Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:59][CH2:58][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:56][CH2:55]3)[CH2:50][CH2:49]2)=[CH:41][C:42]([O:46][CH3:47])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:48]4[CH2:49][CH2:50][CH:51]([N:54]5[CH2:55][CH2:56][N:57]([S:60]([CH3:63])(=[O:62])=[O:61])[CH2:58][CH2:59]5)[CH2:52][CH2:53]4)=[CH:41][C:42]=3[O:46][CH3:47])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCc1cc(N)c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(CC)c(N4CCC(N5CCN(S(C)(=O)=O)CC5)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 170 °C
Yield: 70.1 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.125 g, 0.247 mmol), 5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (0.098 g, 0.247 mmol) and HCl (4N,1,4-Dioxane, 0.12 mL, 0.494 mmol) in trifluoroethanol (8 mL) was heated at 170° C. for 40 min in the microwave. The reaction was quenched with 7 N NH3 in MeOH and then concentrated to dryness. The residue was then dissolved in DCM and concentrated onto silica gel. Purification by flash column chromatography followed by recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamide (0.150 g, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 9.30-9.43 (m, 1H), 8.50 (s, 1H), 8.25 (d, J=5.22 Hz, 1H), 8.06 (d, J=2.02 Hz, 1H), 7.74-7.80 (m, 1H), 7.71 (d, J=8.89 Hz, 1H), 7.53 (s, 1H), 7.34-7.49 (m, 2H), 7.28 (d, J=8.43 Hz, 1H), 7.16-7.25 (m, 2H), 6.91-7.00 (m, 1H), 6.83 (s, 1H), 6.58 (d, J=5.04 Hz, 1H), 4.20-4.33 (m, 2H), 3.81 (s, 3H), 3.08-3.16 (m, 4H), 3.00-3.08 (m, 2H), 2.88 (s, 3H), 2.67-2.78 (m, 2H), 2.61-2.66 (m, 4H), 2.56 (q, J=7.51 Hz, 2H), 2.38-2.47 (m, 1H), 1.79-1.92 (m, 2H), 1.52-1.68 (m, 2H), 1.44 (t, J=6.92 Hz, 3H), 1.11 (t, J=7.51 Hz, 3H). MS (M+H, ES+) 866.
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:11])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[Na+].[OH:13][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][CH2:16][C:17]([O-:19])=[O:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:11][C:4]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][O:19][C:17](=[O:18])[CH2:16][CH2:15][CH:14]([OH:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC(O)CCC(=O)[O-]
Reactant: CC(C)=CCCC(C)=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCC(O)CCC(=O)OCC=C(C)CCC=C(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 31.8 %

Procedure:
A mixture of 155 g 1-chloro-3,7-dimethyl-octa-2,6-diene, 202 g 4-hydroxy-undecanoic acid sodium salt and 5 g tetrabutylammoniumbromide in 800 ml of dimethylformamide was heated to 50° C. After stirring for 24 hours, the mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with ether, washed with water, 2N HCl, saturated sodium bicarbonate and brine. The organic phase was dried and evaporated to dryness. The resulting yellow oil was purified by wipe film distillation to yield 96.6 g of a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][CH:9]=2)[N:4]([OH:13])[C:3]1=[O:14].BrC1C=C2C(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2OC(OC(C)(C)C)=O)=CC=1>>[NH2:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([Br:12])=[CH:8][CH:9]=2)[N:4]([OH:13])[C:3]1=[O:14]
Reactant: N[C@@H]1Cc2ccc(Br)cc2N(O)C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1Cc2ccc(Br)cc2N(OC(=O)OC(C)(C)C)C1=O
Product: N[C@H]1Cc2ccc(Br)cc2N(O)C1=O

Procedure:
Following the procedure for the preparation of (3R)-3-amino-7-bromo-1-hydroxy-3,4-dihydroquinolin-2(1H)-one (29) in Example 5 but using tert-butyl {(3S)-7-bromo-1-[(tert-butoxycarbonyl)oxy]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}carbamate (28) as starting material, the title product was obtained as a white powder (23 mg, 62%). LCMS m/z 258.9 (M+1). 1H NMR (500 MHz, DMSO-d6) δ 2.70 (br dd, J=15.6, 12.7 Hz, 1H) 2.99 (dd, J=15.6, 6.1 Hz, 1H), 3.52 (dd, J=12.7, 6.0 Hz, 1H), 7.16-7.20 (m, 2H), 7.28 (d, J=1.6 Hz, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:12]([C:24](OCC)=[O:25])=[CH:11]2>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:12]([CH2:24][OH:25])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1CCCS(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CS(=O)(=O)CCCn1c(CO)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.2 %

