Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C@H:21]([CH3:30])[C:22](N3CCOCC3)=[O:23])=[CH:15][CH:14]=1)[C:7]([CH3:31])=[C:6]2[C:32]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)=[O:33].C1C[O:44]CC1.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C@H:21]([CH3:30])[C:22]([OH:23])=[O:44])=[CH:15][CH:14]=1)[C:7]([CH3:31])=[C:6]2[C:32](=[O:33])[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1
Reactant: COc1ccc2c(c1)c(C(=O)c1ccc(C)cc1)c(C)n2Cc1ccc(CO[C@H](C)C(=O)N2CCOCC2)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c(C(=O)c1ccc(C)cc1)c(C)n2Cc1ccc(CO[C@H](C)C(=O)O)cc1
Yield: 31 %

Procedure:
The compound of Example 40-1 (142 mg, 0.26 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N lithium hydroxide solution (0.5 ml), followed by stirring under reflux for 15 hours. The reaction mixture was diluted with water and washed with diethyl ether. The aqueous layer was adjusted to around pH4 with 5% aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (39 mg, 31%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[N:20]1([CH2:25][CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][N:32]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:31][CH2:30]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: C(CCN1CCCC1)CC1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2N(C(=O)N2CCC(CCCCN3CCCC3)CC2)c2ncccc21
Yield: 72 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 4-[4-(1-pyrrolidinyl)butyl]piperidine in a yield of 72% of theory. Colourless crystals, m.p. 193°-195° C. (ethanol).
Reaction SMILES: C([O:8][CH2:9][C:10]1[O:15][C:14](=[O:16])[C:13]([CH3:17])=[C:12]([O:18][CH2:19][O:20][CH3:21])[C:11]=1[CH3:22])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:17][C:13]1[C:14](=[O:16])[O:15][C:10]([CH2:9][OH:8])=[C:11]([CH3:22])[C:12]=1[O:18][CH2:19][O:20][CH3:21]
Reactant: COCOc1c(C)c(COCc2ccccc2)oc(=O)c1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COCOc1c(C)c(CO)oc(=O)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20% Pd(OH)2/C (360 mg) was added to a solution of 6-(benzyloxy)methyl-3,5-dimethyl-4-methoxymethoxy-2H-pyran-2-one (1.80 g) in EtOH (50 ml), and the mixture was vigorously stirred at room temperature for 3 hours under a hydrogen gas atmosphere. The reaction solution was celite filtered and the mother liquor was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to obtain 3,5-dimethyl-6-hydroxymethyl-4-methoxymethoxy-2H-pyran-2-one.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.Cl.N([O-])=O.[Na+].[O:18]([CH2:22][CH3:23])[C:19]([S-:21])=[S:20].[K+]>CO.O>[Cl:12][C:4]1[CH:3]=[C:2]([S:21][C:19]([O:18][CH2:22][CH3:23])=[S:20])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCOC(=S)Sc1ccc(C(=O)OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0 C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0° C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 50˜60° C. The reaction was heated to 65° C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25° C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70° C. for 1 h. Upon completion, the mixture was cooled to 25° C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH4+:25].[OH-]>O1CCOCC1.O>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:25])[N:8]=1
Reactant: [NH4+]
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(N)n1
Yield: 91 %

Procedure:
4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (1 g, 2.4 mmol) was combined with aqueous 28% NH4OH solution (8 mL) in 1,4-dioxane (8 mL) and the resulting mixture was split evenly between two reaction vials. Each was irradiated in a microwave reactor for 40 minutes at 130° C. TLC analysis indicated complete reaction. The combined reactions were then diluted with water (100 mL) followed by extraction with EtOAc (100 mL). The EtOAc layer was washed with brine then dried (Na2SO4), and concentrated. Purification of the resulting residue by flash chromatography on silica gel using an EtOAc-hexanes gradient (0 to 60%) provided 0.87 g of (2.1 mmol, 91%) of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-amine as a white solid: LCMS(m/z): 410.0 (MH+), tR=0.81 minute.
Reaction SMILES: [CH3:1][C:2]1([O:8][C:9](=[O:23])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:24]1[CH2:28][CH2:27][O:26][CH:25]1[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:31][CH:30]=1>CO.ClCCl.C(OCC)(=O)C>[O:24]1[CH2:28][CH2:27][O:26][CH:25]1[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]([CH2:37][CH2:38][N:5]2[CH2:6][CH2:7][C:2]([O:8][C:9](=[O:23])[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([CH3:1])[CH2:3][CH2:4]2)=[O:39])=[CH:33][CH:34]=1
Reactant: CC1(OC(=O)Nc2ccccc2-c2ccccc2)CCNCC1
Reactant: C=CC(=O)Nc1ccc(C2OCCO2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC1(OC(=O)Nc2ccccc2-c2ccccc2)CCN(CCC(=O)Nc2ccc(C3OCCO3)cc2)CC1

