Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@@H:3]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.CN1CCOCC1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](Cl)=[O:26]>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25]([N:2]([C@@H:3]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1])=[O:26]
Reactant: CN[C@H](CN1CCCC1)C(C)(C)C
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(Cl)c1)[C@H](CN1CCCC1)C(C)(C)C
Yield: 74.4 %

Procedure:
To a solution of (S)—N,3,3-trimethyl-1-(pyrrolidin-1-yl)butan-2-amine (Compound M1) (75 mg, 0.41 mmol) in DMF (1.5 mL) was NMM (0.049 mL, 0.45 mmol) and 3,4-dichlorobenzoyl chloride (0.074 mL, 0.53 mmol) added. The resultant mixture was stirred at rt overnight. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (109 mg, 75%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6) δ 0.97, 1.35-1.99, 2.07-2.43, 2.52-2.73, 2.93-3.18, 4.57, 6.86-7.18, 7.18-7.37, 7.37-7.61, 7.61-7.88. Total no of protons: 26. HRMS (M+H)+: calculated 357.1500. found 357.1470.
Reaction SMILES: O1CCOCC1.[CH2:7]([S:9]([N:12](S(CC)(=O)=O)[C:13]1[C:14]([Cl:33])=[CH:15][C:16]([Cl:32])=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[CH:18]=1)(=[O:11])=[O:10])[CH3:8].[OH-].[Na+].Cl>O>[Cl:32][C:16]1[CH:15]=[C:14]([Cl:33])[C:13]([NH:12][S:9]([CH2:7][CH3:8])(=[O:10])=[O:11])=[CH:18][C:17]=1[N:19]1[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[N:21]([CH3:30])[C:20]1=[O:31]
Reactant: CCS(=O)(=O)N(c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl)S(=O)(=O)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To 8 ml of dioxane, 0.80 g of the obtained 3-[5-bis(ethanesulfonyl)amino-2,4-dichlorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved and 0.12 g of sodium hydroxide (93%) and 2 ml of water were added to the obtained solution After the mixed solution was stirred for 4 hours, a dilute hydrochloric acid was added thereto in order to acidify the resultant solution. The reaction mixture was extracted with ethyl acetate. The obtained extract of the ethyl acetate layer was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Then ethyl acetate was distilled off to obtain a crude product. The obtained product was purified by preparative thin-layer chromatography (developing solvent: hexane/ethyl acetate =3/2) to obtain 0.46 g of the objective product as white crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([C:10]#[C:9][C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:12]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(C#CC2CCCNC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCCC(C#Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 24 h
Yield: 45 %

Procedure:
To a mixture of 3-(4-Fluoro-phenylethynyl)-piperidine hydrochloride (0.14 g, 0.58 mmol) in THF (2.3 ml, 0.5M) was added DIEA (0.5 ml, 2.92 mmol). The reaction mixture was cooled to 0° C. and 4-Fluoro-benzoyl chloride (0.139 g-0.87 mmol) was slowly added. The reaction was to go up to R.T and stirred for 24 h. The solution was concentrated and DCM was added following by HCl 1N. The aqueous phase was separated and organic phase was extracted twice with HCl 1N and twice with water, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (DCM/MeOH: 98/2) to afford 0.86 mg (45%) of (4-Fluoro-phenyl)-[3-(4-fluoro-phenylethynyl)-piperidin-1-yl]-methanone as a brown oil. Rf=0.39 (DCM/MeOH: 98/2); LCMS (Tr): 4.14 min (Method C); MS (ES+) gave m/z: 326.2;
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[CH2:11]([Cl:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(#N)C>[ClH:20].[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:13])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc2cccnc2[nH]1
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Product: Cc1cc2cccn(CC(=O)c3ccccc3)c-2n1
Product: Cl
Yield: 87.6 %

