Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([OH:10])[CH:6]=1)=[O:4].[N:11]1([CH2:17][CH2:18][CH2:19]O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:19][CH2:18][CH2:17][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)no1
Reactant: OCCCN1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc(OCCCN2CCCCC2)no1
Reaction time: 0.17 h
Yield: 192.6 %

Procedure:
3-Hydroxy-isoxazole-5-carboxylic acid methyl ester (0.859 g., 6.00 mmol) and 3-piperidin-1-yl-propan-1-ol (0.860 g., 6.00 mmol) were dissolved in DCM (30 mL), and polymer-supported Ph3P resin (3 mmol/g, 3.1 g, 9.30 mmol) was added. The mixture was stirred for 10 min and di-tert-butyl azodicarboxylate (2.14 g, 9.30 mmol) was then added. The reaction mixture was stirred under nitrogen for 18 h. The reaction was quenched with 1 N NaOH (20 mL) and was stirred for 30 min. The resulting mixture was extracted with DCM (3×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to yield a crude oily product (3.1 g), which was purified (SiO2: 5% 2 M NH3 in MeOH/DCM) to yield the title compound (0.88 g, 58%). MS (ESI): exact mass calcd. for C13H20N2O4, 268.14; m/z found, 269.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 6.53 (s, 1H), 4.34-4.30 (m, 2H), 3.94 (s, 3H), 2.47-2.34 ( 6H), 2.02-1.94 (m, 2H), 1.61-1.54 (m, 4H), 1.47-1.39 (m, 2H).
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl.CCOC(C)=O>[CH3:23][S:24]([O:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:21])[C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:22])[F:1])=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)c1ccc(OC(F)F)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)c1ccc(OC(F)F)cc1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a stirred solution of 386 (550 mg, 1.73 mmol) in DCM (20 mL) at 0° C. was added TEA (290 μL, 2.08 mmol) and MeSO2Cl (148 μL, 1.91 mmol) and stirring was continued for 1 h at 0° C. The mixture was diluted with EtOAc, washed sequentially with water, dilute HCl solution, aq. satd. NaHCO3 and brine, dried (MgSO4), and concentrated to afford 685 mg (100%) of (R)-3-(tert-butoxycarbonylamino)-3-(4-(difluoromethoxy)phenyl)propyl methanesulfonate (388) containing some of the corresponding chloride.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][NH:3]1.P(Br)(Br)(Br)(Br)[Br:17]>ClCCCl.CC(O)=O>[Br:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=[O:15])[NH:4][N:3]=1
Reactant: O=C(O)c1ccc2c(=O)[nH][nH]c(=O)c2c1
Reactant: BrP(Br)(Br)(Br)Br
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(O)c1ccc2c(Br)n[nH]c(=O)c2c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
1,4-Dioxo-1,2,3,4-tetrahydro-phthalazine-6-carboxylic acid (91.0 g, 0.44 mol) was suspended in DCE (1.0 L) and phosphorus pentabromide (761.0 g, 1.77 mol) was added in three portions and the reaction heated to reflux for 24 hours. The reaction was cooled to RT and poured onto ice (2.5 kg) and the resulting precipitate filtered and washed with water to give the crude product (130.0 g). This crude material was suspended in HOAc (1.6 L) and heated to 125° C. for 2 h. The reaction was cooled to RT and poured onto ice (1.5 kg) and the resulting precipitate filtered. The solid was washed with water and dried to give the title compound (85 g, 73% yield) as a yellow solid. Tr=0.94 min, m/z (ES+) (M+H)+ 310 & 312
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:25]([S:29](Cl)(=[O:31])=[O:30])[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([S:29]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[CH:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)(=[O:31])=[O:30])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
In 50 ml of dimethylformamide were dissolved 1.14 g of 2-amino-5-[pyridazin-3(2H)-on-6-yl]indane and 0.8 g of triethyl amine, and 1.25 g of n-butanesulfonyl chloride was added thereto. The mixture was stirred at 50° C for 30 minutes and then stirred at room temperature overnight. The solvent was removed, water was added to the residue, and crystals precipitated were collected by filtration. The resulting crystals were recrystallized from methanol to obtain 1.27 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccccc1C#N