Procedure:
A mixture of biphenyl-2-ylcarbamic acid 4-methylpiperidin-4-yl ester (2.73 g, 8.79 mmol) and N-(4-[1,3]dioxolan-2-yl-phenyl)acrylamide (2.05 g, 8.80 mmol) were heated in 100 mL of 1:1 methanol/dichloromethane at 50° C. under nitrogen for 1 h. The solution was then diluted with ethyl acetate and the organic layer was washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to give the title compound. MS m/z calcd for C31H35N3O5 (M+H)+ 530.6; found 530.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.[CH-]1C=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=C1.Cl[Pd]Cl.[Fe+2]>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 166, step 1, (E)-5-(3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one (example 224, step 4) was reacted with 4-carboxyphenylboronic acid in the presence of dichloro(1,1′-bis(diphenylphosphino)ferrocene) palladium(II) dichloromethane adduct in a mixture of 1,4-dioxane, water and 2 M aqueous sodium carbonate solution to give the title compound containing 10% of the corresponding Z isomer as a colorless solid, MS (ESI+): m/z=485.19 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([CH3:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: [Rh]
Solvent: CO
Product: CC1CCC(NC(=O)OC(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
A stainless steel autoclave was charged with a solution of the t-butyl-(6-methylpyridin-3-yl)carbamate (6.2 g, 3.12 mmol) in MeOH (100 mL) and treated with 5 wt % Rhodium on alumina (3.06 g, 0.312 mmol). The vessel was evacuated and back-filled with N2 three times. Next, it was evacuated, and then back-filled with H2 to a pressure of 500 psi, and stirred vigorously at room temperature for 2 days. The vessel was depressurized, the mixture was filtered though Celite®, and the filter cake was washed with EtOAc (300 mL). The filtrate was concentrated in vacuo to a tan oil, which was sufficiently pure to use in the subsequent step without further purification (5.4 g, 85% yield, dr=2:1). Data for G-2 (major diastereomer): 1H NMR (500 MHz, CDCl3) δ 5.46 (br s, 1H), 3.71 (br s, 1H), 2.91 (dt, J 12.0, 2.3 Hz, 1H), 2.79 (d, J=10.7 Hz, 1H), 2.57-2.63 (m, 1H), 1.79 (d, J=13.4 Hz, 1H), 1.40-1.61 (m, 3H), 1.42 (s, 9H), 1.10-1.25 (m, 1H); 1.03 (d, J=5.9 Hz, 3H). Data for G-2 (minor diastereomer): 1H NMR (500 MHz, CDCl3) δ 4.38 (br s, 1H), 3.40 (br s, 1H), 3.25 (ddd, J=11.7, 4.2, 2.0 Hz, 1H), 2.50-2.59 (m, 1H), 2.33 (t, J=11.2 Hz, 1H), 1.68 (d, J=9.5 Hz, 1H), 1.40-1.61 (m, 3H), 1.40 (s, 9H), 1.10-1.25 (m, 1H); 1.04 (d, J=6.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1>N.CO.[Ni].C(Cl)Cl>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc(N)cc1C(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (5.0 g, 26.7 mmol) in 7.0 M ammonia in MeOH (20.0 mL) was added Raney Nickel 2800 (50% slurry in water, 320 mg). The mixture was allowed to stir under an atmosphere of hydrogen for 18 h, then at 50 psi for 18 h. The mixture was diluted with DCM and filtered through Celite. The filtrate was evaporated and the residue was purified by column chromatography on silica to 4-(aminomethyl)-3-(trifluoro-methyl)aniline as an orange solid (3.43 g, 67%). LCMS: (FA) ES+ 187.1 ES− 185.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[C:16]([F:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cr](O)(O)(=O)=[O:28].S(=O)(=O)(O)O>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:28])=[O:21])=[C:16]([F:22])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[Cr](=O)(O)O
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Yield: 68.2 %

