Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCC1CCCCN1C1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]2[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[N:30]=1.[N:47]1([CH2:52][C@H:53]2[CH2:57][CH2:56][CH2:55][NH:54]2)[CH2:51][CH2:50][CH2:49][CH2:48]1>>[N:47]1([CH2:52][C@H:53]2[CH2:57][CH2:56][CH2:55][N:54]2[C:29]2[N:34]=[CH:33][N:32]=[C:31]([NH:35][C:36]3[CH:37]=[C:38]([CH2:42][S:43]([NH2:46])(=[O:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[N:30]=2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: C1CN[C@@H](CN2CCCC2)C1
Agent: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC[C@@H]3CN3CCCC3)n2)c1

Procedure:
B31 was prepared following the procedure reported for B4 using A1 and (R)-2-((pyrrolidin-1-yl)methyl)pyrrolidine. It was obtained as a white crystalline solid; yield: 65 mg (17%). MS (ES) C19H27N7O2S requires: 417. found: 418 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[C:6]([CH3:12])[CH:5]=1.C[CH2:14][O:15][C:16]([CH2:18][CH:19]1[C:24](=O)[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:17]>>[Cl:1][C:9]1[CH:8]=[CH:7][C:6]([CH2:12][N:10]2[C:24]3[CH:19]([CH2:18][C:16]([O:15][CH3:14])=[O:17])[CH2:20][CH2:21][CH2:22][C:23]=3[C:8]3[C:7]2=[C:6]([CH3:12])[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)c(C)c1
Reactant: Cl
Reactant: CCOC(=O)CC1CCCCC1=O
Product: COC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(C)cc(OC)cc21

Procedure:
Following the procedure of Example 30, but using 1-(4-methoxy-2-methylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate in Step I, as starting material, the title compound is prepared.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=2)[C:13]#[N:14])=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1>>[C:17]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)[CH:29]=3)=[O:31])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14])#[N:18]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1C#N
Reactant: O=C(O)c1cc(-c2ccccn2)n[nH]1
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4ccccn4)n[nH]3)n2)cc1C#N

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)phthalonitrile (0.050 g) and 3-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (0.042 g) using the method of Example 34(d). Yield 0.062 g. 1H-NMR (400 MHz; d6-DMSO): δ 3.72 (t, 2H), 4.40 (t, 2H), 7.01 (s, 1H), 7.27-7.40 (m, 2H), 7.88-7.94 (m, 3H), 8.14 (d, 1H), 8.32 (d, 1H), 8.35-8.65 (m, 3H), 13.9 (br s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:31]=[N:32][CH:33]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncc(F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1) and (5-fluoropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 3) tR=1.04 min, m/z=451.3 [M+H]+, m/z=449.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H) 3.44-3.51 (m, 2H) 3.56 (q, J=5.40 Hz, 2H) 4.68 (t, J=5.14 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.82-7.87 (m, 2H) 7.87-7.93 (m, 1H) 8.12 (d, J=2.38 Hz, 1H) 8.58 (d, J=2.76 Hz, 1H) 8.61 (t, J=1.69 Hz, 1H) 8.75 (d, J=2.38 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-allyloxy-8-acetylcoumarin (1.93 g, 0.0075 mol) and 4-chlorobenzaldehyde (1.05 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.1 g of product m.p. 153-155° C., 1H-NMR (CDCl3) δ: 2.42 (d, J=1.2 Hz, 3H), 4.65 (m, 2H), 5.2 (m, 2H), 6.15 (m, 1H), 6.91-7.61 (m, 8H).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[NH3:20]>CO>[NH2:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1c(OCCc2ccccc2)ccnc1F
Reactant: N
Solvent: CO
Product: Nc1nccc(OCCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.02 g of 2-fluoro-4-(2-phenylethoxy)-3-nitropyridine (starting material K3) are dissolved in 10 ml of a 5M solution of ammonia in methanol and stirred at ambient temperature for 16 hours. The solvent is distilled off and the residue is chromatographed on silica gel (dichloromethane/petroleum ether 4:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 1.16 g of the title compound as a yellow solid of m.p. 131–132° C. The mass spectrum shows the molecular peak MH+ at 260.0 Da.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[C:24]([CH3:25])=[C:23]([NH2:26])[O:22][N:21]=1>O1CCCC1>[CH3:19][C:20]1[C:24]([CH3:25])=[C:23]([NH:26][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[O:22][N:21]=1
Reactant: Cc1noc(N)c1C
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1noc(NC=C2C(=O)Nc3ccccc32)c1C