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and 1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide is heated at 150°-155° C. for 40 minutes. The cooled mixture is poured into ice-water and the mixture filtered to give 2 g of methyl [N-(2-cyanophenyl)amino]acetate as a yellow solid, m.p. 70°-78° C. The preceding compound (2.0 g) is added to a solution of 0.5 g of sodium methoxide in 50 ml of methanol. The mixture is shaken under an atmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated. Water is added to the residue and the mixture filtered to give 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-3-one as a yellow solid, m.p. 167°-170° C.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1>>[CH3:13][C:12]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2nc(NCc3ccccn3)nc(C)c2C)c1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using m-toluidine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.07 (s, 3H), 2.28 (s, 3H), 2.33 (s, 3H), 4.74 (d, J=3.0 Hz, 2H), 5.79 (bs, 1H), 6.31 (s, 1H), 6.84 (d, J=8.1 Hz, 1H), 7.10-7.17 (m, 2H), 7.30-7.40 (m, 3H), 7.60 (t, J=7.8 Hz, 1H), 8.57 (d, J=2.8 Hz, 1H); MS (ESI) m/z 320.7 (M+1)+.
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20](=[O:28])[CH:19]=1)[C:12](OCC)=O)=[O:10]>CO.O>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][CH3:27])[C:20](=[O:28])[CH:19]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: CCCCn1ccc(CC(C=O)C(=O)OCC)cc1=O
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCCCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Temperature: 0 °C

Procedure:
To a stirred solution of sodium (6.77 g) in methanol (120 ml) was added nitroguanidine (27.25 g. containing 25% water) and methanol (30 ml). The mixture was refluxed for 45 minutes and then was added dropwise ethyl α-formyl-β-(N-n-butyl-2-oxo-4-pyridyl)propionate (54.85 g) in methanol (150 ml) over 90 minutes. The reaction mixture was refluxed for 23 hours and evaporated under reduced pressure to give an oil. This oil was dissolved in water (200 ml) and extracted with chloroform (3×65 ml). The combined chloroform extracts were washed with water (2×35 ml). The combined aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid whereupon a brown oil came out of solution. This was dissolved with warming in isopropanol (75 ml) and cooled at 0° C. overnight to yield after filtration, washing and drying in vacuo 2-nitroamino-5-(1-n-butyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one as a solid (19.46 g), recrystallisation from aqueous acetic acid gave material with m.p. 198°-201° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:19]O>C(OCC)(=O)C>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:19])=[O:8])=[CH:10][CH:11]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (1 g, 7 mmol) in MeOH (10 mL) was added dropwise concentrated H2SO4 (1 mL). Upon completion of addition, the reaction mixture was heated to 60° C. where it stirred for 12 h. After this time, the reaction mixture was concentrated under reduced pressure to yield a residue. The residue was dissolved in ethyl acetate and then carefully neutralized with a 10% NaOH solution. The organic layer was separated and washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 4-(aminomethyl)benzoate (2.5 g) as a white solid. LCMS Method O: retention time 0.49 min, [M+1]=166.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1.ClC1C=CC=C(C(OO)=[O:47])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:47])=[CH:4][C:3]=1[N:15]1[C:19]([NH:20][CH3:21])=[CH:18][C:17]([O:22][C:23]([F:38])([F:37])[C:24]([F:35])([F:36])[C:25]([F:33])([F:34])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: ClC(Cl)Cl
Product: CNc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
0.25 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methylamino-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole was dissolved in 10 mL of chloroform, and 95 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.23 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methylamino-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=O)[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].[CH2:25](C1N(CCCC(OCC)=O)C2C3N=CC=CC=3N=CC=2N=1)CCC>>[CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:25])[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Reactant: CCCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(C)=O