Procedure:
2-Methyl-pyrrolo[2,3-b]pyridine (0.5 g, 3.78 mmol), phenacyl chloride (0.62 g, 4.0 mmol ) and acetonitrile (10 ml) were refluxed for 12 h. The solid was filtered off and washed with cold carbon tetrachlorid (2 ml). The crude product was recrystallized from chloroform/ether, 1:1, to give 0.95 g (88%) title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2Cl.Cl.[CH3:18][C:19]1([NH2:25])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2[NH:25][C:19]1([CH3:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: CC1(N)CCOCC1
Reactant: O=[N+]([O-])c1cnc2cc(F)c(Br)cc2c1Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1(Nc2c([N+](=O)[O-])cnc3cc(F)c(Br)cc23)CCOCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
6-Bromo-4-chloro-7-fluoro-3-nitroquinoline (1 g, 3.27 mmol) was added to a solution of 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (0.596 g, 3.93 mmol) and DIPEA (1.715 mL, 9.82 mmol) in DMA (10 mL) and the resulting mixture stirred at 100° C. for 4 h. The reaction mixture was diluted with water and the solid collected by filtration and dried to afford the desired material (1.215 g, 97%) as a brown solid which was used without further purification.
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[OH-].[Na+].[CH2:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[C:28](=[CH:33]OC)[C:27]1=[O:36])[CH3:25]>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[CH:33][C:28]3[C:27](=[O:36])[N:26]([CH2:24][CH3:25])[CH2:31][CH2:30][C:29]=3[N:8]=2)[CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCN1CCC(=O)C(=COC)C1=O
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2C1=O
Yield: 80.8 %

Procedure:
1.56 g of 1-amidino-4-benzylpiperazine sulfate was added to an ethanol solution containing 0.23 g of sodium hydroxide. To the resulting suspension was added 1.07 g of 1-ethyl-3-methoxymethylenepiperidine-2,4-dione, and they were refluxed for 2 hours. Ethanol was distilled off. Then, water was added and extraction by chloroform was conducted. The chloroform layer was dried and concentrated to obtain 1.4 g of 2-(4-benzylpiperazino)-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine with an yield of 69%.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:12])=O>ClCCCl>[Cl:12][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[ClH:12]
Reactant: OCCc1ccccn1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cl
Product: ClCCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
2-(2-hydroxyethyl)pyridine (5 g, 41 mmol) was dissolved in 10 mL of 1,2-dichloroethane, and thionyl chloride (9.67 g, 81 mmol) was added slowly at room temperature. The reaction mixture was stirred for one hour at room temperature and was then concentrated at reduced pressure. Methylene chloride (20 mL) was twice added to the concentrated residue and then removed under reduced pressure. The resulting concentrated residue was dried in vacuo to give 7.17 g (98.5%) of 2-(2-chloroethyl) pyridine·hydrochloride as a yellow solid: HRMS: calcd for C7 H8N1Cl1 142.0424, found 142.0400.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])=[C:9]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CCO>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[C:9]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:18][C:17]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: C=CC(=O)Nc1c(C(=O)NCC)noc1-c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C1COCCN1
Solvent: CCO
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1NC(=O)CCN1CCOCC1

Procedure:
A solution of 4-acryloylamino-5-(2,4-bis-benzyloxy-5-chloro-phenyl)-isoxazole-3-carboxylic acid ethylamide as described in example 7 (step viii), (170 mg, 0.32 mmol) and morpholine (1 ml) in EtOH (5 ml) was heated under reflux for 1 h.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(#N)C>[Br-:10].[CH2:22]([N+:7]1[CH:6]=[C:5]2[S:1][CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCBr
Reactant: c1cc2ccsc2cn1
Solvent: CC#N
Product: CCCCCCCCCCCC[n+]1ccc2ccsc2c1
Product: [Br-]
Yield: 60 %

Procedure:
A mixture of thieno[2,3-c]pyridine (7 g; 0.052 mole), 1-bromododecane (13 g; 0.052 mole) and acetonitrile (100 cc) is refluxed during 4 hours. The solution is then concentrated in vacuo and the residue is triturated with ether to give, after filtration and drying, 12 g (Yield: 60%; m.p. = 95-100° C) 6-dodecyl-thieno[2,3-c]pyridinium bromide (derivative of the formula (IV)).
Reaction SMILES: CC(S([NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10])=O)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH2:19])=[O:18])[CH:12]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C(N)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](N)c1ccnc(C(N)=O)c1
Reaction time: 2 h