Procedure:
To a suspension of LiAlH4 (0.38 g, 10.0 mmol) in 50 mL of THF was added a solution of ethyl 5-chloro-1-[3-(methylsulfonyl)propyl]-1H-indole-2-carboxylate (1.60 g, 4.6 mmol) dropwise at 0° C. The reaction mixture was warmed naturally to RT and then stirred at RT for 2 hours. The reaction was then quenched with methanol. The resulting mixture was filtered through a celite pad. The filtrate was concentrated in vacuo to afford the crude [5-chloro-1-(3-methanesulfonyl-propyl)-1H-indol-2-yl]-methanol (0.60 g, yield: 43.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH2:5][OH:6].[CH3:11][O-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6]
Reactant: C[O-]
Reactant: OCc1ccc(O)c(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-4-hydroxybenzyl alcohol (1.22 g, 6.0 mmol) prepared from i) and sodium methoxide (0.36 g, 6.6 mmol) as base were added to N,N-dimethylformamide (100 ml), and the mixture was stirred for 30 min at room temperature. Chloromethyl resin (Merrifield resin, 1 mmol of chloromethyl site, formula 4; 1.22 g, 2.0 mmol) was added to the reaction solution and stirred for 24 hr at 50° C. The same was filtrated and washed repeatedly with water, methanol and dichloromethane. IR and XPS analyses were performed.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCO>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.C1(C)C=CC=CC=1>[Br:16][C:9]1[C:10]2[C:15]([C:2]([C:19]3[CH:18]=[CH:17][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[C:3]3[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 90 °C
Yield: 60.8 %

Procedure:
A mixture of 15 g (44.6 mmol) of 9,10-dibromoanthracene, 7.7 g (44.6 mmol) of naphthalen-2-ylboronic acid, 0.52 g (0.446 mmol) of Tetrakis(triphenylphosphine)Palladium, 33 ml of 2M Na2CO3, 60 ml of EtOH and 150 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 10.4 g (61%) as a yellow solid.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([NH:2][NH2:3])=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NN
Reactant: COC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Hydrazine monohydrate (7.40 mL) was added to a stirred suspension of methyl [(4-cyclohexylphenyl)amino](oxo)acetate (3990 mg) in ethanol (50 mL) at ambient temperature. The reaction was heated to 85° C. and allowed to stir for a further 3 hours. Allowed to cool to ambient temperature overnight. The precipitate was filtered off, washed with Et2O and dried under vacuum, to give the title compound (Intermediate 47, 3750 mg) as a solid; 1H NMR δ10.42 (1H, s), 10.17 (1H, s), 7.68 (2H, d), 7.16 (2H, d), 4.58 (1H, s), 2.48 (1H+DMSO, m), 1.89-1.65 (5H, m), 1.46-1.13 (5H, m); MS m/e M−H− 260.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:33]CCBr)[CH:29]=2)[CH:24]=1)[C:16]1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:15][O:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: BrCCOc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc4cc(O)ccc4c3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-Methylbenzyl)-piperidine and and 2-benzyloxy-6-(2-bromo-ethoxy)-naphthalene and potassium carbonate in two steps as a solid, mp 164-166° C. Analysis calculated for CH25H29O2 : C, 79.96; H, 7.78; N, 3.73. Found: C, 79.63; H, 7.84; N, 3.67.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)(=[O:13])=[O:12].[H-].[Na+].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)#[N:24]>C1COCC1.CN(C=O)C>[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:17]2[CH2:18][CH2:19][N:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[CH2:15][C:16]2=[O:20])=[CH:27][CH:26]=1)#[N:24]
Reactant: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Reactant: N#Cc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2=O)cc1
Reaction time: 0.33 h
Yield: 54.3 %

