Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)\[C:15]([OH:17])=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]CO.C1CCC1>CS(C)=O>[C:1]([O:5][C:6]([C:8]1([O:12]/[N:13]=[C:14](/[C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)\[C:15]([O:17][CH3:23])=[O:16])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2ccco2)CCC1
Reactant: CCO
Agent: C1CCC1
Solvent: CS(C)=O
Product: COC(=O)/C(=N\OC1(C(=O)OC(C)(C)C)CCC1)c1ccco1
Yield: 98 %

Procedure:
This compound was prepared from Z-2-(1-tertbutyloxycarbonylcyclobutyloxyimino)-2-(fur-2-yl)acetic acid as described in Preparation 7(a). λmax (EtOH) 281.5 nm (ε17,000), νmax (Nujol) 1745 (--CO2R), 1723 cm-1 (α,β-unsaturated --CO2R), τ(DMSO d6) 8.59 (--C(Me)3), 7.3-8.4 (cyclobutane), 2.1, 3.15, 3.35 (furyl), 6.09 (--CO2CH3). Yield 98%.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([S:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)([F:36])[F:37]
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: FC(F)(F)Sc1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Sc1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.00 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethylsulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 301 mg (60%) pale beige powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>CC(O)C>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[N:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1nc(-c2ccccc2)c2ccccc2n1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(C)O
Product: O=C(O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-4-phenylquinazoline (9.6 g, 40 mmol) in 2-propanol (130 mL) was added 4-aminobenzoic acid (8.2 g, 60 mmol) and the mixture was stirred at reflux for 4 h. The mixture was cooled to rt and the precipitate was collected by filtration and washed with 2-propanol. The product, 4-(4-phenylquinazolin-2-ylamino)benzoic acid, was isolated as a yellow solid (12.9 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:25]([CH3:24])(=[O:27])=[O:26])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Cl)ccc1NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc(Cl)ccc1N(Cc1cccnc1)S(C)(=O)=O

Procedure:
A 2.5 g. portion of 3-(4-chloro-2-methoxyphenylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane, and to it were added 2.1 g. of potassium carbonate and 1.2 ml. of methanesulfonyl chloride. The mixture was stirred with gentle heating for 2 days, and was then extracted with aqueous sodium bicarbonate. The organic phase was dried and evaporated under vacuum, and the residue was redissolved in dichloromethane and 2.6 g. of methanesulfonic anhydride was added. The mixture was stirred at ambient temperature for several days, and another 2.6 g. of the anhydride was added, together with 2.5 g. of additional starting amine. The mixture was stirred at ambient temperature for several days more, and was then diluted with 20 ml. of aqueous sodium bicarbonate and 15 ml. of dichloromethane, and the organic phase was dried over magnesium sulfate and evaporated to an oil. The oil was taken up in chloroform and chromatographed over silica gel, eluting with chloroform, to obtain 1.17 g. of the desired compound, m.p. 121°-123°.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:16](=[O:17])[C:15]2([CH2:22][CH2:21][N:20](C(OCC3C=CC=CC=3)=O)[CH2:19][CH2:18]2)[N:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[O:17]=[C:16]1[C:15]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:13][N:12]1[CH2:11][C:10]1[CH:9]=[C:8]([CH:41]=[CH:40][CH:39]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of benzyl 3-(3-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (5 g, 9.0 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (1 g, 20%/wt) and the resulting mixture was stabilized to a hydrogen atmosphere. The reaction was stirred as such for 2 h, filtered through Celite and the filtrate was concentrated in vacuo to afford the title compound as a grey foam (3.69 g, 97%); 1H NMR (400 MHz, DMSO-d6): δ 1.52 (s, 9H); 1.54-1.56 (m, 2H); 2.43-2.49 (m, 2H); 2.88-2.93 (m, 2H); 3.18-3.24 (m, 2H); 4.58 (s, 2H); 4.62 (s, 2H); 6.74 (t, 2H, J=6.8 and 7.6 Hz); 6.88 (d, 2H, J=8 Hz); 7.18-7.22 (m, 2H); 7.49-7.55 (m, 2H); 7.79-7.85 (m, 2H); MS for C25H31N3O3 m/z 422.24 (M+H)+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:21]N1C(C)(C)C(=O)N(Br)C1=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:21][C:13]1[CH:12]=[C:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:10]=[C:9]([N+:18]([O-:20])=[O:19])[C:8]=1[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cc(Br)c(NC2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
A room temperature solution of Example 3A (1.81 g, 6.0 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (950 mg, 3.3 mmol) in dichloromethane was treated with trifluoracetic acid (796 uL, 9.0 mmol), stirred in darkness for 18 hours, treated with saturated NaHCO3, and extracted with diethyl ether. The combined extracts were washed with brine, dried (Na2SO4), and concentrated. The concentrate was purified by flash column chromatography on silica gel with 15% ethyl acetate/hexanes to provide the desired product. MS (ESI(−)) m/e 376 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][C:15]1[O:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.[BH4-].[Na+]>CCO.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:20][C:18]2[O:19][C:15]([CH3:14])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1ccc(C=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COc1ccc(CCNCc2ccc(C)o2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4.82 g (26.6 mmol) of 2-(3,4-dimethoxyphenyl)ethylamine and 3.0 g (27.2 mmol) of 5-methylfuran-2-carbaldehyde in 65 ml of EtOH, 18.3 g of molecular sieves (0.3 nm) were added and the mixture was refluxed for 4 hours. After this time the reaction mixture was cooled to room temperature and filtered. The solution obtained was concentrated in vacuo to obtain an oil. This oil was dissolved in 65 ml of MeOH and 1.01 g (26.6 mmol) of NaBH4 were added in small portions, maintaining the temperature of the reaction at room temperature. The mixture was stirred at this temperature for 16 hours more. After this time the solvent was evaporated in vacuo and the residue was treated with 150 ml of water and extracted twice with ether.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1cc(F)cc(F)c1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cc(F)cc(F)c1

