Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.C([Li])CCC.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]2=[O:15])(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc[nH]c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cccc(O)c2=O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To stirred solution of 3-[(tert-butyldimethylsilyl)oxy]pyridin-2(1H)-one (1) (4.66 g, 20.7 mmol) in dry THF (150 mL), maintained at −78° C. under a dry nitrogen atmosphere is added n-butyl lithium (1.6 M solution in hexane, 21.0 mmol). After 20 minutes, 4-methylbenzenesulfonyl chloride (3.95 g, 20.7 mmol) is added as a THF solution. The solution is allowed to warm to room temperature over one hour, the water (10 mL) is added and the contents of the reaction vessel is extracted with EtOAc (3×), washed with brine (1×), dried over Na2SO4 and concentrated. The combined organic layers are dried over Na2SO4 and concentrated. The residue is taken up in ethanol (10 mL) and treated with conc. HCl (2 mL). The mixture is allowed to stir for 1 hour and the solvent is removed under reduced pressure to afford the desired compound as a white solid. 1H NMR (300 MHz, DMSO) δ 2.43 (s, 3H), 6.14 (t, J=6.9 Hz, 1H), 6.76 (dd, J=7.65 Hz, 1.5 Hz, 1H), 7.18 (dd, J=6.6 Hz, 1.8 Hz, 1H), 7.32 (d, J=7.3 Hz, 2H), 7.98 (d, J=7.9 Hz, 2H).
Reaction SMILES: [CH:1]1([C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2C=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2C=CC=CC=2)CCCCCC1.Cl[CH:30]([O:32]C(Cl)Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([C:8]2[CH:9]=[CH:12][C:13]([CH:30]=[O:32])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=Cc1ccccc1C1CCCCCC1
Reactant: ClC(Cl)OC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: c1ccc(C2CCCCCC2)cc1
Solvent: ClCCl
Product: O=Cc1ccc(C2CCCCCC2)cc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
Cycloheptylbenzaldehyde can be manufactured as follows: 200 ml of titanium tetrachloride are added dropwise, whilst stirring, to a solution of 200 g of cycloheptylbenzene in 600 ml of absolute methylene chloride under a nitrogen atmosphere at -10°C, and thereafter 132.5 g of dichloromethyl ether are added similarly at 0°C. The reaction mixture is then stirred for a further 30 minutes at 10°C and poured onto 3 kg of ice, and the whole is extracted twice with 500 ml of methylene chloride. The organic phases are washed with water, dried over sodium sulphate and evaporated to dryness in vacuo. Distillation of the evaporation residue in a high vacuum yields 4-cycloheptyl-benzaldehyde in the fraction boiling at 120-130°C/0.8 mm Hg.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:21])(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CI.Cl>O1CCCC1>[CH3:1][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:21])=[O:20]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 100 ml. of dry tetrahydrofuran containing 11.8 ml. of dry diisopropylamine and 55 ml. of 1.6M n-butyl lithium was added 5.4 ml. of n-heptanoic acid and the mixture allow to stir at room temperature for one hour. The resulting solution was cooled to 0° C. and 7.2 ml. of methyl iodide was added. The reaction was stirred at room temperature under nitrogen for 1.5 hours, and was then poured into 10% hydrochloric acid and extracted with diethyl ether (3×100 ml.). The extracts were combined, washed with 10% hydrochloric acid, water, 20% sodium bisulfite and a brine solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue, 5.61 g., dissolved in methanol containing 5.1 g. of potassium hydroxide. After stirring overnight the mehtanol was removed and the residue dissolved in 150 ml. of water. The aqueous layer was washed with ether (2×100 ml.) and acidified with 10% hydrochloric acid. The product was extracted with ether, washed with a 20% sodium bisulfite solution and brine and dried over magnesium sulfate. Removal of the ether gave 5.0 g. of the product as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1cccnc1Nc1ccc(Cl)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture of N2-(4-chlorophenyl)pyridine-2,3-diamine (64 mg, 0.291 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (61 mg, 0.32 mmol), HOAt (44 mg, 0.32 mmol), 4-methylmorpholine (70 μL, 0.641 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) in DCM (10 mL) was stirred at RT for 1 h then left standing at RT for 64 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried and concentrated in vacuo. The resulting {(S)-1-[2-(4-chlorophenylamino)pyridin-3-ylcarbamoyl]ethyl}carbamic acid tert-butyl ester, as a brown oil (136 mg), was dissolved in AcOH (5 mL) and heated at 70° C. for 4 h. After cooling to RT, the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic fraction was washed with water, followed by brine, dried (Na2SO4) and concentrated in vacuo. The resulting brown oil was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) to afford the title compound as an orange/brown oil (99 mg, 91% over two steps). LCMS (Method C): RT 3.33 min [M+H]+ 373.2.
Reaction SMILES: CCC.[OH:4][C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1.[Cl:11][CH2:12][CH2:13]O>O.[Cl-].[Zn+2].[Cl-]>[Cl:11][CH2:12][CH2:13][O:4][C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1
Reactant: N#CC1(O)CCC1
Reactant: OCCCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC
Solvent: O
Product: N#CC1(OCCCl)CCC1
Temperature: 90 °C
Yield: 20.1 %

