Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14]([NH2:16])=O)=N.C[O:18][CH:19](OC)[N:20](C)C>CC#N>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:11]=[N:13][C:14]([NH2:16])=[N:20][C:19]1=[O:18]
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc(C)c1NC(=N)NC(N)=O
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(C)c1-n1cnc(N)nc1=O
Reaction time: 0.17 h

Procedure:
To a magnetically stirred suspension of 9.7 g. (40 mmol) of 1-(2',6'-dimethylphenyl)amidinourea hydrochloride in 50 ml. of CH3CN at room temperature is added 5.7 g. (48 mmol) of N,N-dimethylformamide dimethylacetal. The reaction mixture is stirred for 10 minutes after which all of the solid material goes into solution. The solution is stirred for 5 minutes after which a seed crystal is added. A white solid precipitates. The reaction mixture is stirred for an additional 1.5 hours, after which the solid precipitate is filtered to yield 1-(2',6'-dimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one, melting point 248.5°-249.5° C. When recrystallized from absolute EtOH the product is obtained as a white solid with melting point 258.6°-259° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[O:31])[CH2:20][CH2:21]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3Cl)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3Cl)CC2)CC1

Procedure:
The title compound was prepared as described on example 1 from Trans (4-{2-[4-(2,4-Dichloro-benzoyl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester and trifluoroacetic acid (m/e): 383.3 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C@H:22]1[NH:27][C@@H:26]([CH3:28])[CH2:25][N:24]([CH2:29][C:30]2[C:31]([CH3:38])=[C:32]([CH:36]=O)[NH:33][C:34]=2[CH3:35])[CH2:23]1>>[CH3:28][C@H:26]1[NH:27][C@@H:22]([CH3:21])[CH2:23][N:24]([CH2:29][C:30]2[C:31]([CH3:38])=[C:32](/[CH:36]=[C:14]3\[C:15](=[O:20])[NH:16][C:17]4[C:13]\3=[CH:12][C:11]([S:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:10])=[O:9])=[CH:19][CH:18]=4)[NH:33][C:34]=2[CH3:35])[CH2:25]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CN1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-Phenylmethanesulfonyl-1,3-dihydro-indol-2-one was condensed with 4-((3R,5S)-3,5-dimethyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde to give the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([NH:19][C:20](=O)[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>P(Cl)(Cl)(Cl)=O>[CH2:12]([N:19]1[C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([Cl:11])=[CH:8][CH:7]=2)[N:1]=[C:20]1[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CC(=O)NCc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
2-Amino-4-chlorobenzoic acid (250 mg, 1 eq.) and N-benzylacetamide (261 mg, 1.2 eq.) were dissolved in phosphorus oxychloride (2 ml). The reaction was placed in the microwave for 10 minutes at 150° C. The reaction was quenched by pouring the mixture into ice. The crude product was extracted into ethyl acetate. The ethyl acetate layer was washed with water, 10% aqueous sodium hydroxide, dried with magnesium sulfate, filtered, and concentrated to yield 3-benzyl-7-chloro-2-methylquinazolin-4 (3H)-one as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12]CC1C=CC=CC=1)=[O:11].C(=O)(O)[O-].[Na+:24].C>CO.O.[Pd]>[Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O-:12])=[O:11].[Na+:24]
Reactant: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C([O-])C1=C(Cl)CC2CC(=O)N12

