Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])[CH2:8][CH2:7]1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 36.2 %

Procedure:
A mixture of 4-(3,4-dichlorophenoxy)piperidine (WO 0058305, WO 0177101) (4.40 g) and 2-(2-oxiran-2-ylethyl)-1H-isoindole-1,3(2H)-dione (J. Med. Chem. 1979, 22(6), 631-9. 5.00 g) in ethanol (50 ml) was stirred at 60° C. for 12 h. The mixture was cooled down and left overnight. The formed crystals were collected by filtration, washed with cold ethanol and dried under vacuum to afford the sub-title compound as a white solid (3.0 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[N:19]([CH2:26][CH3:27])[N:18]=2)=[CH:13][CH:12]=1.CI.[C:30]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:26]([N:19]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:2]3[N:1]([CH3:30])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[CH:12][CH:13]=2)=[N:18]1)[CH3:27]
Reactant: CCn1nc(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCn1nc(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncccc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
A suspension of 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine (150 mg), MeI (0.039 mL), and K2CO3 (117 mg) in DMF (1.5 ml) was stirred overnight at 40° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was crystallized from hexane/AcOEt to give the title compound (128 mg).
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[CH:27]([O:30][C:31]1[CH:32]=[CH:33]C(C#N)=[N:35][CH:36]=1)([CH3:29])[CH3:28]>C1COCC1>[CH:27]([O:30][C:31]1[CH:32]=[CH:33][C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)=[N:35][CH:36]=1)([CH3:29])[CH3:28]
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: CC(C)Oc1ccc(C#N)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc2c(O)nc(-c3ccc(OC(C)C)cn3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.4 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (4.43 g, 20 mmol) in THF (100 ml) at −78° C., tert-butyllithium 1.7 M in pentane (17.65 ml, 30.0 mmol) solution was added dropwise. The reaction mixture was stirred for 0.5 h before addition of 5-isopropoxypicolinonitrile (3.41 g, 21.00 mmol) in THF (2 mL). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid (5 g) was collected and washed with water to give the product 3-(5-isopropoxypyridin-2-yl)-6-methoxyisoquinolin-1-ol 4 g as a white solid. MS: MS m/z 311.11 (M++1).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21](/[CH:23]=[CH:24]/[C:25]([NH:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][CH2:24][C:25]([NH:27][CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:26])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2c(-c3nc(/C=C/C(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(-c2c(-c3nc(CCC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1
Yield: 54 %

Procedure:
A solution of (2E)-3-{2-[1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}-N-(tetrahydro-2H-pyran-4-ylmethyl)prop-2-enamide (46.7 mg, 0.10 mmol) and 10% palladium carbon (10 mg, 0.09 mmol) in methanol (15 mL) was stirred under 1 atm hydrogen atmosphere at room temperature for 14 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (solvent gradient; 0→50% ethyl acetate/hexane) and crystallized from ethyl acetate and hexane to give the title compound (26.2 mg, 0.054 mmol, 55.9%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl.Cl[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>CO>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][S:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:15]=1
Reactant: Nc1ccc(S)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(SCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
4-aminothiophenol (10 g) was dissolved in methanol (200 ml), aqueous solution of sodium hydroxide (15.7 g, 60 ml) was added to the mixture, 3-(chloromethyl)pyridine hydrochloride (14.4 g) was added to the mixture at 0° C., and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure, and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 4-[(3-pyridinylmethyl)sulfanyl]aniline (13.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH2:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CN1CCCC1=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:43][CH2:42][CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 105 °C
Yield: 90.1 %