Procedure:
The named compound is prepared by substituting 3,4-dimethyl-isoxazol-5-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1388 gms. 3,4-dimethyl-isoxazol-5-ylamine by refluxing in tetrahydrofuran (2.7 mL).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[NH:9][C:10]([NH:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].[CH3:35][Si:36]([CH3:43])([CH3:42])[CH2:37][CH2:38][O:39][CH2:40]Cl.O.[O:45]1[CH2:49][CH2:48]C[CH2:46]1>>[CH3:1][O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:46][O:45][CH2:49][CH2:48][Si:36]([CH3:42])([CH3:37])[CH3:35])[C:10]([N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:43])([CH3:42])[CH3:35])=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: C[Si](C)(C)CCOCCl
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(N(COCC[Si](C)(C)C)CC1CCN(Cc3cccc4ccccc34)CC1)n2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1.2 h

Procedure:
After dissolving 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboxylic acid methyl ester (1 g, 2.33 mmol) in anhydrous tetrahydrofuran (30 ml) under a nitrogen stream, the mixture was cooled to 0° C. Next, 60% sodium hydride (187 mg, 4.89 mmol) was added and the mixture was stirred at 0° C. for 72 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (815.8 mg, 4.89 mmol) was further added, the mixture was stirred at 0° C. for 30 minutes, and then water was added. The solution was extracted with ethyl acetate and then with dichloromethane, and each extract was washed with saturated brine and then combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/3→3/2→1/0) to obtain 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-(2-trimethylsilanyl-ethoxymethyl)-amino]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzimidazole-5-carboxylic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[O:7][C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:34][CH:2]([F:1])[C:3]1[O:7][C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][NH:25][CH3:26])=[CH:12]2)(=[O:10])=[O:9])=[CH:5][CH:4]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C(F)F)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(C(F)F)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of tert-butyl {[1-{[5-(difluoromethyl)-2-furyl]sulfonyl}-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (154 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solution of ethyl acetate-ethanol to give the title compound as a white solid (yield 96.3 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(CN)o1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1ccc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)o1
Yield: 48 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (5-methylfuran-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.68 (t, J=5.6 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.45-7.31 (m, 5H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 6.09 (d, J=3.0 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 5.16 (s, 2H), 4.30 (d, J=5.6 Hz, 2H), 2.52 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 436.5 (M+1).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH:27]=[CH:26][C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: Oc1ccc(OCCCn2ccnn2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(C=Cc2nc(COc3ccc(OCCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 27 %

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(3-[1,2,3]triazol-1-yl-propoxy)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 8 ml water the resulting precipitate was collected and purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 4:1) to yield 70 mg (27%) colorless powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]2[CH2:10][CH2:9][CH2:8]2)=[CH:5][N:6]=1.C(N(C(C)C)CC)(C)C.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:20]1([O:26][C:27](=[O:28])[NH:1][C:2]2[S:3][C:4]([CH:7]3[CH2:10][CH2:9][CH2:8]3)=[CH:5][N:6]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ncc(C2CCC2)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ncc(C2CCC2)s1)Oc1ccccc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 212.6 %