Procedure:
Zinc chloride (36.03 g, 264 mmol) was fused using a propane torch while under vacuum. The molten salt was cooled and the evacuated flask was flushed with nitrogen. The flask was loaded with 1-hydroxycyclobutanecarbonitrile (15.10 g,) and 2-chloroethanol (17.7 g, 218 mmol) and stirred with heating (90° C.) for 20 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (1×150 mL, 4×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to an oil in-vacuo. The crude product was purified by vacuum distillation (b.p.12 85° C.) to give title compound (5.00 g, 31.3 mmol, 16.4% over two steps) as a clear liquid. 1H NMR (500 MHz, CDCl3) δ: 3.75 (2H, t, J=5.5 Hz), 3.65 (2H, t, J=5.6 Hz), 2.52-2.61 (2H, m), 2.31-2.43 (2H, m), 1.91-2.06 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:11]([C:21](=O)[C:22]([CH3:32])([CH3:31])[CH2:23][O:24]C3CCCCO3)=[C:10](O)[C:9]2=[O:35])=[CH:4][CH:3]=1.O.[NH2:37][NH2:38].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:11]3[C:21]([C:22]([CH2:23][OH:24])([CH3:32])[CH3:31])=[N:38][NH:37][C:10]=3[C:9]2=[O:35])=[CH:4][CH:3]=1
Reactant: NN
Reactant: COc1ccccc1C1C(C(=O)C(C)(C)COC2CCCCO2)=C(O)C(=O)N1c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1C1c2c(C(C)(C)CO)n[nH]c2C(=O)N1c1ccc(Br)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
A mixture of 1-(4-bromophenyl)-4-(2,2-dimethyl-3-tetrahydro-2H-pyrane-2-yloxypropionyl)-3-hydroxy-5-(2-methoxyphenyl)-1,5-dihydropyrrole-2-one (1.51 g, 2.77 mmol), hydrazine hydrate (0.204 mL, 4.16 mmol) and acetic acid (3 mL) was stirred at 95° C. for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution (150 mL) was poured into the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was triturated with ethyl acetate to give 5-(4-bromophenyl)-3-(1-hydroxymethyl-1-methylethyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (1.02 g, yield: 81%) as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:29]Br>O1CCOCC1.O>[Br:29][C:19]1[NH:20][C:21]2[C:17]([N:18]=1)=[C:16]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[N:15]=[C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[N:22]=2
Reactant: BrBr
Reactant: COc1ccc(CCNc2nc(N3CCOCC3)c3nc[nH]c3n2)cc1OC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CCNc2nc(N3CCOCC3)c3nc(Br)[nH]c3n2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of [2-(3,4-dimethoxy-phenyl)-ethyl]-(6-morpholin-4-yl-9H-purin-2-yl) amine (1.16 g, 3 mmol) in dioxane (75 mL) was added bromine (0.180 mL, 3.3 mmol) in dioxane (5 mL) dropwise over a period of 1 hour. The mixture was stirred at room temperature for additional 4 hours and diluted with water (25 mL) and extracted with EtOAc. The organic phase was washed with brine, water, dried over Na2SO4. The solvent was evaporated in vacuo and solid was washed with methanol to give (8-bromo-6-morpholin-4-yl-9H-purin-2-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine as a white solid (1.05 g, 75% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)[CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Brc1ccccn1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1cncc(-n2ccc3ccccc32)c1
Temperature: 100 °C
Yield: 14.6 %