Procedure:
Sulfone 9.1 (2.24 g, 5.4 mmol) was combined with N-tert-butoxycarbonyl-4-aminomethylpiperidine (5.6 g, 16.2 mmol) and 1-methyl-2-pyrrolidinone (9 mL). The mixture was heated to 100-110° C. for 2 hours at which time it was cooled to room temperature and ethyl acetate was added. The resultant white solid was filtered and washed with ethyl acetate to give 2.3 g of 3-(2-chlorophenyl)-7-[(1-tert-butoxycarbony-piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (MH+=473). Hydrogen chloride gas was bubbled into 2.1 g of the protected amine which was suspended in 1,4-dioxane (22 mL), and the suspension stirred for 1 hour, concentrated in vacuo and dried to give the intermediate 3-(2-chlorophenyl)-7-[(piperidin-4-ylmethyl)amino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(O)cc2)COC1(C)C
Reactant: COc1ccc(I)cc1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(C[C@H]3COC(C)(C)N3C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of (S)-4-(4-Hydroxy-benzyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol, 1 eq.)), 4-iodoanisole (180 mg, 0.75 mmol, 1.5 eq.) in dioxane (4 ml) was added CuI(I) (20 mg, 0.05 mmol, 0.1 eq.), N,N-dimethylglycine (30 mg, 0.15 mmol, 0.3 eq.) and cesium carbonate (500 mg, 1.5 mmol, 3 eq.). The resulting mixture was stirred under Ar at reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure to give a residue, which was partitioned between water (10 ml) and ethyl acetate (10 ml). The ethyl acetate layer was separated and dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave a residue, which was passed through a plug of silica gel using dichloromethane (50 ml) as eluent to give 106 mg of desired product (51% yield).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][C:27]2[CH:28]=[C:29]([NH:33][S:35]([CH3:34])(=[O:37])=[O:36])[CH:30]=[CH:31][CH:32]=2)[N:22]=[CH:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(1-trityl-1H-imidazol-4-ylmethoxy)phenylamine (0.7 g, from above) and methanesulfonyl chloride (0.3 mL) in pyridine (12 mL) was stirred at room temperature overnight. Pyridine was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water and brine. After drying over sodium sulfate and evaporation of the solvent, N-[3-(1-trityl-1H-imidazol-4-ylmethoxy)-phenyl]methanesulfonamide (0.7 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>ClCCl.CN(C=O)C>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][C:15]=1[NH:20][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Nc1ccc(Cl)cc1NC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
Method 7—Step a A mixture of 5-Bromo-2-fluoro-benzoic acid (3.00 g, 13.70 mmol), 4-chloro-benzene-1,2-diamine (2.42 g, 16.99 mmol), HATU (5.47 g, 14.38 mmol) and TEA (1.91 mL, 13.83 mmol) in dichloromethane (70 mL) and DMF (16 mL) was stirred at room temperature overnight, then water was added (80 mL) and left standing at room temperature overnight. The organic layer was divided and solvent removed under reduced pressure and the crude oil obtained was crystallized from the mixture of solvents dichloromethane:cyclohexane/3:1 (30 mL) to afford 2.19 g of the title compound (52%).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3](C(OCC)=O)[NH:2]1.[Se](=O)=O>C(O)(=O)C>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)C1Cc2c([nH]c3ccccc23)CN1
Agent: O=[Se]=O
Solvent: CC(=O)O
Product: c1ccc2c(c1)[nH]c1cnccc12
Yield: 59.5 %

Procedure:
Compound 10b (24.4 g, 0.1 mol) was mixed with glacial acetic acid (500 ml) followed by the addition of selenium dioxide (20 g, 0.2 mol). The mixture was refluxed for 12 h. The glacial acetic acid was removed I. 1M NaOH solution (200 ml) was added into the residues, then the mixture was extracted with ethyl acetate. The organic phases were combined, washed by 1M NaOH solution, water and brine, dried, decolorized with activated carbon, filtered, evaporated and recrystallized with ethyl acetate to afford white solids (10.0 g, 60%), and mp 197-198° C. (reference[20]: 198 to 200° C.).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=O.Cl.Cl.[NH2:27][OH:28].[OH-].[Na+].O>CO>[N:27](=[C:16]1[CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]34[CH2:6][CH2:5][N:4]([CH2:3][CH:2]=[CH2:1])[C@@H:21]2[CH2:22][C:9]2[CH:10]=[CH:11][C:12]([OH:24])=[C:13]([O:14][C@@H:15]13)[C:8]4=2)[OH:28]
Reactant: NO
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=NO)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of naloxone hydrochloride (1.085 g, 3 mmol) and hydroxylamine hydrochloride (0.28 g, 4 mmol) was taken up in 30 mL of MeOH containing 2.8 mL of 10% aqueous NaOH. The mixture was stirred at room temperature for 24 h. Water was added (100 mL), and the oxime extracted into CHCl3 (3×50 mL). The extract was dried (MgSO4), and the solvent evaporated. The residue obtained was recrystallized from CH2Cl2 -petroleum ether. Yield: 840 mg (81.8%); mp: 119° C. IR: (KBr): No C=O absorption at 1717 cm-1. 1H NMR (CDCl3) δ4.98 (s,C5H); Rf: silica gel 60 in EtOAc-EtOH-NH4OH (100:1:1) 0.13. Anal. Calcd for: C19H22N2O4 : C, 66.65; H, 6.48; N, 8.18. Found: C, 66.70; H, 6.52; N, 8.08.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29]C)=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[OH-].[Na+]>C(#N)C.O>[CH3:26][O:25][C:24]1[C:3](=[O:2])[C:4]([CH3:31])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:22](=[O:29])[C:23]=1[O:27][CH3:28]
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl) benzoic acid (500 mg, 1.1820 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (1.62 g, 2.9562 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water, neutralized with a 1N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (10% methanol-methylene chloride) to give the title compound (270 mg, 0.6870 mmol, 58%).
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.O>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccccn1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccn1)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (from Example 1, 50 mg, 0.17 mmol) and triethylamine (0.07 mL, 0.52 mmol) in toluene (5 mL), previously cooled to 0° C. was treated with 2,4,6-trichlorobenzoyl chloride (0.03 mL, 0.19 mmol) and the mixture was stirred at 0° C. After 1 h, 2-aminopyridine (20 mg, 0.21 mmol) and 4-dimethylaminopyridine (5 mg, 0.035 mmol) were added and the stirring was continued for 1 h at 0° C. The reaction was checked for completion, then it was diluted with water (10 mL) and extracted with dichloromethane (3 ×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 12M column, 80/20 hexanes/ethyl acetate) to give rac-2-cyclopentyloxy-2-(3,4- dichloro-phenyl)-N-pyridin-2-yl-acetamide (48 mg, 76% yield) as a white foam: EI-HRMS m/e calculated for C18H18N2O2Cl2 (M+) 364.0745, found 364.0746.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].[Cl:11][CH2:12][CH2:13][C:14]#[N:15]>C(Cl)Cl.CC(C)=O>[S:6](=[O:8])(=[O:7])([OH:10])[OH:9].[S:1]([NH:5][C:14](=[NH:15])[CH2:13][CH2:12][Cl:11])(=[O:3])(=[O:2])[NH2:4]
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a solution of conc. sulfuric acid (98%, 9.8 g, 0.1 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml), and the suspension filtered and the product dried.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][Si:5]1([CH3:12])[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:8]1([OH:11])[CH2:9][CH2:10][Si:5]([CH3:12])([CH3:4])[CH2:6][CH2:7]1
Reactant: C[Si]1(C)CCC(=O)CC1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CC[Si](C)(C)CC1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a tetrahydrofuran solution of 1.0M methylmagnesium chloride under ice cooling was added dropwise 14.2 g of 4,4-dimethyl-4-silacyclohexanone (which is synthesized by the disclosure of JP-A 7-309878). After two hours of agitation, an aqueous solution of ammonium chloride was added for hydrolysis. After ordinary post-treatments including extraction, washing and concentration, the product was purified by sublimation, obtaining 14.2 g (yield 90%) of 1,4,4-trimethyl-4-silacyclohexanol.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][C:22]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:24][CH:23]=4)[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc2cc3ccccc3cc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3cc4ccccc4cc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
Under an argon atmosphere, 14.5 g of phenylboronic acid, 25.7 g of 2-bromoanthracene, 4.62 g of tetraxis(triphenylphosphine)palladium(0), 400 mL of toluene and 200 mL of a 2M aqueous solution of sodium carbonate were mixed. The resultant was refluxed with stirring for 8 hours. After cooling to room temperature, deposited crystals were separated by filtration. By repetition of recrystallization and washing of the obtained solids using toluene-hexane, 19.1 g (yield: 75%) of 2-phenylanthracene was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:6]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:36][CH2:35]2)=[C:5]([CH3:53])[N:4]=1>C(OCC)(OCC)(OCC)C>[CH2:9]([O:11][C:12](=[N:2][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:6]([C:23](=[O:52])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][C:37]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:38][CH2:39]2)=[C:5]([CH3:53])[N:4]=1)[CH3:13])[CH3:8]
Reactant: CCOC(=O)c1c(N)nc(C)c(C(=O)CCCCCCCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)c1-c1cccc([N+](=O)[O-])c1
Agent: CCOC(C)(OCC)OCC
Agent: Cl
Product: CCOC(=O)c1c(N=C(C)OCC)nc(C)c(C(=O)CCCCCCCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)c1-c1cccc([N+](=O)[O-])c1
Yield: 100.7 %

