm (26.0%) of the title compound as a brown oil.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2CCc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCC=C1c2ccccc2CCc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 10,11-dihydro-5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α-isomer) for the 5-(3-dimethylaminopropylidene)- 5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the procedure of Example 6, Steps A and B, 10,11-dihydro-5-(3 -methylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (α-isomer) is obtained as a yellow oil. The product is converted to the hydrochloride that melts at 275.5°-276.5°C. (sintered, 274.5°C.) after recrystallization from methanol-ether mixtures.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[N:4][C:5]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:42]OC(OC)OC.O>>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:5]2[N:4]=[C:3]3[C:2]([N:1]=[CH:42][N:28]3[CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:6]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COC(OC)OC
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c(N2CCOCC2)n1
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2ncn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (Example 96) (250 mg, 0.435 mmol), trimethylorthoformate (5 mL), and p-TSOH.H2O (8.3 mg, 0.0436 mmol) was heated at 95-100° C. for 3 hrs. The mixture was cooled to room temperature and the solvent was removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 99:1), gave tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-9H-purin-9-yl]-1-piperidinecarboxylate (193 mg, 76%): mp (CH2Cl2/MeOH) 213-215° C.; 1H NMR (CDCl3) 7.82 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.44 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 4.57 (tt, J=12.0, 4.0 Hz, 1H), 4.38 (m, 6H), 4.06 (s, 3H), 3.88 (t, J=4.9 Hz, 4H), 2.95 (t, J=12.6 Hz, 2H), 2.19 (dd, J=12.1, 2.0 Hz, 2H), 2.05 (dq, J=12.3, 4.2 Hz, 2H), 1.49 (s, 9H); Anal. Calcd. for C28H34F2N8O4: C, 57.5; H, 5.9; N, 19.2. Found: C, 57.3; H, 5.8; N, 19.1%.
Reaction SMILES: [Na].[SH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:7]([O:6][C:4]([CH2:3][S:2][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:8]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)CCCCl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCCSCC(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
Sodium metal (4.3 g, 0.18 mol) was added cautiously in small portions to ethanol (150 mL). After the sodium completely dissolved, the mixture was cooled to 0° C. and ethyl 2-sulfanylacetate (21.9 g, 0.18 mol), was added. Ethyl 4-chlorobutanoate (27.4 g, 0.18 mol) was then added slowly and the resulting mixture stirred overnight at rt. The solid was filtered off, and then the filtrate concentrated under reduced pressure. The oil obtained was partitioned between water and ethyl acetate. The organic layer was collected, dried over anhydrous Na2SO4 and concentrated under vacuum to give the desired ethyl 4-((ethoxycarbonyl)methylthio)butanoate (40.2 g, 95%) as colorless oil. The crude material was used without further purification in the follow step.
Reaction SMILES: [OH-].[K+].C(O)COCCOCCO.O=[C:14]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18].O.NN>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH2:14][C:20]1[CH:21]=[CH:22][C:23]([Br:26])=[CH:24][CH:25]=1
Reactant: CC(C)CCC(=O)c1ccc(Br)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: CC(C)CCCc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 8.5 h

Procedure:
A mixture of 6.45 g (115 mmol) of potassium hydroxide and 42 ml of triethylene glycol was heated at around 100 degrees C. until the potassium hydroxide was dissolved. The mixture was allowed to cool and then treated with 10 g (39 mmol) of 4-(1-oxo-4-methylpentyl) bromobenzene (Compound 31) followed by 3 g (94 mmol) of hydrazine hydrate. The mixture was slowly brought to reflux and heated at reflux for 1 hour. The apparatus was modified for distillation and the mixture heated until approximately 7 ml of liquid had distilled over and the flask temperature had reached 220 degrees C. The apparatus was again modified for reflux and the mixture was heated at reflux for 5 hours and then stirred at room temperature for 8.5 hours. The mixture was then heated to 100 degrees C. and poured into 40 ml of water and the flask rinsed with an additional 25 ml of water. This diluted mixture was acidified to pH=2 with conc. HCl and extracted with ether. The ether extract was washed successively with water and saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue subjected to kugelrohr distillation (70 degrees C., 0.05 mm) to give the title compound as a colorless oil. PMR (CDCl3): δ0.88 (6H, d, J~6 Hz), 1.12-1.26 (2H, m), 1.48-1.66 (3H, m), 2.54 (2H, t, J~7.7 Hz) 7.06 (2H, d, J~8.3 Hz), 7.39 (2H, d, J~8.3 Hz).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=2)[N:4]=1.[CH3:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:23])([F:1])[F:22])=[N:4]2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}acetic acid and N-methylbenzylamine using a similar procedure to that described for Example 13, but purified by flash column chromatography eluting from 0-66% ethyl acetate in hexane.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:37]1[CH:38]=[CH:39][C:40]2[C:41]3[N:50]([CH2:51][CH2:52][CH2:53][CH2:54][N:55]4[CH2:59][CH2:58][CH2:57][S:56]4(=[O:61])=[O:60])[C:49]([CH2:62][O:63][CH2:64][CH3:65])=[N:48][C:42]=3[C:43]([NH2:47])=[N:44][C:45]=2[CH:46]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:47][C:43]1[C:42]2[N:48]=[C:49]([CH2:62][O:63][CH2:64][CH3:65])[N:50]([CH2:51][CH2:52][CH2:53][CH2:54][N:55]3[CH2:59][CH2:58][CH2:57][S:56]3(=[O:61])=[O:60])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[CH:46][C:45]=2[N:44]=1
Reactant: C=CC(=O)OC
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN1CCCS1(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CCCCN1CCCS1(=O)=O
Temperature: 90 °C