Procedure:
In a solution of 0.95 g of 5-(3,5-dichlorophenyl)-3-(3-fluoro-4-hydroxymethylphenyl)-5-trifluoromethyl-4,5-dihy droisoxazole in 25 ml of acetone, Johnes' Reagent prepared from 1.50 g of chromic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water was added dropwise under cooling with ice and with stirring, after the completion of the addition dropwise, continued to stir at room temperature for further 1.5 hour. After the completion of the reaction, the reaction mixture was poured in 50 ml of water and extracted with diethyl ether (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residual solid was washed with hexane to obtain 0.67 g of the aimed product as beige crystal.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[Br:12]Br>CO>[CH:4]1([C:2]([CH2:1][Br:12])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)C1CCCCCCC1
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)C1CCCCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 217.9 %

Procedure:
An ice cold solution of 5.5 g of cyclooctyl methyl ketone in 50 ml of methyl alcohol was treated dropwise with 1.95 g of bromine. After 5 min, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then diluted with 200 ml of water and extracted with ethyl ether (3×60 ml). The combined extracts were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and condensed in vacuo to yield 6.2 g of bromomethyl cyclooctyl ketone as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[Cl:15].C1COCC1.CO>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[Cl:15]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(OCc2ccccc2Cl)c(Cl)c1

Procedure:
To a three-neck flask (500 ml) was added 1-(2-chlorobenzyloxy)-2-chloro-4-nitrobenzene (8.567 g). To the flask were added THF (100 ml) and methanol (50 ml). The solution was mechanically stirred and heated under reflux. Glacial acetic acid (17 ml) and reduced iron powders (16.8 g) were added into the solution. The mixture reacted for 1 hr. After the reaction finished, the resultant substance was filtered in vacuo and the filtrate was rotary-evaporated to dryness. To the resultant crude product was added HCl (4N, 200 ml). The mixture was sufficiently vibrated and then filtered in vacuo. To the resultant filter cake was added water (100 ml). The pH of the mixture was adjusted to 12 with 5% sodium hydroxide. Ethyl acetate (700 ml) was added. The solution was sufficiently vibrated and separated. The ethyl acetate layer was washed with saturated sodium carbonate (200 ml), water (200 ml) and staturated saline solution (200 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was rotary-evaporated to dryness. The resultant substance was recrystallized with ethyl acetate to give the target compound.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([CH2:10][OH:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.OCC1C(CO)=CC=CC=1.ClCC1C(CCl)=CC=CC=1>>[CH2:3]1[O:11][CH2:10][C:5]2[C:4]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: OCc1ccccc1CCl
Agent: Cl
Agent: ClCc1ccccc1CCl
Agent: OCc1ccccc1CO
Product: c1ccc2c(c1)COC2
Temperature: 70 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
A reagent, α,α′-dihydroxy-o-xylene, produced by Aldrich Co. (69.5 g, 0.5 mol) was placed in a 500-mL four-neck flask equipped with a condenser tube, a stirring blade, a thermometer, and a dropping funnel, and 35% hydrochloric acid (100 g, 1.0 mol) was added thereto. The mixture was stirred at 70° C. for one hour. After completion of reaction, the reaction mixture was allowed to stand, so that two-separated layers were formed. The reaction was analyzed through GC while stirring again during sampling. From the obtained concentration of α-chloro-α′-hydroxy-o-xylene, the yield of α-chloro-α′-hydroxy-o-xylene was calculated to be 91% based on α,α′-dihydroxy-o-xylene. The conversion of α,α′-dihydroxy-o-xylene was 99%, and α,α′-dichloro-o-xylene (5%) and phthalan (2%) were formed as by-products.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:9]([CH3:11])[CH3:10])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1.CCCCCC>[CH:9]([O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:20]=[O:21])([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A solution of 1-bromo-3-iso-propyloxybenzene (2.16 g, 10 mmol) in dry THF (30 mL) was cooled to −78° C. and n-BuLi (4.8 mL of a 2.5 m solution in hexane, 12 mmol) was added. The resulting solution was stirred 0.5 hours and DMF (7.3 g, 10 mmol) was added at −78° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. Purification on silica gel with 25% ethyl acetate/hexane afforded the title compound (1.64 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@H:7]([OH:21])[CH2:8][NH:9][C@H:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][C@H:10]([N:9]1[CH2:8][C@H:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CN(C)C=O
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)NC[C@@H](O)COc1cccc(Cl)c1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)N1C[C@H](COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 3.45 g of 1(R)-(3-chlorophenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1(R)-methylethylamino)ethanol (prepared as described in Preparation 42), 1.78 g of N,N'-carbonyldiimidazole and 30 ml of anhydrous dimethylformamide were used, to give 3.52 g of the title compound having an Rf value of 0.74 (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =-53.3° (methanol, c=1.020).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([N+:16]([O-])=O)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl-].[NH4+]>O.CO.[Fe]>[NH2:16][C:9]1[CH:8]=[C:7]([O:19][CH3:20])[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1N
Yield: 93 %