Procedure:
5.7 g of ethyl 2-amino-6-methyl-4-(3-nitrophenyl)-5-[1-oxo-11-(4,4-diphenyl-1-piperidinyl)undecyl]pyridine-3-carboxylate hydrochloride and 150 ml of triethyl orthoacetate are heated at 125° C. for 72 h with passage of nitrogen. The solution is concentrated in vacuo, and the residue is dried and then chromatographed through a silica gel column using petroleum ether/ethyl acetate/triethylamine 7:3:0.5 as eluent. The pure fractions are combined and concentrated, and the residue is dried in a high vacuum. 3 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:11][C:10]=2[F:24])=[O:5])C.[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C(O)(=O)C.Cl>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[OH:16])=[CH:13][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:11][C:10]=3[F:24])=[O:5])=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(F)cc(-c3ccccc3C)cc2c1O
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 190 °C

Procedure:
6-Iodo-8-fluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (903 mg) from Example No. 5 and o-tolueneboronic acid (374 mg) are dissolved in DMF (50 mL) and at 50° C. a solution of barium hydroxide octahydrate (1.18 g) in water (5 mL) is added followed by palladium tetrakistriphenylphosphine (58 mg). The mixture is heated at 80° C. for 20 h, allowed to cool to rt, poured into water (200 mL), and extracted with ethyl acetate (3×100 mL). The organic layer is washed with brine (25 mL), dried (MgSO4), and concentrated. The solid is then triturated with MTBE, and filtered to afford 382 mg of 6-(2-methylphenyl)-8-fluoro-4-hydroxy-3-quinoline-carboxylic acid ethyl ester. The crude ester is mixed with 4-chlorobenzylamine (380 mg) and is heated to 190° C. for 1 h. The mixture is diluted with toluene (4 mL), allowed to cool to rt, poured into a mixture of 50% acetic acid (10 mL) and 1 N hydrochloric acid (25 mL), and is extracted with ethyl acetate (3×25 mL). The organic layer is dried (MgSO4) and allowed to crystallize. Recrystallization from acetic acid/water affords 166 mg of the title compound.