Procedure:
Under an argon atmosphere, a solution of bromopyridine (1.7 mL, 17.6 mmol) in toluene (15 mL) is added to indole (2.0 g, 17.1 mmol), tris(dibenzylideneacetone)palladium (480 mg, 0.52 mmol), 2-(di-tert-butylphosphino)biphenyl (5.52 mg, 0.76 mmol), sodium tert-butoxide and toluene (25 mL) and the stirred mixture is heated at 100° C. for 48 hr. After cooling to room temperature, ether is added and the reaction mixture is filtered through Hi-Flo and concentrated. The residue is purified by chromatography eluting with pentane-25% ethyl acetate. Product containing fractions are combined and concentrated to afford 1-(pyridin-3-yl)-1H-indole (485 mg, 15%) as a yellow-brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4](N(C)C)=[O:5].CC1C=CC([N+]([O-])=O)=CC=1C(O)=O.S(Cl)([Cl:31])=O>>[CH3:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([Cl:31])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)N(C)C
Reactant: O=S(Cl)Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl

Procedure:
The preparation of 2,N,N-trimethyl-5-nitrobenzamide utilized the procedure described in U.S. Pat. No. 4,942,163. The reaction mixture of 2-methyl-5-nitrobenzoic acid (5 g, 27.6 mmol) and thionyl chloride (16.4 g, 138 mmol) was refluxed overnight. The excess thionyl chloride was removed by vacuum distillation to afford 2-methyl-5-nitro-benzoyl chloride as a solid residue. This material was dissolved in methylene chloride (30 mL) and added dropwise with stirring to a commercial 40% dimethylamine solution (30 g, 270 mmol) maintaining the temperature at 0 to 12° C. After complete addition, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried and concentrated. The residue was purified by column chromatography with n-hexane-ethyl acetate (3:1) to afford amide as a solid (5.46 g, 95%). The identity was verified by 1H NMR
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(N(CC)CC)C>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (689 mg) (starting compound A) and 4-t-butylphenylboronic acid (450 mg) (starting compound B) were dissolved in a mixed solution composed of dichloromethane (50 ml) and triethylamine (0.7 ml) to prepare a solution. Copper(II) acetate (450 mg) was added to the solution, and the mixture was stirred at room temperature for 16 hr. The mixture was filtered, and the filtrate was then concentrated to give a crude which was then purified by chromatography on silica gel to give the title compound (500 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.[CH3:19][NH:20][CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([N:20]([CH3:21])[CH3:19])=[O:10])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CN(C)C(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Bis-(4-chloro-phenyl)-acetic acid was reacted with dimethylamine following the procedure set out in Example 8D to give the title compound. LC/MS: (PS-A2) Rt 3.40 [M+H]+ 309.95.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH2:23].CO>ClCCl>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[N:23]([CH3:22])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(O)C(F)(F)F
Reaction time: 1 h
Yield: 77 %

Procedure:
In each of four parallel synthesis tubes equipped with a magnetic stir bar was placed 5-benzyloxy-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-pyran-4-one (0.90 g, 3.0 mmol), and a 2M methylamine solution in MeOH (5.5 mL, 11 mmol). The resulting solution was heated to reflux. The reaction was completed in 60 min. The solutions from the four reaction tubes were combined, and evaporated to dryness to give a semi solid mixture. The mixture was taken up in dichloromethane (15 mL) to give a thick solution. On standing, a solid product precipitated out to give the first crop of the title compound (2.90 g, 77% yield, HPLC Method 1 (Example 24); RT=13.0 min, HPLC purity (peak percent area): 99.5% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.64 (s, 1H), 7.37 (m, 5H), 6.49 (s, 1H), 5.38 (q, J=6.5 Hz, 1H), 4.97 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C@@H:8]([F:21])[CH2:7]1)=[O:5])C.[OH-].[Li+].C(O)(=O)C>CO>[C:4]([OH:5])(=[O:3])[CH3:6].[F:21][C@@H:8]1[C@H:9]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CC[C@@H](N[C@H](C)c2ccccc2)[C@@H](F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](N[C@@H]1CC[C@@H](C(=O)O)C[C@@H]1F)c1ccccc1
Yield: 122.6 %