Procedure:
Benzyl 3-chloro-1azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (28 mg) in methanol (2.5 ml) and water (0.5 ml) containing sodium bicarbonate (8.5 ml) is hydrogenated with 10% palladium on powdered charcoal (30 mg) at 40 psi for 30 minutes. The mixture is filtered and the catalyst is washed with water (5 ml). The combined filtrate is concentrated in vacuo to 1/2 its volume, washed with ethylacetate, and lyophilized to provide sodium 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:26])=[C:20]([CH2:22][CH2:23][CH:24]=[O:25])[N:21]=2)=[CH:13][CH:12]=1.Cl>ClCCl>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][C:19]([CH3:26])=[C:20]([CH2:22][CH2:23][CH2:24][OH:25])[N:21]=2)=[CH:15][CH:16]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCC=O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCCO
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Add DIBAL-H (1M in THF, 2.0 mL, 2.0 mmol) to a 0° C. solution of 3-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-propionaldehyde (0.395 g, 1.39 mmol) in dichloromethane. After 15 min add 1N HCl and warm to room temperature. Add 5N HCl and stir until two clear, homogeneous layers are formed. Separate the layers and extract the aqueous layer with dichloromethane. Dry the crude organic extracts over MgSO4, filter, and concentrate. Purify on silica gel (0-70% EtOAc/Hexanes) to give the title compound (0.315 g, 79%): MS (m/e): 296 (M+1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH2:28][N:29]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:30][Si](C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]1[C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH2:30][N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C(/C=C/c1ccc(F)cc1F)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC[C@H](Cc2ccccc2)N1C(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1F
Temperature: -12 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4S)-4-benzyl-3-[(2E)-3-(2,4-difluorophenyl)prop-2-enoyl]-1,3-oxazolidin-2-one, from preparation 28 (46.83 g, 140 mmol) in dichloromethane (300 mL) was added N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine (50.2 mL, 210 mmol) at room temperature. The solution was cooled to −12° C. and a solution of trifluoroacetic acid (1.05 mL) in dichloromethane (10 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 24 hours and saturated sodium hydrogen carbonate solution (180 mL) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (180 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude residue. Purification of the residue by column chromatography using toluene:methyl tert-butyl ether (12:1) followed by dichloromethane:methyl tert-butyl ether (19:1) as the eluent afforded the title compound (which is the second eluting diastereomer), 63.0 g (49%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](O)[C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([Cl:21])[C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)ccnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: O=[N+]([O-])c1c(NCc2ccccc2)ccnc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
4-benzylamino-3-nitro-pyridin-2-ol (6.15 g, 25.07 mmol) was suspended in 100 mL of acetonitrile then phosphorus oxychloride (12 mL, 125.40 mmol) was added followed by tetraethyl ammonium chloride (4.15 g, 25.07 mmol) and the mixture was stirred at 85° C. overnight. The solvent was removed in vacuo and the residue was suspended in water (300 mL) and extracted with dichloromethane (2×200 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 5.9 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](O)=[O:9])[CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=1.CN1CCOCC1>CN(C)C=O>[CH3:21][O:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[N:17]=1)=[O:19]
Reactant: COC(=O)c1cccc(N)n1
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 93 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (16.3 g, 103 mmol), methyl 6-aminopicolinate (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylumnium hexafluorophosphate (HATU, 41.1 g, 108 mmol), and N-methyl morpholine (12.5 mL, 108 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 m L) and dried under reduced pressure to afford 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester as a white powder (25.6, 93% yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[C:13]([NH:21][NH2:22])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N(CC)CC)C>CC1C=CC(C)=CC=1>[Cl:1][C:2]1[C:7]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]2[N:4]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:21][N:22]=2)[N:3]=1
Reactant: Clc1cc(C2CCC2)c(Cl)nn1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C)cc1
Product: Clc1nn2c(-c3ccccc3)nnc2cc1C1CCC1
Yield: 34 %