Procedure:
Med. Chem., 44, 3965 (2001) describes a process for preparing a 4-alkoxy-5-halogenoalkoxyanthranilic acid compound from a 4-alkoxy-5-halogenoalkoxy-2-nitrobenzoic acid compound. For example, methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate is reacted with a very excessive amount of iron and ammonium chloride in a mixture of water and methanol, to give methyl 2-amino-5-(3-chloropropoxy)-4-methoxybenzoate (i.e., methyl 5-(3-chloropropoxy)-4-methoxyanthranilate) in 93% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.CCOC(C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Fc1ccc(Br)nc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 69.1 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (10.0 g, 56.82 mmol, Aldrich) in tetrahydrofuran (100 ml) was added tetrakis (triphenylphosphine)Pd complex and stirred for 10 min. Then, phenylmagnesium bromide (68.2 ml, 1.00 M in THF, 68.19 mmol) was added drop-wise at 0° C. The mixture was stirred overnight. Then the reaction was diluted with EtOAc (600 ml), and filtered. The filtrate was concentrated and purified by flash chromatography by eluting with 2% EtOAc-Hexane to obtain 6.8 g (69%) of 5-fluoro-2-phenylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:13][N:12]=[C:11]([NH:28][CH2:29][CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][N:33]=2)[N:10]=1.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)=[CH:13][N:12]=[C:11]([NH:28][CH2:29][CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][N:33]=2)[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)CC1
Agent: Cl
Solvent: CO
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(N3CCNCC3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
1 mmol of tert-butyl 4-[4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))amino]ethyl}amino)pyrimidin-5-yl]piperazinecarboxylate is heated to 60° C. 3M HCl in MeOH for one hour and concentrated in vacuo to obtain [4-(2,4-dichlorophenyl)-5-piperazinylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[S:15][C:16]=2[NH2:17])=O)=[CH:6][CH:5]=1.[CH:23]1([C:26](=[O:31])[CH2:27][C:28](=O)[CH3:29])[CH2:25][CH2:24]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:27]([C:26]([CH:23]3[CH2:25][CH2:24]3)=[O:31])=[C:28]([CH3:29])[N:17]=[C:16]3[S:15][C:14]4[CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]=23)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: COC(=O)c1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.3 %

Procedure:
To a stirred solution of 60 mg (0.19 mmol) 4-(2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 2 ml acetic acid was added 32 mg (0.25 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 28 mg (37%) 4-(3-cyclopropanecarbonyl-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-4-yl)-benzoic acid methyl ester as a light pink solid. ES-MS m/e (%): 406 (M+H+, 100).