Procedure:
To a solution of 85% 4-[(S)-1-(2-methyl-propane-2-sulfinylamino)-propyl]-pyridine-2-carboxylic acid amide (5.5 g, 16.5 mmol) in methanol (50 mL) was added a 4 N solution of HCl in dioxane (4.33 mL, 17.32 mmol). After 2 hour, additional 4 N HCl in dioxane (0.5 mL) was added. The reaction was monitored by TLC (eluting with EtOAc). After 1.5 hours, the mixture was concentrated in vacuo to remove MeOH and EtOAc (400 mL) was added. The mixture was washed with saturated sodium carbonate solution (100 mL) and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 4-((S)-1-amino-propyl)-pyridine-2-carboxylic acid amide.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:45].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][N:4]1[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:45])[C:6]=2[N:15]=[C:3]1[CH2:1][CH3:2]
Reactant: CCc1nc2cnc3ccccc3c2n1CCOCCON1C(=O)c2ccccc2C1=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCON
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-{2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethoxy}-1H-isoindole-1,3(2H)-dione (11.0 g, 25.5 mmol) in chloroform (150 mL) was added mCPBA (11.4 g, 51.1 mmol). The solution was stirred at room temperature for 2 hours. Concentrated ammonium hydroxide (100 mL) was added, followed by p-toluenesulfonyl chloride (5.40 g, 28.1 mmol). The mixture was stirred overnight at room temperature. The mixture was transferred to a separatory funnel and was washed twice with 5% aqueous ammonium chloride and once with aqueous sodium carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, gradient elution with 0-5% methanol in dichloromethane) to provide 6 g of 1-{2-[2-(aminooxy)ethoxy]ethyl}-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.[CH2:31]([O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH2:43][CH3:44])[CH:37]=O)[CH3:32].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:37][C:36]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][CH3:44])=[C:34]([O:33][CH2:31][CH3:32])[CH:35]=2)[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)cc1OCC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 3,4-diethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL), and acetic acid (0.050 mL) was added NaBH3CN (0.25 mmol) in methanol (0.50 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material were added dichloromethane (2 mL) and phenyl isocyanate (0.10 mL) and the solution was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL) and 4 N HCl in dioxane (0.125 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(3,4-diethoxybenzyl)piperidine (Compound No. 2065) (21.2 mg, 84%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 505.2 (M++H, C26H34F2N4O4).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[OH:17].[OH-].[Na+].O>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[O:17][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: CCN1CC2OC2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN1C[C@@H](O)[C@H](Oc2c(Cl)cccc2Cl)C1

Procedure:
A mixture of 11.3 g. (0.10 mole) of 1-ethyl-3,4-epoxypyrrolidine, 18.0 g. (0.11 mole) of 2,6-dichlorophenol and 2 drops concentrated hydrochloric acid was heated on a steam bath overnight. The oil was dissolved in methylene chloride and wahed with three 50-ml. portions of 5% sodium hydroxide an one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatogrpahed on silica gel to give 12.9 g. (47%) of and oil residue. The oil was converted to the hydrchloride and recrystallized from isopropyl alcohol-diethyl ether to yield 12.3 g. (39%), m.p. 160°-162° C.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:14]([C@@:15]4([CH3:23])[CH2:16][CH2:17][C:18](=O)[C:19]([CH3:21])([CH3:20])[C@:2]124)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[OH:24].[ClH:25].Cl.[NH2:27][CH2:28][CH2:29][O:30][NH2:31]>>[ClH:25].[NH2:27][CH2:28][CH2:29][O:30]/[N:31]=[C:18]1/[C:19]([CH3:21])([CH3:20])[C@:2]23[O:1][C@H:3]2[CH2:4][C@@H:5]2[C@@H:14]([C@@:15]3([CH3:23])[CH2:16][CH2:17]/1)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C@@H:9]1[OH:24]
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Reactant: NCCON
Agent: Cl
Product: CC1(C)/C(=N/OCCN)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@@H]3O[C@]312
Yield: 68 %