Procedure:
A mixture of 3,6-dichloro-4-cyclobutylpyridazine from above (55.7 g, 0.27 mol), benzoic hydrazide (41.1 g, 0.30 mol) and triethylamine hydrochloride (41.5 g, 0.30 mol) in p-xylene (0.4 l) was stirred and heated at reflux under a stream of nitrogen for 24 hours. Upon cooling the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and water. The aqueous was basified by the addition of solid potassium carbonate. Some dark insoluble material was removed by filtration at this stage. The aqueous phase was further extracted with dichloromethane (×2). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel eluting with 5%→10%→25% ethyl acetate/dichloromethane to give the title compound, (26.4 g, 34%) as an off-white solid. Data for the title compound: 1H NMR (360 MHz, CDCl3) δ 1.90–2.00 (1H, m), 2.12–2.28 (3H, m), 2.48–2.57 (2H, m), 3.69–3.78 (1H,m), 7.49–7.59 (3H, m), 7.97 (1H, s), 8.45–8.48 (2H, m); MS (ES+) m/e 285 [MH]+, 287 [MH]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:18]2[CH2:23][NH:22][CH2:21][CH2:20][CH:19]=2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16].I[CH:25]([CH3:27])[CH3:26]>C(#N)C>[CH3:26][CH:25]([N:22]1[CH2:23][C:18]([C:11]2[CH:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:9]([O:8][CH3:7])[CH:10]=2)=[CH:19][CH2:20][CH2:21]1)[CH3:27]
Reactant: CC(C)I
Reactant: COc1cc(C2=CCCNC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2=CCCN(C(C)C)C2)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a pressure vessel containing acetonitrile (40 mL) and potassium carbonate (4.0 g, 29.2 mmol) was added 5-[3-(methyloxy)-4-nitrophenyl]-1,2,3,6-tetrahydropyridine (1.7 g, 7.3 mmol) and 2-iodopropane (1.85 g, 10.9 mmol). The reaction was stirred at 85° C. overnight. After removal of the solvent under reduced pressure the residue was diluted with ethyl acetate (30 mL) and washed with water (40 mL). After partitioning and extraction of the aqueous layer (Ethyl acetate 2×15 mL), the organic layer was dried over sodium sulfate, filtered, concentrated and purified via chromatography on SiO2 to afford 1-(1-methylethyl)-5-[3-(methyloxy)-4-nitrophenyl]-1,2,3,6-tetrahydropyridine (1.6 g, 80% yield.) ESIMS (M+H)+=277.1.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:24](O)=[O:25]>>[OH:10][C:9]1[CH:8]=[C:7]([CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[OH:1])[CH:24]=[O:25]
Reactant: N#Cc1cccc(O)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: N#Cc1cc(C=O)cc(O)c1O

Procedure:
A solution containing 1.35 g of 2,3-dihydroxybenzonitrile and 1.4 g of hexamethylene tetramine in 20 ml of trifluoroacetic acid was refluxed for 1.5 h. Water was added and the product was filtered. Yield 0.9 g (55%), m.p. 211°-215° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)=[O:27]
Reactant: COc1ccccc1C(=O)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1C(=O)OC1CCN(Cc2ccccc2)CC1
Yield: 68.7 %

Procedure:
1.41 g (0.00733 mol) of 1-benzyl-4-hydroxypiperidine and 1.8 ml (0.0129 mol) of triethylamine were dissolved in 50 ml of toluene and treated with 0.79 ml (0.00586 mol) of 2-methoxy-benzoyl chloride. The mixture was boiled at reflux for 2 hrs., the precipitate was filtered off and the filtrate was concentrated. The residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 1.31 g (69%) of 1-benzyl-piperidin-4-yl 2-methoxy-benzoate were obtained as a yellowish oil. MS: me/e=326 (C20H24NO3 +).
Reaction SMILES: [OH:1][C:2]1[C:19]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:18]([O:25][CH3:26])[CH:17]=[C:16]([O:27][CH3:28])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>[Pd].C(OCC)(=O)C>[OH:1][C:2]1[C:19]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[C:18]([O:25][CH3:26])[CH:17]=[C:16]([O:27][CH3:28])[C:3]=1[C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COc1ccc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)cc1
Reaction time: 3 h
Yield: 94.4 %

Procedure:
Then, 13.05 g of the so-obtained 2'-hydroxy-4,4',6'-trimethoxy-3'-(3-methyl-2-butenyl)chalcone was catalytically reduced by using 410 ml of ethyl acetate and 4.0 g of 5% palladium/carbon according to customary procedures, and after the reaction was conducted for 3 hours, the reaction liquid mixture was filtered, and the solvent was removed from the filtrate by distillation. The obtained residue was recrystallized from methanol to obtain 12.45 g (yield=94.11%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a light-yellow needle.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[N:3]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4]2[C:9]([C:10]=1[C:11]([OH:22])=[O:12])=[CH:8][CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2
Reactant: COc1ccc2c(C=O)c(Cl)n(-c3ccccc3)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ccc2c(C(=O)O)c(Cl)n(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.8 %

