Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.O>[I:1][C:2]1[CH:3]=[C:4]([NH:5][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:12]([C:11]([F:10])([F:21])[F:22])[CH:13]=2)[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I

Procedure:
A solution of 3-iodo-4-methylaniline (1.22 g, 5.25 mmol), 3-(trifluoromethyl)benzoic acid (0.95 g, 5 mmol), HOBt (0.68 g, 5 mmol), and EDCl (1.05 g, 5.5 mmol) in THF (20 mL) was stirred overnight at rt. Water was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then subjected to silica gel column chromatography (3:1 hexane/ethyl acetate) yielding the desired product.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[C:39]([F:45])[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1F
Yield: 64.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.0 g) as starting compound, potassium carbonate (1.5 g) and 6-bromo-1-(3-fluoro-4-methoxyphenyl)-1-hexanone (0.94 g) were reacted and treated in the same manner as in Example 172 to give 0.90 g of 4-amino-5-chloro-N-((1-(6-(3-fluoro-4-methoxyphenyl)-6-oxohexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: ClC1C=CC=CC=1Cl.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24](=[O:25])[CH:23]3[CH:18]([CH2:19][CH:20]=[C:21]4OC5C=CC=CC=5[CH:22]43)[C:17]2=[O:33])=[CH:12][CH:11]=1.C([C:36]1[C:42](=O)[C:41](Cl)=[C:40](Cl)[C:38](=[O:39])[C:37]=1C#N)#N>C(Cl)(Cl)Cl>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24](=[O:25])[C:23]34[C:37]5[CH:36]=[CH:42][CH:41]=[CH:40][C:38]=5[O:39][C:22]3=[CH:21][CH:20]=[CH:19][CH:18]4[C:17]2=[O:33])=[CH:12][CH:11]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Cc1ccc(N2C(=O)C3CC=C4Oc5ccccc5C4C3C2=O)cc1
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(N2C(=O)C3C=CC=C4Oc5ccccc5C43C2=O)cc1
Yield: 36.2 %

Procedure:
15 ml of o-dichlorobenzene was added to a mixture of 0.50 g of 2-(4-methylphenyl)-3a,4,10b,10c-tetrahydro-1H-benzofuro[3,2-e]isoindole-1,3(2H)-dione and 0.75 g of DDQ. The mixture was refluxed for 4 hours. The reaction mixture was mixed with 50 ml of chloroform. The resulting mixture was washed with an aqueous 10% potassium carbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from methanol to obtain 0.18 g (yield: 36%) of 2-(4-methylphenyl)-1H-benzofuro-[3,2-d]isoindole-1,3(2H)-dione as light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([OH:14])=O.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C(Cl)Cl.O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[C:12]([N:48]1[CH2:47][CH2:46][N:45]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:50][CH2:49]1)=[O:14]
Reactant: O=C1COc2c1ccc(O)c2C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(O)ccc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.1 %

Procedure:
A solution of 6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylic acid (0.060 g, 0.31 mmol) in methylene chloride (2.0 mL) was successively added with 1-hydroxybenzotriazole monohydrate (0.008 g, 0.052 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.086 g, 0.45 mmol), and N-Boc-piperazine (0.067 g, 0.36 mmol), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was added with water, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→90:10)) to obtain tert-butyl 4-(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-carbonyl)piperazine-1-carboxylate (0.072 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:18]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To solution of (2,4-dichloro-phenoxyacetic acid (0.200 g, 0.9 mmol), 2-amino isonicotinic acid methyl ester (207 mg, 1.36 mmol) and DMAP (0.222 g, 1.81 mmol) in DMF 13 mL was added PyBOP (946 mg, 1.81 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9-4:6) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.229 g, 71% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8].[C:23](Cl)(=[O:25])[CH3:24]>>[C:23]([O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=1[Cl:20])=[O:8])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1O
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Cl
Yield: 34 %

