Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:8]([CH2:9][CH2:10][CH3:11])[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][C:5]=1[C:19]([NH2:21])=[O:20].[O:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:12]([C:7]1[N:8]([CH2:9][CH2:10][CH3:11])[C:4]([NH:3][C:26](=[O:22])[C:25]2[CH:11]=[CH:10][CH:9]=[CH:23][C:24]=2[O:20][CH2:19][CH3:5])=[C:5]([C:19]([NH2:21])=[O:20])[N:6]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1CCOC1
Reactant: CCCn1c(Cc2ccccc2)nc(C(N)=O)c1N
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(Cc2ccccc2)nc(C(N)=O)c1NC(=O)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
Sodium hydride (48 mg, 60% dispersion in mineral oil, 1.2 mmol) was added to a solution of 5-amino-2-benzyl-1-n-propylimidazole-4-carboxamide (Preparation 2; 200 mg, 0.77 mmol) in tetrahydrofuran (5 mL), and the mixture stirred for 3 hours at room temperature. The prepared solution of acid chloride (from (i) above) was then added and the reaction stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure, the residue partitioned between dichloromethane and water, and the layers separated. The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel twice, using an elution gradient of dichloromethane: methanol (100:0 to 95:5) to afford the title compound (114 mg, 36%).
Reaction SMILES: C[O-].[Na+].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CO>[CH2:14]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCC(C(=O)OC)C(=O)OC
Yield: 78.3 %

Procedure:
350.1 g of 30 percent sodium methylate solution in methanol were diluted with 550 ml of methanol under nitrogen and while stirring. 264.2 g of dimethyl malonate were added dropwise. After warming the suspension to 40° 321.0 g of 1-bromohexane were added dropwise. After stirring at 40° for 1 hour, under reflux for 2 hours, at 65°-69° for 2.5 hours and cooling the suspension to room temperature water was added and the mixture was stirred. The organic phase was separated. The aqueous phase was extracted with methylene chloride, the combined organic extracts were dried and filtered, the filter cake was washed with methylene chloride and the combined filtrates were concentrated. After distillation of the product there were obtained 329.3 g (78.3%) of dimethyl n-hexylmalonate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[NH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][NH:17][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)OC(=O)c1cccc(CCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of tert-butyl 3-(chloromethyl)benzoate (25.3 g) in N,N-dimethylformamide (250 mL) were added tert-butyl glycinate hydrochloride (37.4 g) and potassium carbonate (61.7 g), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (23.0 g).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([O:21]CC)=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:26](CCN)CC)C.C(N(C(C)C)CC)(C)C>CCOCC>[C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][N:9]([CH2:18][C:19]([NH2:26])=[O:21])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CCN(CC)CCN
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Cn1cc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 18 h

Procedure:
A mixture of 10 g (0.033 mol) of ethyl 3,4-diphenyl-1H-pyrazole-1-acetate, 6.9 mL (0.049 mol) of diethylaminoethylamine and 39 mL of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. The reaction was stripped, the residue taken up in about 300 mL of ether and washed twice with water. The ether layer was extracted twice with a total of 150 mL of cold water containing 20 mL of 10% HCl. The combined water extracts were washed once with ether, colled, made basic with solid sodium carbonate, extracted several times with methylene dichloride, dried over sodium sulphate, treated with decolorizing carbon, filtered and stripped. The oily red residue was crystallized from ether to yield 6.86 g of N-[2-diethylamino)ethyl]-3,4-diphenyl-1H-pyrazole-1-acetamide, mp 80°-83° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.BrBr.[Br:12][C:13]1[CH:14]=[C:15]([Cl:20])[N:16]=[N:17][C:18]=1[NH2:19].O>C(Cl)(Cl)Cl>[Br:12][C:13]1[C:18]2[N:17]([CH:5]=[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[N:19]=2)[N:16]=[C:15]([Cl:20])[CH:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nnc(Cl)cc1Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)Cc1cn2nc(Cl)cc(Br)c2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetoacetate (2.55 mL, 20.0 mmol) was dissolved in CHCl3 (5 mL) and then the solution was cooled to 0° C. Bromine (1.03 mL, 20.0 mmol) in CHCl3 (6 mL) was added dropwise and then the reaction was stirred at 0° C. for 2 h. The reaction was warmed to rt and stirred for 16 h. The headspace of the reaction vessel was purged with air to remove HBr, and then the reaction was stirred an additional 2 h open to air. The reaction was washed with ice-cold water (20 mL) and then the aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with brine and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was placed in a 100 mL round bottom flask equipped with a stir bar and then dry DMF (10 mL) was added. 5-Bromo-3-chloro-6-aminopyridazine (2.08 g, 10.0 mmol) was added and then the reaction was stirred at rt for 4 d. The reaction was poured into water (50 mL) and then the mixture was extracted with EtOAc (3×30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), and then dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on an 80 g SiO2 pre-packed column eluting with 0-20% EtOAc/DCM to afford the title compound 28a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.05 (s, 1H), 7.35 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.95 (s, 2H), 1.30 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C10H9BrClN3O2: 318.0 (M+H). Found: 318.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>>[F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[C:5]2[O:9][CH:8]([CH2:10][NH:11][C:33](=[O:34])[O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:7][C:6]=2[CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(F)cc(-c3ccccc3C(F)(F)F)c2O1)OCc1ccccc1