Procedure:
The title compound was prepared as described in Example 2 starting from 5α,6α-epoxy-17β-hydroxy-4,4-dimethylandrostan-3-one, (Preparation 8, 54 mg) and 2-aminoethoxyamine dihydrochloride (97 mg). The solution was evaporated, water was added and the aqueous phase was extracted with THF. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was triturated with diisopropyl ether/MeOH 95/5 and the precipitate was filtered to give the title compound (47 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].[CH2:12](O)[CH2:13][CH2:14]C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)c1ccccc1N
Reactant: CCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCOC(=O)c1ccccc1N
Reaction time: 8 h
Yield: 97 %

Procedure:
453 parts of anthranilic acid methyl ester, 444 parts of n-butanol and 11 parts of potassium carbonate are heated together and the methanol thus formed is distilled off over a column. A subsequent intermediate fraction contains both methanol and n-butanol. Finally, the excess quantity of n-butanol is distilled off, preferably in vacuo towards the end of this operational step. The reaction time lasts for about 8 hours. After filtration of the catalyst there are obtained 562 parts of anthranilic acid n-butyl ester (nD25 1.545; accoding to gas chromatography of 99-100% purity). Yield: 97% of the theory.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[O:8][C:9]([CH3:11])([CH3:10])[C:4]=2[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[CH3:10][C:9]1([CH3:11])[O:8][C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)=[CH:3][C:4]1=2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC1(C)OC(=O)Nc2ccc(I)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 6-iodo4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-nitrophenyl boronic acid according to Procedure A. Yellowish solid: mp 244-245° C.; 1H-NMR (DMSO-d6) δ10.38 (s, 1H, D2O exchangeable), 8.47 (s, 1H), 8.14-8.20 (m, 2H), 7.70-7.76 (m, 3H), 7.01 (d, 1H, J=8.1 Hz), 1.68 (s, 6H); MS (EI) m/z 297([M−H]31 , 100%). Anal. Calc. For C16H14N2O4: C, 64.42, H, 4.73, N, 9.39. Found: C, 63.93, H, 4.91, N, 8.71.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13](=[O:31])[CH:12]=1>>[CH3:10][C:11]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13](=[O:31])[C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: CCCn1c(=O)cc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCn1c(=O)c([N+](=O)[O-])c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To concentrated sulfuric acid (2.0 ml) were added in ice bath fuming nitric acid (0.2 ml), 6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 21) (200.0 mg) and the resulting mixture was stirred for three hours in ice bath. The reaction mixture was poured into ice water, and the precipitated solids were collected by filtration to afford 6-methyl-5-nitro-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (219.0 mg).
Reaction SMILES: [CH2:1]([Al:5](CC(C)C)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[CH2:14]([OH:16])[CH3:15]>CCCCCC>[O-:16][CH2:14][CH3:15].[CH2:1]([Al+:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: CCCCCC
Product: CC(C)C[Al+]CC(C)C
Product: CC[O-]
Temperature: 25 °C

Procedure:
In a 200-mL flask which had been previously purged with nitrogen, 97 mL of hexane which had been purified by distillation was charged, and 2.54 mL (10 mmoles) of triisobutylaluminum, manufactured by Tosoh Finechem Corporation was then added for dissolution. Subsequently, 0.58 mL (10 mmoles) of ethanol, manufactured by Aldrich was added. The flask was heated on an oil bath, and hexane was refluxed for 2 hours, thereby terminating the reaction. The reaction mixture was directly cooled to room temperature, thereby obtaining a 0.1 moles/L hexane solution of diisobutylaluminum ethoxide.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([NH:28][C:29](=[O:31])[CH3:30])[S:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25]([NH:28][C:29](=[O:31])[CH3:30])[S:26][CH:27]=2)=[CH:19][CH:20]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(COc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc(COc2ccc(CCOC(=O)NN)cc2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a solution of 2-(4{[2-(acetylamino)-1,3-thiazol-4-yl]methoxy}phenyl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (0.855 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (3.18 ml, 42.8 mmol) at 0° C. After stirring at 0° C. for 30 min, the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 4 times with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (20 ml) was added to suspend the residue. The suspension was filtered and washed once with ethyl acetate and 5 times with diethyl ether, and dried under reduced pressure to give the title compound (105.9 mg, 0.302 mmol, yield 35.3%) as a white solid.