Procedure:
A 50-mL thick walled glass vessel was charged with palladium (II) acetate (67 mg, 0.3 mmol), acetonitrile (2 mL), methyl acrylate (0.26 g, 3.0 mmol), triethylamine (0.9 g, 9.0 mmol), tri-o-tolylphosphine (0.18 g, 0.6 mmol) and 7-bromo-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 152-156, 1.5 g, 3.0 mmol). An additional 13 mL of acetonitrile was added. The reaction mixture was purged with nitrogen then heated to 90° C. The turbid orange mixture was maintained at 90° C. overnight. Anhydrous DMF (30 mL) was added to dissolve the 7-bromoquinoline starting material. The reaction was then heated at 120° C. overnight. The reaction mixture was filtered to remove the catalyst then concentrated to dryness. The desired product was isolated by column chromatography on silica gel (eluting with a gradient of 2%-8% methanol in dichloromethane). The resulting peach solid was taken up in saturated potassium carbonate solution and dichloromethane and stirred overnight at ambient temperature. The organic layer was separated and concentrated to dryness. The residue was recrystallized from acetonitrile to yield 0.65 g of Methyl(2E)-3-[4-amino-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a pale yellow solid, mp 162-163° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24].Cl.[OH-].[Na+]>O.C(O)C>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1
Yield: 26.9 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol), 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) and 2N HCl (150 μl) in water:ethanol (2:1, 10 ml) was refluxed for 24 h. The mixture was cooled to room temperature and neutralized with aqueous 2N NaOH to pH 6-7. The mixture was extracted with ethyl acetate (75 ml), washed with water (2×20 ml), aqueous saturated NaCl (1×20 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness and the residue was purified by column chromatography to give a yellow solid (18 mg, 27%). 1H NMR (Acetone-d6): 9.53-9.51 (m, 1H), 8.85 (s, 1H), 8.71 (dd, J=1.8, 4.8 Hz, 1H), 8.67-8.63 (m, 1H), 8.49 (s, 1H), 7.53-7.48 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.98 (s, 1H), 6.75 (dd, J=2.4, 8.4 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([O-])=O>[Pd].CCO.C1COCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([S:15][C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: O=[N+]([O-])c1ccc2c(c1)Sc1ccccc1N2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2c(c1)Sc1ccccc1N2
Yield: 97 %

Procedure:
Reduction of the nitro function of 3-nitro-10H-phenothiazine (J. Org. Chem. (1972) 37, 2691) is carried out in the presence of Pd/C in an EtOH/THF mixture under the conditions described for intermediate 2.2. A grey solid is obtained with a yield of 97%. Melting point: 150-156° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C1COCC1.CN(C=O)C>[CH:22]([NH:25][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)([CH3:24])[CH3:23]
Reactant: CC(C)N
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.8 %

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Isopropylamine (511 μL, 6 mmol) was then added into the acid chloride solution at 0° C. The reaction was then stirred at room temperature for 18 hours. The reaction was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography: SiO2, CH2Cl2/AcOEt 95:5 to give a white solid (167 mg, 58%). NMR 1H (ppm, CDCl3): 7.96 (s, 1H), 7.69 (d, J3=7.68 Hz, 2H), 7.59 (d, J3=7.14 Hz, 2H), 7.50-7.33 (m, 4H), 5.93 (br. s., 1H), 4.14 (oct., J3=6.66 Hz, 1H), 1.27 (d, J=6.43 Hz, 6H).