Procedure:
Treatment of (±)-1-{5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.87 g, 5.38 mmol) with diisopropylethylamine (1.74 g, 13.4 mmol) and benzyl chloroformate (1.01 g, 5.92 mmol) following the procedure described for Intermediate 12 provided 2.03 (85%) of (±)-benzyl {5-fluoro-7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a white solid. Rf=0.69 (silica, ethyl acetate:hexanes 1:9); mp 76-80° C.; Anal. calcd. for C24H19F4NO3: C, 64.72; H, 4.3; N, 3.14. Found: C, 65.01; H, 4.3; N, 2.99.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 4-hydroxy-benzonitrile (1 g, 8.395 mmol) in dimethylformamide (10 mL) were added potassium carbonate (2.321 g, 16.79 mmol) and ethyl bromoacetate (1.117 mL, 10.07 mmol), respectively. The reaction mixture was stirred at room temperature for 23 h. It was taken in ethyl acetate and diethyl ether (1:1 ratio), and the solid was filtered off. The filtrate was washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo to afford ethyl (4-cyano-phenoxy)-acetate. It was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:37])C(=O)C1.C(OOC(=O)CCCCCCCCCCC)(=O)CCCCCCCCCCC>C(Cl)(Cl)(Cl)Cl>[Br:37][CH:22]1[C:9]2[C:10](=[N:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: O=C1CCC(=O)N1Br
Agent: CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-Butyl 2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 1)(25 g, 64.5 mmol) in carbon tetrachloride (645 ml) at RT under N2 was added NBS (13.78 g, 77 mmol) followed directly by lauroyl peroxide (0.257 g, 0.645 mmol) and the solution was heated at 60° C. for 4 h 15 mins. The mixture was filtered through filter paper and the filtrate was washed with sat. NaHCO3 (300 ml), 2 M Na2SO3 (300 ml) and sat. brine (300 ml). The solution was dried over MgSO4 and filtered, washing MgSO4 bed with DCM (100 ml). The solvent was removed in vacuo. The crude product was dissolved in diethyl ether (300 ml) and was allowed to stand at RT and placed in a fridge overnight. The resulting crystalline solid was isolated by decanting off the mother liquors. The crystals were washed with diethyl ether to afford the title compound. Further product was obtained by chromatography of the mother liquors eluting with iso-hexane/EtOAc to afford the title product;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:38][C:39]1([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42][CH2:41][CH2:40]1)(=O)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:38][C:39]1([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42][CH2:41][CH2:40]1)[CH:6]=[C:5]2[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)c(=O)c3ccc(Br)cc23)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 59.5 %