Procedure:
A solution of 2-amino-5-cyclobutyl thiazole (Preparation 2; 2.5 g, 1 6 mmol) and diisopropylethylamine (2.82 mL, 16 mmol) in methylene chloride (200 mL) was cooled to −78° C. and phenylchloroformate (2 mL, 16 mmol) was added dropwise. The reaction mixture was slowly warmed to 23° C., was stirred for 1 hour at this temperature, than was washed with aqueous saturated sodium bicarbonate (2 times) and brine (1 time), was dried (MgSO4), was filtered, and was concentrated in vacuo. The resulting white solid was purified by silica gel chromatography (5:1 CHCl3-hexanes) to afford 3.5 g of the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[C:14]([NH2:15])=[C:13]2[O:16][CH2:17][O:18][C:12]2=[C:11](I)[CH:10]=1.[CH2:20]([O:23][CH3:24])[C:21]#[CH:22]>C(OCC)(=O)C.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)I>[Cl:8][C:9]1[C:14]([NH2:15])=[C:13]2[O:16][CH2:17][O:18][C:12]2=[C:11]([C:22]#[C:21][CH2:20][O:23][CH3:24])[CH:10]=1
Reactant: C#CCOC
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: 25 °C

Procedure:
Bis(Triphenyl-phosphine)palladium(II) chloride (472 mg), copper iodide (192 mg) and diisopropylamine (680 mg) were added to a stirred solution of 6-chloro-4-iodo-2,3-methylenedioxyaniline (1000 mg) and methyl propargyl ether (471 mg) in ethyl acetate (10 mls) at −20° C. The reaction was allowed to warm to ambient temperature over 16 hours. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3. The organics were washed with water and saturated brine and dried over magnesium sulfate. The product was purified by column chromatography on silica using a gradient of 80–100% Dichloromethane/isohexane as eluent. 6-chloro-4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline was thus obtained as a tan crystalline solid (200 mg); NMR Spectrum: (DMSOd6) 3.28 (s, 3H), 4.26 (s, 2H), 5.52 (s, 2H), 6.05 (s, 2H), 6.93 (s, 1H).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:25])[CH:16]=2)=[C:12]([OH:26])[C:11]([CH:27]=[O:28])=[C:10]([CH3:29])[C:9]=1[Cl:30].C1COCC1.Cl>O.CO>[Cl:30][C:9]1[C:10]([CH3:29])=[C:11]([CH:27]=[O:28])[C:12]([OH:26])=[C:13]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[Cl:25])[CH:16]=2)[C:8]=1[O:7][CH2:6][C:5]([OH:31])=[O:4]
Reactant: COC(=O)COc1c(Cl)c(C)c(C=O)c(O)c1Cc1ccc2c(Cl)cccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cl)c(OCC(=O)O)c(Cc2ccc3c(Cl)cccc3c2)c(O)c1C=O
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Aqueous potassium hydroxide (10%, 2.7 mL) was added in to a solution of [2-chloro-6-(5-chloro-naphthalen-2-ylmethyl)-4-formyl-5-hydroxy-3-methyl-phenoxy]-acetic acid methy ester (1.14 g, 2.63 mmol), THF(15 mL) and MeOH (15 mL). The mixture was stirred for 1 hour, poured into water, acidified with HCl (2N), and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from hexane/EtOAc, gave a light yellow solid (0.65 g, 60% yield, m.p. 194°-196° C.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH:24]=[CH:25][C:26]#[N:27])=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O>[Pd].CO>[NH2:27][CH2:26][CH2:25][CH2:24][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:14]([CH2:15][CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[C:13]([CH2:22][CH3:23])=[N:12][C:11]=3[C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=1
Reactant: CCc1nc2c(N)nc3cc(C=CC#N)ccc3c2n1CC1CCOCC1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC1CCOCC1
Reaction time: 18 h
Yield: 87 %