Procedure:
A solution of ester (c) (1.5 g) in methanol (50 mL) was treated with lithium hydroxide (630 mg). After 2 hours acetic acid (1 mL) was added and the mixture was evaporated to dryness. Chromatography on silica eluting with 1:9:90 (acetic acid:methanol:dichloromethane) afforded an oil (1.02 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]3[O:19][CH2:20][O:21][C:15]=3[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:24][CH2:23][O:22][C:8]=3[CH:9]=2)[N:4]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CCO>[CH2:23]1[O:24][C:7]2[CH:6]=[C:5]3[C:10]([C:11]([C:13]4[CH:18]=[CH:17][C:16]5[O:19][CH2:20][O:21][C:15]=5[CH:14]=4)=[N:12][C:3]([CH2:2][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[N:4]3)=[CH:9][C:8]=2[O:22]1
Reactant: ClCc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Reactant: C1CNCCN1
Solvent: CCO
Product: c1cc2c(cc1-c1nc(CN3CCNCC3)nc3cc4c(cc13)OCO4)OCO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
A suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxy-phenyl)quinazoline (96 mg, 0.3 mmol) in EtOH (9 mL) was treated with piperazine (860 mg, 10 mmol). The mixture was stirred at rt for 15 h, then it was poured into ice cold dilute NaHCO3 solution. On standing at rt for 72 h the title compound was crystallized out as colorless plates. It was collected by filtration, washed with water, and dried to give 74 mg of solid; mp 73-76° C. 1H NMR (CDCl3) 7.37 (d, J=8.4, 1H), 7.16-7.24 (m, 3H), 6.97 (d, J=8.4, 1H), 6.14 (s, 2H), 6.07 (s, 2H), 3.95 (s, 2H), 2.97 (bs, 4H), 2.65 (bs, 4H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:25])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].Cl[CH2:27][O:28][CH2:29][CH3:30].C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:27][O:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOCCl
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@]32O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](OC(C)=O)CC[C@@]21C

Procedure:
A solution of 9.20 g of 3β-acetoxy-14β-hydroxyandrosta-5,15-dien-17-one (G. Groszek et al., Bull. Pol. Acad. Sci., Chem., 34, 1986, 313), 11 ml of ethyl chloromethyl ether, 54 ml of diisopropylethylamine in 750 ml of dichloromethane was heated at reflux for 24 hrs. The solution was then cooled and poured into 500 ml of aq. 8% citric acid solution. The lower layer was separated, washed with water, dried over sodium sulfate and avaporated to dryness. The crude product was purified by chromatography using cyclohexane/chloroform/acetone 80/10/10 as eluant to give 6.10 g of 3β-acetoxy-14β-ethoxymethoxyandrosta-5,15-dien-17-one as a white solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:29][C:30]1[S:34][CH:33]=[N:32][CH:31]=1>>[CH3:29][C:30]1[S:34][C:33]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[N:32][CH:31]=1
Reactant: Cc1cncs1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12f and 5-methylthiazole
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>>[N:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[NH:25][C:21]=1[CH2:20][S:1][C:2]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Product: O=c1c2ccccc2nc(SCc2nc3ccccc3[nH]2)n1-c1ccccc1
Yield: 39.3 %

Procedure:
The title compound was prepared in a yield of 39.3%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3- isobutyl-2-mercapto-4(3H)-quinazolinone and 2-chloromethylbenzimidazole in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]12[CH2:26][CH2:25][C:22]([C:27](O)=[O:28])([CH2:23][CH2:24]1)[CH2:21][CH2:20]2)=[O:18]>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([C:22]12[CH2:25][CH2:26][C:19]([C:17]([O:16][CH3:15])=[O:18])([CH2:20][CH2:21]1)[CH2:24][CH2:23]2)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C12CCC(C(=O)OC)(CC1)CC2

Procedure:
The product from Example 92B and 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (Oakwood) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.23-1.36 (m, 2H), 1.58 (s, 9H), 1.58-1.66 (m, 2H), 1.70-1.83 (m, 12H), 2.61-2.66 (m, 2H), 3.58 (s, 3H), 8.49 (s, 1H). (ESI+) m/z 407 (M+H)+. Anal. calcd. for C22H34N2O3S: C, 64.99; H, 8.43; N, 6.89. Found: C, 64.65; H, 8.24; N, 6.72.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH:33]=O)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.O1CCCC1.[CH3:40][NH:41][CH3:42].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][N:41]([CH3:42])[CH3:40])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CC3)c2)c(C=O)c2c(=O)[nH]ncc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cn[nH]c(=O)c12
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To 133 mg (0.270 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 10-(a) and 112 mg of Molecular sieve (3A) was added 5 ml of tetrahydrofuran solution containing 2M dimethylamine at room temperature, and the mixture was stirred for 10 minutes. Then, 156 mg (0.740 mmol) of sodium triacetoxyborohydride was added to the mixture, and the mixture was stirred for further 17 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; ethyl acetate→chloroform:methanol=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 74 mg of the title compound as a pale yellowish solid. (Yield: 53%)