Procedure:
A solution of tert-butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate (Example 27b, 0.171 g) dissolved in DMF (5 mL) was treated with cesium carbonate (0.264 g) and [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl methanesulfonate [Archiv der Pharmazie (Weinheim, Germany), 2005, 338 (11), 522-7] (0.187 g) under nitrogen. The resulting mixture was stirred at 70° C. for 7 h. The reaction was diluted with water (300 mL), and extracted with diethyl ether (300 mL×3). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 6-12% ethyl acetate/isohexane) to afford the subtitle compound (0.153 g).
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:4][C:3]1=2.[NH:16]1[CH:20]=[C:19]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[N:18]=[CH:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O>C1COCC1>[CH:24]([O:23][C:21]([C:19]1[N:18]([CH:2]2[C:3]3[C:8](=[CH:7][C:6]([NH:12][C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=3)[CH2:9][CH2:10][CH2:11]2)[CH:17]=[N:16][CH:20]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2O
Reactant: CC(C)OC(=O)c1c[nH]cn1
Agent: COC(=O)N=NC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(c1)CCCC2n1cncc1C(=O)OC(C)C
Reaction time: 0.25 h

Procedure:
To a suspension of N-(5-hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetamide (0.553 g, 2.69 mmol) and isopropyl 4-imidazolecarboxylate (0.290 g, 1.88 mmol), which can be prepared as described in Example 1, in THF (10 mL) at 0° C. is added triphenylphosphine (1.415 g, 5.39 mmol) and dimethyl azodicarboxylate (40% wt. in toluene, 1.97 g, 5.39 mmol). The cooling bath is removed and the mixture is stirred for 15 min. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The resulting residue is purified by silica gel chromatography (elution with dichloromethane-methanol mixtures) to give 3-(6-acetylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; MS: (ESI) m/z 342.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.39 (d, J=6.3 Hz, 3 H), 1.40 (d, J=6.0 Hz, 3 H), 1.71-1.82 (m, 1 H), 1.83-1.92 (m, 1 H), 2.16 (s, 3H), 2.17-2.30 (m, 2 H), 2.86 (ddd, J=16.9, 8.3; 5.6 Hz, 1 H), 3.00 (dt, J=16.9, 5.6 Hz, 1 H), 5.25 (sept., J=6.3 Hz, 1 H), 6.30 (t, J=5.3 Hz, 1 H), 6.93 (d, J=8.3 Hz, 1 H), 7.34-7.36 (m, 2 H), 7.53 (d, J=1.8 Hz, 1 H), 7.74 (d, J=1.0 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>C(O)(=O)C>[N+:18]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2([C:11]#[N:12])[CH2:10][CH2:9][CH2:8]2)=[CH:2][CH:3]=1)([O-:20])=[O:19]
Reactant: N#CC1(c2ccccc2)CCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: N#CC1(c2ccc([N+](=O)[O-])cc2)CCC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-phenylcyclobutanecarbonitrile (5 g) and acetic acid (15 ml) and H2SO4 (10 ml) and KNO3 (1.1 eq) was stirred at 0° C. for 20 min. The mixture was warmed to RT and stirred for two hours. The mixture was poured on ice and stirred until all ice melted. The precipitate was filtered and recrystalized from EtOH to give 1-(4-nitrophenyl)-cyclobutanecarbonitrile. The above product (2 g) was mixed with Pd—C (10%, 800 mg) in EtOH (100 ml) and hydrogenated under H2 atmosphere for 1 hour. The reaction was filtered through Celite and evaporated to give 1-(4-aminophenyl)-cyclobutanecarbonitrile, Mass: (M+1) 172, which was used for next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13]Br)[CH2:3]1.[OH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:3]1
Reactant: Oc1cccnc1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc3cccnc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 3α-hydroxy-21-bromo-5β-pregnan-20-one-(300 mg, 0.76 mmol) in DMF (5 mL) was added 3-hydroxypyridine (215 mg, 2.27 mmol) and K2CO3 (313 mg, 2.27 mmol) and the mixture obtained was stirred at 25° C. for 0.5 h. The reaction mixture was then poured into a separatory funnel containing water (30 mL) and the mixture was extracted with EtOAc (3×35 mL). The combined extracts were washed with water (2×25 mL) and then dried over Na2SO4. Removal of the solvent in vacuo resulted in the crude product which was purified by flash chromatography over silica gel to yield the pure 3α-hydroxy-21-(pyrid-3-yl)oxy-5β-pregnan-20-one (50 mg); mp 63-66° C.; TLC Rf (MeOH:CH2Cl2 5:95)=0.5.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37](Cl)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:32][CH:31]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:27])([F:1])[F:28])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Reactant: Fc1ccc(N=C(Cl)c2ccccc2)cc1
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccc(F)cc3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(4-fluorophenyl)-benzimidoyl chloride (2.5 g, 9.15%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:11][C:12]1[O:13][C:14]([CH3:28])([CH3:27])[CH:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[S:16](=[O:19])(=[O:18])[N:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:29]C(C)([O-])C.[K+].CI>CN(C)C=O>[CH3:29][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH:15]2[C:14]([CH3:28])([CH3:27])[O:13][C:12]([NH:11][C@H:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:3][CH2:2][OH:1])=[N:17][S:16]2(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1c1ccc(O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C2C(C)(C)OC(N[C@@H](CCO)c3ccccc3)=NS2(=O)=O)cc1
Yield: 24.4 %