Procedure:
Using 5-chloro-N-[2-chloro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide and acetyl chloride as the raw materials, the same operation as the example 96 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH:12]([NH2:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][CH:12]([NH:14][C:22](=[O:23])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(N)CCCc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CCCc1ccc(Cl)c(Cl)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
Intermediate 18A (0.500 g, 2.15 mmol) and sodium carbonate (0.50 g, 4.7 mmol) were combined in THF (10 mL) and treated with benzyl chloroformate (0.31 mL, 2.2 mmol) drop wise over 15 min. The reaction mixture was stirred at rt for 18 h. The mixture was concentrated in vacuo, diluted with DCM and washed with saturated Na2CO3 twice, brine and the organic portion dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-50%, column 40 g) to give benzyl 5-(3,4-dichlorophenyl)pentan-2-ylcarbamate (440 mg, 1.20 mmol, 56.0%) as a clear oil. HPLC/MS (HPLC Method L): RT=2.32 min, [M+1]+ =366.0. The racemates were separated on chiral prep HPLC (chiral AD 10 micron 4.6×250 mm, 15 min 5% isocratic. A=EtOH/MeOH (50/50). B=Heptane; retention time=9.8 min) to afford Intermediate 18B (220 mg, 0.600 mmol, 28.0%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07 (3H, d), 1.32-1.41 (2H, m), 1.51-1.62 (2H, m), 2.42-2.57 (2H, m), 3.62-3.75 (1H, m), 4.42 (1H, br. s.), 5.02 (2H, s), 6.91 (1H, d, J=7.5 Hz), 7.17 (1H, br. s.), 7.23-7.31 (6H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:28])[CH:12]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[N:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc([N+](=O)[O-])cc2)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(N)cc2)nc1
Yield: 100.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-nitro-phenyl)-propionylamino]-nicotinic acid methyl ester (300 mg, 0.75 mmol) in ethyl acetate (30 mL) and methanol (5 mL) was treated with 10% palladium on activated carbon (30 mg). The reaction mixture was shaken under 60 psi of hydrogen gas at 25° C. for 16 h. The catalyst was then removed by filtration through a pad of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 6-[2-(4-amino-phenyl)-3-cyclopentyl-propionylamino]-nicotinic acid methyl ester (277.4 mg, quant) as a pale yellow glass: mp 65-68° C.; EI-HRMS m/e calcd for C21H25N3O3 (M+) 367.1893, found 367.1899.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH:17]=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O.[NH2:20][NH2:21]>C(O)C>[NH2:20][N:21]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: O=CNc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1
Yield: 95 %

Procedure:
To a solution of 2.7 parts of 5-chloro-2-formamidobenzophenone in 40 volume parts of ethanol is added 2.5 volume parts of hydrazine hydrate, followed by refluxing for 20 minutes. After cooling, the resulting crystals are recovered by filtration and washed with ethanol and ether and then dried. This procedure gives 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-phenylquinazoline as crystals melting at 189° to 192° C. Yield: 95%.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:32]=[O:33])(=[O:3])[CH3:2].O.P([O-])(O)(O)=[O:36].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:32]([OH:36])=[O:33])(=[O:3])[CH3:2]
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.4 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (60 mg, 0.13 mmol) in t-butanol (0.5 mL) and water (0.5 mL) solution was added sodium dihydrogenphosphate monohydrate (73 mg, 0.53 mmol), 2-methyl-2-butene (0.090 mL, 0.80 mmol) and sodium chlorite (72.2 mg, 0.80 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid (13 mg, 21% yield) as a yellow solid. HR-MS m/e calcd for C25H25N1O8 (M−H+) 468.1653, found 468.1657; 1H NMR (300 MHz) compatible.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:41])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:42].O1CCOCC1>O1CCOCC1>[ClH:42].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([N+:38]([O-:40])=[O:39])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:41])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc([N+](=O)[O-])ccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2cc([N+](=O)[O-])ccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-nitro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The resulting solid was filtered to give 24 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-6-nitroquinolin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C:17](=O)[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[NH2:29][O:30][CH2:31][CH3:32].Cl>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16]/[C:17](=[N:29]\[O:30][CH2:31][CH3:32])/[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: CCON
Reactant: C[C@]12CCCCC1C(=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: Cl
Product: CCO/N=C1\C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Yield: 90 %