Procedure:
In THF (8 ml) and DMF (2 ml) was dissolved 4-(naphthalene-2-sulfonyl)-2-piperazinone (290 mg), and to the mixture was added sodium hydride (60% in oil, 40 mg) at 0° C. The mixture was stirred for 20 minutes, to which was added 4-cyanobenzylchloride (182 mg), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (MgSO4) and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of the title compound (220 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][CH:9]([NH2:11])[CH2:8][CH:7]2[N:3]1[CH2:4][CH2:5][CH2:6]2.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][N:15]=1.O>CO>[Cl:13][C:14]1[N:19]=[C:18]([NH:11][CH:9]2[CH2:8][CH:7]3[N:3]([CH2:4][CH2:5][CH2:6]3)[C:2]([CH3:12])([CH3:1])[CH2:10]2)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][N:15]=1
Reactant: NC(=O)c1cnc(Cl)nc1Cl
Reactant: CC1(C)CC(N)CC2CCCN21
Solvent: O
Solvent: CO
Product: CC1(C)CC(Nc2nc(Cl)ncc2C(N)=O)CC2CCCN21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-octahydro-5,5-dimethylindolizin-7-amine (0.65 g, 3.9 mmol) in MeOH (10 ml) was added to a stirred solution of 2,4-dichloropyrimidine-5-carboxamide (0.75 g, 3.9 mmol; prepared according to the procedure set forth in US patent application publication US20110130415, page 41) in MeOH (30 ml) and H2O (4 ml) at 0° C. under nitrogen. After complete addition, the mixture was slowly warmed to room temperature and stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue partitioned between EtOAc (150 ml) and 1N NaOH (100 ml). The aqueous layer was extracted with EtOAc (1×100 ml) and the combined organic extracts were dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was dry-loaded on to basic alumina (Brockmann grade IV) and then purified by column chromatography on basic alumina (Brockmann grade IV) using CH2Cl2/MeOH (1:0 to 95:5) as eluent to give the product (550 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][S:19](=[O:23])(=[O:22])[CH2:18][CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C:31]1[N:35]([C:2]2[N:3]=[C:4]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([N:16]5[CH2:17][CH2:18][S:19](=[O:22])(=[O:23])[CH2:20][CH2:21]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1
Reactant: O=S1(=O)CCN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)C2)CC1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCS(=O)(=O)CC4)C3)sc2n1
Temperature: 145 °C
Yield: 40.4 %

Procedure:
A mixture of 5-chloro-2-[3-(1,1-dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (150 mg, 0.33 mmol), 2-methylbenzimidazole (52 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 0.02 mmol), Xphos (31 mg, 0.07 mmol) and Cs2CO3 (213 mg, 0.65 mmol) in dioxane (3 mL) was purged with argon then heated at 145° C. for 45 min in a microwave reactor. The reaction mixture was filtered through a pad of celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) affording 448 as a foam (74 mg, 40%). LCMS (Method I): RT 2.45 min, [M+H]+ 555.2. 1H NMR (CDCl3, 400 MHz): δ 8.09-8.04 (m, 1 H); 7.74-7.69 (m, 1 H); 7.34-7.26 (m, 2 H); 4.41 (m, 4 H); 4.01 (s, 2 H); 3.88 (m, 4 H); 3.71 (t, J=6.7 Hz, 2 H); 3.37-3.30 (m, 1 H); 3.15 (t, J=6.7 Hz, 2 H); 3.09 (m, 4 H); 2.94 (s, 3 H) and 2.88 (m, 4 H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([OH:21])=[CH:16][C:15]=2[CH3:22])=[CH:11][C:10]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:43])(Br)[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:36]([CH3:43])([CH3:35])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:16][C:15]=2[CH3:22])=[CH:11][C:10]=1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)(=[O:26])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc(C)c1Cc1ccc(OCc2ccccc2)c(S(=O)(=O)c2ccc(F)cc2)c1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1cc(C)c(Cc2ccc(OCc3ccccc3)c(S(=O)(=O)c3ccc(F)cc3)c2)c(C)c1