Procedure:
To a solution of 40 mg of 4-[2-((S)-3-hydroxy-1-phenylpropylamino)-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-1,4,3-oxathiazin-5-yl]phenol in 1 ml of N,N-dimethylformamide were added, at room temperature, 11 mg of potassium tert-butoxide and 28 mg of methyl iodide, and the reaction mixture was stirred at constant temperature for 3 hours. The reaction solution was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and lyophilized. This gave the product (10 mg) with a molecular weight of 418.5 g/mol (C21H26N2O5S); MS (ESI): m/e=419 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.C[O-].[Na+].CO.Br[CH2:15][CH2:16][CH2:17][Cl:18].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:15][CH2:16][CH2:17][Cl:18])=[N:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Sc1ccc(Cl)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ClCCCSc1ccc(Cl)cn1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 92.8 %

Procedure:
5-Chloropyridine-2-thiol (600 mg, 4.12 mmol) synthesized in Example (119a) was dissolved in methanol (15 mL), and 28% sodium methoxide/methanol solution (0.95 mL, 4.94 mmol) and 1-bromo-3-chloropropane (0.61 mL, 6.18 mmol) were added, followed by stirring at 60° C. for 1.5 hours. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and vacuum drying was carried out to afford the desired compound (849 mg, yield 92%) as a colorless oil.
Reaction SMILES: ClC1C=C(NC2C3C(=CC(OCCOC)=C(N)C=3)N=CN=2)C=CC=1F.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([N+:37]([O-])=O)[CH:35]=2)[N:30]=[CH:29][N:28]=1.[Cl:42][C:43]1[CH:51]=[CH:50][C:46]2[O:47][CH2:48][O:49][C:45]=2[C:44]=1[NH2:52]>>[Cl:42][C:43]1[CH:51]=[CH:50][C:46]2[O:47][CH2:48][O:49][C:45]=2[C:44]=1[NH:52][C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:40][CH3:41])=[C:34]([NH2:37])[CH:35]=2)[N:30]=[CH:29][N:28]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: COc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Agent: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Product: COc1cc2ncnc(Nc3c(Cl)ccc4c3OCO4)c2cc1N

Procedure:
Starting material: N4-(5-chlorobenzo[d][1,3]dioxol-4-yl)-7-methoxyquinazoline-4,6-diamine was prepared according to the same method of preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but the starting material were 4-chloro-7-methoxy-6-nitroquinazoline and 5-chlorobenzo[d][1,3]dioxolan-4-amine; other starting materials were prepared as example 1.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@H:26]([OH:29])[CH2:27][NH2:28]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][CH2:27][C@@H:26]([OH:29])[CH3:25])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C[C@H](O)CN
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(NC[C@H](C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 116 μL of S-(+)-1-amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield (S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide. MS (Q1) 397.4 (M)+.