Procedure:
17,17-Bis(ethylendioxy)-6(E)-ethoxyiminoandrostane was prepared in 90% yield starting from 3,3:17,17-bis(ethylendioxy)androstan-6-one and NH2OCH2CH3.HCl by the procedure described above in Prepn. 21. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.99 (2H, q), 3.92-3.75 (8H, m), 3.25 (1H, dd), 2.25 (1H, m), 1.99-0.94 (18H, m), 1.17 (3H, t), 0.82 (3H, s), 0.75 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]=[CH:21][C:22]1[CH:30]=[CH:29][C:27]([OH:28])=[C:24]([O:25][CH3:26])[CH:23]=1.CN(C)C=O>O>[CH3:26][O:25][C:24]1[CH:23]=[C:22]([CH:30]=[CH:29][C:27]=1[O:28][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH:21]=[O:20]
Reactant: ClCc1csc(N2CCOCC2)n1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1csc(N2CCOCC2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A mixture of 4-(4-chloromethyl-1,3-thiazol-2-yl)morpholine (1.00 g), potassium carbonate (0.64 g), vanillin (0.70 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (1.33 g, 86%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CS(C)=O>[N:11]1([C:8]2[N:7]=[C:6]([C:17]3[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=3)[N:5]=[C:4]3[C:9]=2[N:10]=[C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:3]3[CH2:24][CH:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CCOC4)c3n2)cn1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CCOC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
Dimethyl sulfoxide (1 ml) was added to a mixture of 5-[8-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.24 mmol) and morpholine (63 μl, 0.72 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was cooled and then partitioned with chloroform and water, and the organic layer was washed again with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel chromatography (chloroform:methanol=10:0 to 25:1 to 20:1) to give the title compound (75 mg, 67%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[N:32]1([CH2:37][C@@H:38]2[CH2:42][CH2:41][CH2:40][NH:39]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:30])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[CH2:37][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: C1CN[C@H](CN2CCCC2)C1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC[C@H]1CN1CCCC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with (S)-2-(1-pyrrolidinylmethyl)pyrrolidine as in General Procedure 10 to give the title compound. LCMS: m/z=583.96 (M+H+); retention time=0.58 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][O:10][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: OCc1c(F)cccc1F
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1COc1ccccn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 2 ml (18.0 mmol) of (2,6-difluorophenyl)methanol in 15 ml of dry tetrahydrofuran stirred at 0° C. was admixed with 865.9 mg (21.6 mmol) of sodium hydride (60% in mineral oil), followed by 1.72 ml (18.0 mmol) of 2-bromopyridine. The resulting solution was stirred at room temperature for 15 h. The reaction mixture was diluted with water (15 ml) and extracted with dichloromethane (2×20 ml). The organic phase was removed, dried with a phase separation cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 800 mg (15% of theory, 77% pure) of the target compound.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CC1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (500 mg, 1.67 mmol, 1.00 equiv), 2-methylpyrrolidine (285 mg, 2.92 mmol, 2.00 equiv), potassium carbonate (693.8 mg, 4.01 mmol, 3.00 equiv), N,N-dimethylformamide (6 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 12×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 590.7 mg (92%) of methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil. Then the isomer was sent for chiral-prep-HPLC to get the product of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (193.6 mg).
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH3:22])[N:6]([CH2:7][CH:8]2[O:10][CH2:9]2)[C:5](=[O:11])[C:4]2([CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]2)[O:3]1.C(O)=[O:24]>>[CH3:1][C:2]1([CH2:21][CH3:22])[N:6]([CH2:7][CH:8]([OH:24])[CH2:9][OH:10])[C:5](=[O:11])[C:4]2([CH2:16][C:15]([CH3:17])([CH3:18])[NH:14][C:13]([CH3:19])([CH3:20])[CH2:12]2)[O:3]1
Reactant: CCC1(C)OC2(CC(C)(C)NC(C)(C)C2)C(=O)N1CC1CO1
Reactant: O=CO
Product: CCC1(C)OC2(CC(C)(C)NC(C)(C)C2)C(=O)N1CC(O)CO
Reaction time: 2 h

Procedure:
50 g of 2,7,7,9,9-pentamethyl-2-ethyl-3-(2,3-epoxypropyl)-1-oxa-3,8-diaza-spiro[4.5]decan-4-one in 200 g of formic acid were boiled under reflux for 4 hours. The formic acid was removed by distillation in vacuo and the residue was boiled for 2 hours in 100 ml of 10% strength NaOH. An oily layer was formed, this was separated off and it solidified after a little time. The product was pulverized, washed with water and dried.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH2:13][N:12]1C(OCC1C=CC=CC=1)=O)[CH2:8]2>O1CCCC1.[C].[Pd]>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[N:11]1[C:14](=[O:15])[CH2:13][NH:12]1)[CH2:10]2
Reactant: O=C(OCc1ccccc1)N1CC(=O)N1C1C2CC3CC(C2)CC1C3
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1CNN1C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 10 h
Yield: 56.8 %

Procedure:
A solution of benzyl 2-(adamantan-2-yl)-3-oxo-1,2-diazetidine-1-carboxylate (100 mg, 0.29 mmol) in tetrahydrofuran (5 mL) was added with 10% palladium carbon (catalyst amount), and under a hydrogen atmosphere, the resultant was stirred at room temperature for 10 hours. The reaction solution was filtered using celite, concentrated in vacuo, and the obtained residue was purified using silica gel chromatography (hexane:ethyl acetate=1:1), and 2-(adamantan-2-yl)-1,2-diazetidin-3-one (34.0 mg, 56.8%) was obtained as a colorless oil.