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitrobenzene (1.757 mL, 16.02 mmol) and 3,5-difluoroaniline (2.069 g, 16.02 mmol) to give N-(3,5-difluorophenyl)-5-fluoro-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.48 (1H, s), 8.23 (1H, dd, J=9.4, 6.1 Hz), 7.05-7.17 (3H, m), 6.99 (1H, tt, J=9.4, 2.3 Hz), 6.84-6.91 (1H, m); LC-MS (ESI) m/z 267.0 [M−H]−.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH2:20][CH2:21][OH:22].Cl>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: NCCCO
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80g, 10 mmol) in 100 ml of THF was cooled to ice temperature and stirred in an ice-bath while a solution of 3-amino-1-propanol (99%) (1.67g, 22 mmol) was added dropwise over a period of 45 minutes. Stirring in the ice-bath was continued for 30 minutes. The reaction miture than was acidified by addition of 3.0 ml of 1.2N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting this solution with 4×20 ml of saturated NaCl solution, the ethyl acetate was evaporated and the residue recrystallized from a mixture of ethyl acetate and hexane to give 2.70g (84.9%) of light yellow crystalline product, m.p., 87-88.5°.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][NH:16][CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>ClCCl>[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][N:16]([S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH2:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CNC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-ylacetonitrile hydrochloride (1.42 g, 0.00456 mol) in dichloromethane (30 mL) was added triethylamine (1.59 mL, 0.0114 mol) followed by ethanesulfonyl chloride (0.497 mL, 0.00525 mol) at 0° C. The reaction was stirred at room temperature for 1 h, quenched with 1N HCl. The organic layer was separated, washed with aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness. The crude product was used directly in next step (1.26 g, 75.3%). LCMS (M+H) 367.3.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3]CC.[F:29][C:30]1[CH:31]=[C:32]([OH:42])[CH:33]=[C:34]([F:41])[C:35]=1[O:36][C:37]([F:40])([F:39])[F:38].C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC=CC=1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15](/[CH:18]=[CH:19]/[C:20]3[CH:28]=[CH:27][C:23]([C:24]([O:42][C:32]4[CH:31]=[C:30]([F:29])[C:35]([O:36][C:37]([F:39])([F:40])[F:38])=[C:34]([F:41])[CH:33]=4)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)[CH2:2][CH3:3]
Reactant: Oc1cc(F)c(OC(F)(F)F)c(F)c1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3ccc(C(=O)O)cc3)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](/C=C/c3ccc(C(=O)Oc4cc(F)c(OC(F)(F)F)c(F)c4)cc3)CC2)CC1
Reaction time: 12 h