Procedure:
A modified version of the general methods described in Parts D-G of Example 4 was sequentially followed with ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate (6.0 g, 18.4 mmol) used in lieu of ethyl 4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyrate as the starting substrate. Isolation after the last step of the sequence afforded 6.06 g of crude 5-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)pentan-2-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[CH2:28]Cl)=[O:22]>[I-].[K+].CC(=O)CC>[CH3:19][O:20][C:21]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1)=[O:22]
Reactant: COC(=O)c1ccsc1CCl
Reactant: OCCCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccsc1COc1ccc(CCCCO)cc1
Yield: 65.4 %

Procedure:
To a stirred mixture of 8.31 g of 4-(4-hydroxyphenyl)butanol, 20.73 g of milled anhydrous potassium carbonate, 0.5 g of powdered potassium iodide and 200 ml of 2-butanone was added, over a few minutes, a solution of 9.45 g 2-chloromethyl-3-thiophenecarboxylic acid methyl ester and 20 ml of 2-butanone. The suspension was heated under reflux overnight, with stirring. The reaction mixture was filtered while hot, and the filter cake was washed with 2-butanone. The combined filtrate was concentrated. The residue was dissolved in 200 ml of dichloromethane, and the solution was washed with 200 ml of 5% sodium hydroxide solution, 200 ml of water and then saturated brine solution. The dried (over anhydrous sodium sulfate) organic phase was filtered and concentrated. The residue was purified by high-pressure liquid chromotography (Water Associates Prep LC/System 500; two silica gel columns; sample applied as a filtered solution in 200 ml of dichloromethane using a little pure dichloromethane to flush the material onto the column before elution; eluted with 10% (V/V) ethylacetate in dichloromethane; 150 ml/min. flow rate maintained until major component began to elute, then increased flow rate to 250 ml/min; U.V. and refractive index detectors used) to afford 10.38 g (65.3%) of product, m.p. 58°-60° C., after concentration and trituration of the eluents with hexane.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-:27])=[O:26])[CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:25]([C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=1)[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Boc-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (2.35 g) was dissolved in CH2Cl2 (60 mL) and TFA (20 mL) was added. After stirring for 1 h at RT, the mixture was concentrated in vacuo to yield 2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine as an oil that solidified upon standing. The material was used as is without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:5][CH:4]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1>C(Cl)Cl>[C:31]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]3[C@H:14]4[C@H:24]([CH2:25][CH2:26][C@:9]23[CH3:10])[C@:22]2([CH3:23])[C@H:17]([N:18]([CH3:28])[C:19](=[O:27])[CH2:20][CH2:21]2)[CH2:16][CH2:15]4)=[CH:29][CH:30]=1)(=[O:33])[CH3:32]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc(N)cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(O[C@H]2CC[C@H]3[C@@H]4CC[C@H]5N(C)C(=O)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 17β-(4-aminophenoxy)-4-methyl-5α-4-azaandrostan-3-one hydrochloride (7 mg) in CH2Cl2 (100 μl) was added acetic anhydride (30 μl) followed by adding pyridine (50 μl). The mixture was stirred at room temperature for 1 hr and then concentrated to dryness. The residue was purified via a silica gel plate developed with 5% MeOH-EtOAc (Rf=0.3) to give the title product, mp. 340° C.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[C:28]([O:37][CH3:38])[C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][N:18]([C:23]3[C:32]4[C:27](=[C:28]([O:37][CH3:38])[C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH2:17][CH2:16]2)[C:4]1=[O:21]
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2c(OC)c1OC
Yield: 25 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 1.06 g (3.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-6,7,8-trimethoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 365.1 mg (yield: 25%) of Compound 86 was obtained as white crystals.