Procedure:
The compound of step 2 (365 mg, 1.27 mmol) was dissolved in tert-butanol (15 ml) and 2-methyl-2-butene (3 ml), and a solution of sodium chlorite (1.06 g, 11.7 mmol) and sodium dihydrogenphosphate (1.06 g, 8.82 mmol) in water (6 ml) was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure to give 394 mg of the crude title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH2:21]([Si:23]([O:28][C:29](=[O:39])[CH2:30][O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])([CH2:26]C)[CH2:24]C)C>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:39][CH:29]([O:28][Si:23]([CH3:26])([CH3:24])[CH3:21])[CH2:30][O:31][Si:32]([CH2:37][CH3:38])([CH2:33][CH3:34])[CH2:35][CH3:36])[CH3:14]
Reactant: CC[Si](CC)(CC)OCC(=O)O[Si](CC)(CC)CC
Reactant: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)OCC(O[Si](C)(C)C)O[Si](CC)(CC)CC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of triethylsilyl-2-(triethylsiloxy)acetate (37.6 g, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath and the THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 minutes and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give a clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a 1:1 mixture of geometrical isomers.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=2)[CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)C(Cc1cccc(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(COC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(hydroxymethyl)benzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26]C)[C:6]([NH:8][C:9]1[S:10][C:11]([CH3:22])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[N:13]=1)=[O:7].B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[OH:26])[C:6]([NH:8][C:9]1[S:10][C:11]([CH3:22])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[N:13]=1)=[O:7]
Reactant: COc1ccc(-c2nc(NC(=O)c3ccc(OC)c(OC)c3)sc2C)cc1
Agent: BrB(Br)Br
Product: Cc1sc(NC(=O)c2ccc(O)c(O)c2)nc1-c1ccc(O)cc1
Yield: 61.2 %

Procedure:
A procedure similar to that in Example 7 was used. 3,4-dimethoxy-N-[4-(4-methoxy-phenyl)-5-methyl-thiazol-2-yl]-benzamide prepared in Example 54 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a white solid in a yield of 61.2%, mp: 285└(Dec.). 1H-NMR (CD3OD, 400 MHz) δ: 2.46 (3H, s, ArCH3), 6.88˜6.98 (3H, m, ArH), 7.40˜7.51 (4H, m, ArH); EI-MS m/e (%): 342.1 (M+, 29), 206.2 (100), 137.1 (36); HREI-MS Calcd. for C17H14N2O4S: 342.0674. found: 342.0670.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH:42]3[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CC1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CC1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 4-methylcyclohexylamine according to conditions described in general procedure C. Mp: 101-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.82 (d, J=6.6 Hz, 3 H), 0.86-1.59 (m, 15 H), 3.27-3.36 (m, 5 H), 6.27 (bs, 1 H), 6.96 (d, J=12.8, 2 H), 7.15 (d, J=8.4 Hz, 1 H), 7.36-7.39 (m, 1H), 7.43 (s, 1 H), 7.54-7.60 (m, 3 H), 7.79-7.83 (m, 1 H), 7.96 (d, J=7.3 Hz, 1 H), 8.18 (s, 1 H), 10.40 (s, 1 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([C:14]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([O:30]CC)=[O:29])[CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:7]=[C:8]([CH3:10])[CH:9]=1>CO.C(OCC)(=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH2:21][S:20][C:15]2[C:14]([C:12]([NH:11][C:6]3[CH:7]=[C:8]([CH3:10])[CH:9]=[C:4]([CH3:3])[CH:5]=3)=[O:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:27]=[CH:26][N:25]=1)([OH:30])=[O:29]
Reactant: CCOC(=O)c1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(C(=O)O)c2)c1
Yield: 84 %

Procedure:
A 1N aqueous sodium hydroxide solution (0.5 mL) was added to a solution of N-(3,5-dimethylphenyl)-2-(2-ethoxycarbonylpyridin-4-ylmethylthio)pyridine-3-carboxamide (95 mg, 0.22 mmol, Compound No. 1-241) in methanol (2 mL), then the mixture was stirred at room temperature for 1.5 hours. 1N hydrochlroric acid (1 mL) was added to the reaction mixture, and this mixture was diluted with ethyl acetate (35 mL). The mixture was washed with brine (20 mL), and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, then the resulting residue was filtered off. The solid was washed with diethyl ether, and then dried at 50° C. under reduced pressure to give 74 mg of the target compound as an orange solid. (Yield 84%)