Procedure:
(E)-4-(2-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)vinyl)benzoic acid in an amount of 1,3 g (3.7 mmol), 0.8 g (3.7 mmol) of 3,5-difluoro-4-trifluoromethoxyphenol, 0.1 g (1.1 mmol) of DMAP, and 30 ml of dichloromethane were mixed. To this mixture was added dropwise 5 ml of solution of 1.0 g (4.8 mmol) of DCC in dichloromethane while being cooled with ice in 5 min, and stirred as it was for 12 hours. Separated crystals were filtered off, and 80 ml of toluene was added to the filtrate, washed with 2N-NaOH five times and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: toluene) to obtain 1.7 g of a crude (E)-3,5-difluoro-4-trifluoromethoxyphenyl 4-(2-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)vinyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5](Cl)[C:3]=1[NH2:4].[N+](C1C=CC(N)=CC=1)([O-])=O.ClCl.Cl>O.[N+]([O-])(O)=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: ClCl
Agent: Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: O=[N+]([O-])O
Product: Nc1ccc([N+](=O)[O-])cc1Cl
Yield: 90 %

Procedure:
Process for the preparation of 2,6-dichloro-4-nitroaniline by chlorination of 4-nitroaniline with chlorine bleaching liquor in water using acids, which comprises chlorinating 1 mole of 4-nitroaniline in 3-6 moles of hydrochloric acid (HCl) or nitric acid (HNO3) in the form of a dilute, aqueous acid in the presence of a dispersing agent which is stable under the reaction conditions, the chlorination initially being carried out at 5° to 10° C. and then at 15°-20° C. and, finally, after 90-95% of the 2-chloro-4-nitroaniline intermediately formed has been converted into 2,6-dichloro-4-nitroaniline, the temperature of the aqueous suspension being increased from 15°-20° C. to 70° C., without further addition of chlorine bleaching liquor, and then by post-chlorinating, by renewed addition of chlorine bleaching liquor, at temperatures between 20° and 70° C., bringing the pH of the aqueous suspension to 9.0 and filtering off the 2,6-dichloro-4-nitroaniline formed and washing it with dilute mineral acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl:34][C:35]1[CH:36]=[C:37](O)[CH:38]=[C:39]([Cl:41])[CH:40]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:37]2[CH:36]=[C:35]([Cl:34])[CH:40]=[C:39]([Cl:41])[CH:38]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 78.6 %

Procedure:
Triphenylphosphine (786 mg) was added to a solution of N-tert-butoxycarbonyl-4-hydroxypiperidine (603 mg), 3,5-dichlorophenol (489 mg) and diethyl azodicarboxylate (522 mg) in tetrahydrofuran (15 mL) at room temperature. After stirring at room temperature for 14 hr, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:6) to give the titled compound (815 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 9H), 1.75 (m, 2H), 1.90 (m, 2H), 3.37 (m, 2H), 3.66 (m, 2H), 4.44 (m, 1H), 6.80 (d, J=1.5 Hz, 2H), and 6.95 (s, 1H); mass spectrum (EI+) m/e 345 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.Br[CH2:20][C:21]#N.C(N(CC)C(C)C)(C)C.CN(C)C=O>[I-].[Na+]>[CH2:20]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]1)[CH3:21]
Reactant: N#CCBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CC(=O)N(C)c2cc([N+](=O)[O-])c(OC)cc2C1
Yield: 91.3 %

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), Sodium iodide (0.0148 g, 0.0000987 mol), Bromoacetonitrile (0.276 mL, 0.00396 mol) and N,N-Diisopropylethylamine (1.04 mL, 0.00597 mol) in N,N-Dimethylformamide (6 mL, 0.08 mol) was reacted in an analogous manner to example 736-E to give 4-Ethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (0.51 g, 88%). Mp129-131° C.; LCMS (m/e) 291 (M+1); 1H-NMR (DMSO, 400 MHz) δ 7.96 (s, 1H), 7.51 (s, 1H), 3.93-92 (s, 3H), 3.86 (s, 2H), 3.82 (s, 2H), 3.27 (s, 3H), 3.16 (s, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]([F:39])([F:38])[F:37])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([C:15]2[O:17][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[N:26]=2)[CH:12]=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1-c1ccccc1C