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([CH3:36])=[CH:13][N:12]=1)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([CH:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:15]2[C:14]([CH3:36])=[CH:13][N:12]=[C:11]([NH2:10])[CH:16]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: Cc1cnc(NC(=O)OC(C)(C)C)cc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cnc(N)cc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
To an ethanol (5 ml) solution of t-butyl[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-methylpyridin-2-yl]carbamate (200 mg, 0.393 mmol) was added concentrated hydrochloric acid (6 ml). The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was recrystallized from hexane:ethyl acetate to give the title compound (125 mg, 0.306 mmol, 78%) as a white powder.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24][CH:25]([C:29](O)=[O:30])[C:26](O)=[O:27])[CH:15]([CH3:17])[CH3:16]>>[OH:30][C:29]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:26](=[O:27])[C:25]=1[S:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: CC(C)Cc1ccccc1SC(C(=O)O)C(=O)O
Product: CC(C)Cc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.96 g, 10.20 mmol) and diethyl ester of [(2-isobutylphenyl)thio]propanedioic acid (1.64 g, 5.1 mmol). m.p. 195° C. 1H NMR (400 MHz, DMSO-d6) δ 0.83 (d, 6H), 1.64 (m, 1H), 2.39 (d, 2H), 6.89 (s, 1H), 7.06 (s, 4H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: C(O[C:6]([NH:8][NH:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([C:16]2[O:20][N:19]=[C:18]([CH:21]([CH3:23])[CH3:22])[N:17]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.[Cl:24][C:25]1[C:30](C=O)=[C:29](Cl)[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:24][C:25]1[N:26]=[CH:27][N:28]=[C:29]2[N:9]([C@H:10]3[CH2:11][CH2:12][C@@H:13]([C:16]4[O:20][N:19]=[C:18]([CH:21]([CH3:22])[CH3:23])[N:17]=4)[CH2:14][CH2:15]3)[N:8]=[CH:6][C:30]=12
Reactant: CC(C)c1noc([C@H]2CC[C@@H](NNC(=O)OC(C)(C)C)CC2)n1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)c1noc([C@H]2CC[C@@H](n3ncc4c(Cl)ncnc43)CC2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A solution of N′-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-hydrazinecarboxylic acid tert-butyl ester (Intermediate 13; 309 mg, 2.03 mmol) in tetrahydrofuran (3 mL) was added to a cooled (0° C.) solution of 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16; 169 mg, 0.95 mmol) and diisopropylethylamine (337 μL, 1.9 mmol) in tetrahydrofuran (2 mL), and the mixture was stirred at 0° C. for 30 min and then at room temperature for 5 h. The mixture was filtered, and the filtrate was washed with brine. The aqueous layer was extracted with methyl tert-butyl ether and the organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, evaporated, and held under high vacuum. Toluene (10 mL) was added and the mixture was held at 110° C. overnight. The solvent was evaporated and the residue was purified on a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cis-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (211 mg, 64%).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[Br:13][C:11]1[CH2:12][C:4]23[C:5](=[CH:9][CH:10]=1)[O:6][CH2:7][CH2:8][CH:2]=[C:3]2[N:21]=[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]13
Reactant: Nc1ccccn1
Reactant: O=C1c2cc(Br)ccc2OCCC1Br
Product: BrC1=CC=C2OCCC=C3N=C4C=CC=CN4C32C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.2 %

Procedure:
A mixture of compound 4,7-dibromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one (330 mg, 1.031 mmol) and pyridin-2-amine (97 mg, 1.031 mmol) was stirred at 60° C. for 3 hours. The mixture was then purified using chromatography (petroleum ether:ethyl acetate=3:1) to provide 2-bromo-6,7-dihydrobenzo[2′,3′]oxepino[4′,3′:4,5]imidazo[1,2-a]pyridine (40 mg, yield: 12.3%). 1H-NMR (CDCl3, 400 MHz) δ 8.54 (d, J=2.8 Hz, 1H), 7.78 (d, J=6.8 Hz, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.14˜7.24 (m, 2H), 6.78˜6.88 (m, 2H), 4.42 (d, J=5.2 Hz, 2H), 3.21 (d, J=5.2 Hz, 2H). MS (M+H)+: 315/317.