Procedure:
This compound was obtained analogously to Example XI starting from 4-{4-(benzyloxy)-3-[(4-fluorophenyl)sulphonyl]benzyl}-3,5-dimethylphenol (Example X) and ethyl dimethylbromoacetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[H-].[Na+].F[B-](F)(F)F.[NH2:15][C:16]1[C:58]([Cl:59])=[CH:57][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][N+]3C(C4C=CC=CC=4)=CC(C4C=CC=CC=4)=CC=3C3C=CC=CC=3)[CH2:25][C@H:24]2[O:55][CH3:56])=[O:21])=[C:18]([O:60][CH3:61])[CH:17]=1>CC1C=CC=CC=1>[NH2:15][C:16]1[C:58]([Cl:59])=[CH:57][C:19]([C:20]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:25][C@H:24]2[O:55][CH3:56])=[O:21])=[C:18]([O:60][CH3:61])[CH:17]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CC[n+]2c(-c3ccccc3)cc(-c3ccccc3)cc2-c2ccccc2)C[C@H]1OC
Reactant: Oc1ccncc1
Agent: F[B-](F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCOc2ccncc2)C[C@H]1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A mixture of 2.36 parts of 4-pyridinol, 1.2 parts of a sodium hydride dispersion 50% and 18 parts of methylbenzene was stirred for 2 hours at room temperature. A solution of 7.1 parts of cis-1-[2-[4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-3-methoxy-1-piperidinyl]ethyl]-2,4,6-triphenylpyridinium tetrafluoroborate in 9 parts of methylbenzene was added and stirring was continued first for 4 hours at reflux temperature and then overnight at room temperture. The whole was extracted five times with 100 parts of a hydrochloric acid solution 1N. The combined acid aqueous phases were treated with potassium hydroxide and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using first a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volumee as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.23 parts (28.3%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[2-(4-pyridinyloxy)ethyl]-4-piperidinyl]benzamide; mp. 212.2° C. (compound 60).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:5]=1[CH:6]=[O:7].[CH3:17]I>CN(C)C=O>[CH3:17][O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[C:5]=1[CH:6]=[O:7]
Reactant: CI
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C=O)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of NaH (16.0 g, 50% oily dispersion, 337 mM) in dimethylformamide (200 ml) was treated dropwise with a solution of 2-hydroxy-3-methoxy-6-nitrobenzaldehyde (49.0 g, 248 mM) in DMF (300 ml) at such a rate that the temperature did not exceed 35° C. The mixture is aged at room temperature for 1 hour and then a large excess of methyl iodide (100 ml) is added dropwise. A slight exothermic reaction occurs. The mixture is then stirred vigorously for 19 hours at room temperature. After the removal of excess methyl iodide, the reaction mixture is poured into ice-water (1 l). The crude product, a brown solid, is filtered, washed with cold water, and then recrystallized from isopropyl alcohol (700 ml) to afford the product as a tan solid; yield 27.9 g (53.3%); m.p. 106°-108° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17](Cl)[NH:16][C:15]2=[O:23])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[SH2:25].[Na]>CN(C)C=O>[C:1]([O:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:19](=[O:20])[C:18]([CH3:21])=[C:17]([SH:25])[NH:16][C:15]2=[O:23])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)[nH]c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c1=O
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1c(S)[nH]c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
The product of Example 1, Step (A) (0.54 g) was dissolved in dimethylformamide (5 mL) wand treated with sodium hydrogen sulfide (0.29 g) and heated at 60° C. for 18 hours. The solvent was removed in a vacuum and the residue stirred with 1 M hydrochloric acid (15 mL) for 1 hour. The resulting solid was filtered, rinsed with water and dried in a vacuum at room temperature to give 4-(4-mercapto-5-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl)-benzoic acid tert-butyl ester (0.475 g, 91% yield). 1H-NMR (DMSO-d6) δ 10.99 (s), 7.76(d, 2H), 7.27 (d, 2H), 5.52 (s, 2H), 1.91, (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([OH:13])=O)[C:4]=2[CH:3]=1.[CH2:20]([C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[C:23]=1[NH2:24])[CH3:21]>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11]([NH:24][C:23]3[C:25]([CH2:29][CH3:30])=[CH:26][CH:27]=[CH:28][C:22]=3[CH2:20][CH3:21])=[O:13])[C:4]=2[CH:3]=1
Reactant: O=C(O)C1c2ccccc2COc2ccc(Br)cc21
Reactant: CCc1cccc(CC)c1N
Product: CCc1cccc(CC)c1NC(=O)C1c2ccccc2COc2ccc(Br)cc21
Yield: 64 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.37 g of Compound H obtained in Example 46 in place of Compound A and 0.59 g of 2,6-diethylaniline in place of aniline to obtain 1.14 g of Compound 27.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)C>Cl.CC(C)=O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:8][CH:9]=1
Reactant: CCOC(COc1ccc(OC)cc1)OCC
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(OCC=O)cc1

Procedure:
1-(2,2-Diethoxyethoxy)-4-methoxybenzene (4.8 g, 20 mmol) was dissolved in 1% aqueous HCl (30 mL) and acetone (15 mL). The reaction mixture was heated under refluxed for 2 h. Acetone was removed under reduced pressure. The aqueous mixture was neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dried under reduced pressure to afford the desired product which was used in the next step without further purification. (3.30 g, 99.3%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:24]3[CH2:26][CH2:25]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH:24]3[CH2:26][CH2:25]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccc(C(F)(F)F)cn2)nc1C1CC1)C1CCCCC1
Product: O=C(O)CCNC(=O)c1ccc(NC(c2cn(-c3ccc(C(F)(F)F)cn3)nc2C2CC2)C2CCCCC2)cc1
Yield: 19.9 %

Procedure:
Using cyclohexyl{3-cyclopropyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.32 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.15 g, 21%) was obtained as a white solid.