Procedure:
Oxalyl chloride (126 μL; 1.49 mmol; 3 eq.), Intermediate 27 (120 mg; 0.5 mmol; 1 eq.), Intermediate 2 (109 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a white solid.
Reaction SMILES: I.CS[C:4](=[N:19][CH2:20]CCC)[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:24][NH2:25]>>[CH3:24][NH:25][C:4]([NH:19][CH3:20])=[N:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN
Reactant: CCCCN=C(Nc1cc(Cl)ccc1N1CCOCC1)SC
Agent: I
Product: CNC(=Nc1cc(Cl)ccc1N1CCOCC1)NC

Procedure:
A mixture of 2-methyl-1-(5-chloro-2-morpholinophenyl)-3-(n-butyl)-2-thiopseudourea hydroiodide (3.4 g) and a 33% ethanolic solution of methylamine (10 ml) were stored at ambient temperature in a sealed container for 8 months to yield 1,3-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine (m.p. 145°-146° C.) which was recrystallised from hexane. In this reaction the butylamino and the methylthio group of the starting material are replaced by a methylamino group.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].N#N.Br[C:20]1[CH:39]=[N:38][C:23]2[N:24]([CH2:36][CH3:37])[C:25]3[N:33]=[C:32]([F:34])[CH:31]=[C:30]([CH3:35])[C:26]=3[NH:27][C:28](=[O:29])[C:22]=2[CH:21]=1.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:36]([N:24]1[C:23]2[N:38]=[CH:39][C:20]([CH2:3][CH:2]=[CH2:1])=[CH:21][C:22]=2[C:28](=[O:29])[NH:27][C:26]2[C:30]([CH3:35])=[CH:31][C:32]([F:34])=[N:33][C:25]1=2)[CH3:37]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(F)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1cnc2c(c1)C(=O)Nc1c(C)cc(F)nc1N2CC
Temperature: 90 °C
Yield: 44.4 %

Procedure:
Allyltributyltin (7.77 mL, 25.1 mmol) and Pd(Ph3P)4 (1.32 g, 1.14 mmol) were added to a degassed (N2 through solution for 30 min) solution of 8-bromo-5,11-dihydro-11-ethyl-2-fluoro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (8.0 g, 22.8 mmol) in DMF (114 mL). The mixture was heated to 90° C. for 3 h. The mixture was poured into water (250 mL) and extracted with EtOAc (4×250 mL). The combined organic layers were washed with 20% aqueous NH40H (250 mL) and brine (250 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:EtOAc, 4:1 to 1:1) to give the title compound (3.16 g, 51% yield).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:13]=[C:9]([CH:10]=[N:11]O)[C:8]([OH:14])=[C:7]([I:15])[CH:6]=1)([CH3:4])[CH3:3].ClC(Cl)(Cl)C(N=C=O)=O.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([I:15])[C:8]2[O:14][N:11]=[CH:10][C:9]=2[CH:13]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1cc(I)c(O)c(C=NO)c1
Agent: O=C([O-])[O-]
Agent: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(I)c2oncc2c1
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
To a solution of 3.19 g of 5-(1,1-dimethylethyl)-3-iodosalicylaldoxime in 10 ml of tetrahydrofuran is added 2.0 g of trichloroacetylisocyanate in tetrahydrofuran (5 ml) at room temperature followed by addition of 1.52 g of potassium carbonate. The mixture is stirred for an additional 20 minutes before it is poured into 400 ml of water. The precipitate so obtained is crystallized from methanol to afford 1.4 g (46.5%) of 5-(1,1-dimethylethyl)-7-iodo-1,2-benzisoxazole, m.p. 106°-109° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[C:31]([CH3:32])=[C:30]([CH3:33])[NH:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:23]1[C:24]2[C:31]([CH3:32])=[C:30]([CH3:33])[NH:29][C:25]=2[N:26]=[CH:27][N:28]=1)([O-:3])=[O:2]
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c2ncnc(Oc3cccc([N+](=O)[O-])c3)c2c1C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
After adding 3-nitrophenol (243 mg), potassium carbonate (268 mg) and dimethylformamide (2 ml) to the 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (177 mg) described in journal of Medicinal Chemistry, 1996, Vol. 39, No. 12, 2285–2292, the mixture was stirred at 120–130° C. for 72 hours. This was returned to room temperature, water was added, extraction was performed with a tetrahydrofuran and ethyl acetate mixed solution, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crystals were washed with diethyl ether to obtain the title compound (130 mg).