Procedure:
A glass Parr vessel was charged with 10% palladium on carbon (1 g), methanol (50 mL), 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enenitrile (4.0 g, 11.1 mmol) and trifluoroacetic acid (6.3 g, 55 mmol). The vessel was evacuated, charged with hydrogen gas (40 psi, 2.8×105 Pa) and shaken for approximately 18 hours. The mixture was filtered and concentrated under reduced pressure to a yellow oil. The oil was dissolved in 10% aqueous hydrochloric acid and stirred for 18 hours. Chloroform (100 mL) was added followed by slow addition of potassium carbonate until the pH equaled 11. The fractions were separated and the aqueous fraction was extracted with chloroform (4×50 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile provided 3.55 g of the desired product as a white solid. A small amount of this material was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-30% CMA over 1000 mL followed by 30% CMA over 1000 mL). A final recrystallization from acetonitrile provided 7-(3-aminopropyl)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 217-220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:21].C1COCC1.CCO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH3:21]
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(N[C@H](C)c3ccc(Cl)cc3Cl)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Nc1cc(N2CCC(C(=O)O)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a stirred solution of (R)-ethyl 1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidine-4-carboxylate (3.1 g, 6.8 mmol) in 2:1 THF/EtOH (12 mL) was added a solution of sodium hydroxide (1.4 g, 34.1 mmol) dissolved in deionized water (4 mL). The reaction mixture was stirred at room temperature for 4 h, and the mixture was adjusted to pH-7 with aqueous 6 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-25% methanol in dichloromethane) to give (R)-1-(4-chloro-3-(1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidine-4-carboxylic acid (2.4 g, 5.6 mmol, 82%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[I:10].[CH2:11]1[C:16](=O)[CH2:15][C:13](=[O:14])[CH2:12]1.[NH2:18][C:19]1[N:23]([CH3:24])[NH:22][C:21](=[O:25])[CH:20]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[C:20]3[C:21](=[O:25])[NH:22][N:23]([CH3:24])[C:19]=3[NH:18][C:16]3[CH2:11][CH2:12][C:13](=[O:14])[C:15]2=3)=[CH:4][C:3]=1[I:10]
Reactant: O=Cc1ccc(F)c(I)c1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=C1CCC(=O)C1
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)CC1)C2c1ccc(F)c(I)c1
Yield: 63.5 %

Procedure:
4-Fluoro-3-iodobenzaldehyde (0.25 g, 1.0 mmol) from Example 12C, 1,3 cyclopentadione (0.1 g, 1.0 mmol) and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.11 g, 1.0 mmol) were processed as described in Example 1 to provide 0.27 g of the title compound.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31](F)=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.FC1C=CC=CC=1S(Cl)(=O)=O>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: O=S(=O)(Cl)c1ccccc1F
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (0.082 g, 0.239 mmol) and 2-fluorobenzenesulfonyl chloride (0.051 g, 0.263 mmol) the title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2-fluorobenzenesulfonamide was obtained (66 mg, 0.125 mmol, 52.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 7.98 (d, J=5.3 Hz, 1H), 7.63-7.74 (m, 2H), 7.36-7.46 (m, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.20-7.29 (m, 1H), 6.75 (s, 2H), 5.79 (d, J=5.1 Hz, 1H), 1.40 (s, 9H). MS (ES+): 502 [M+H]+.
Reaction SMILES: S([O-])([O-])(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]2[N:15]=[CH:16][NH:17][C:13]=2[CH:12]=1)=[O:10])[CH3:7].C(O)C>[C].[Pd].[H][H]>[CH2:6]([O:8][C:9]([CH:11]1[CH2:19][CH2:18][C:14]2[N:15]=[CH:16][NH:17][C:13]=2[CH2:12]1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)C1CCc2nc[nH]c2C1

Procedure:
A mixture of 10.0 g of sulfate of benzimidazole-5-carboxylic ethyl ester, 5.0 g of 5% palladium-carbon catalyst, and 100 ml of ethanol was stirred in hydrogen for five hours under the conditions of 135° C. and 50 kg/cm2, cooled, then filtered to separate the catalyst, and distilled to expel the ethanol. The residue of the distillation was neutralized with an aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and then distilled to expel chloroform and obtain 6.9 g of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic ethyl ester. This ester and 200 ml of 6N hydrochloric acid added thereto were refluxed together for seven hours. The hydrochloric acid solution was concentrated to dryness, crystallized by addition of acetone, separated by filtration, and then dried to obtain 6.9 g of hydrochloride of 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid.