Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH2:4]1.[N+:19]([O-])([O-:21])=[O:20].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:19]([O-:21])=[O:20])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=[N+]([O-])c1cccc2ccc3c(c12)C(CCl)CN3
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c(c3c([N+](=O)[O-])cccc13)C(CCl)CN2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A stirred solution of amine 136 (900 mg, 3.43 mmol) in conc. H2SO4 (9 mL) was cooled to −5° C. and treated with powdered KNO3 (520 mg, 5.14 mmol). The mixture was stirred at 0° C. for a further 15 min, then poured into ice-water and the solid was collected Chromatography on silica gel, eluting with petroleum ether/EtOAc (3:1), followed by two recrystallizations from CH2Cl2/iPr2O gave 1-(chloromethyl)-5,9-dinitro-1,2-dihydro-3H-benzo[e]indole (137) (394 mg, 37%) as a red solid: mp 130-131° C.; 1H [(CD3)2SO] δ 8.21 (dd, J=8.6, 1.1 Hz, 1H), 8.10 (dd, J=7.6, 1.1 Hz, 1 H), 7.75 (s, 1H), 7.44 (dd, J=−8.6, 7.6 Hz, 1H), 7.02 (s, 1H), 3.89-3.81 (m, 1H), 3.72-3.62 (m, 2H), 3.41-3.35 (m, 2H). Anal. (C13H10ClN3O4) C, H, N, Cl.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O-:18])=[CH:14][CH:13]=1.[Na+].N>O>[CH:4]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)[CH:3]=1
Reactant: [O-]c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: N
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
157.6 g of p-chloronitrobenzene and 150.5 g of sodium 4-chlorophenolate were initially introduced into a steel autoclave. At temperature, 150 g of liquid ammonia were pumped into the vessel, the mixture was brought to 80° C. and stirred at this temperature for 10 hours. 150 g of water were then pumped in the vessel, the mixture was cooled to room temperature, the pressure vessel was let down while removing the ammonia at the same time by distillation, and the reaction mixture was filtered off through a suction filter. The crystalline product was washed with water and dried to give 4-chloro-4'-nitrodiphenyl ether with a yield of 226.7 g=92.3% of the theoretical yield. The product is almost 100% pure.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([CH:5]=1)[CH:3]=[O:2])(=[O:12])[CH3:11]
Reactant: COC(OC)c1cncc(C(C)=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cncc(C=O)c1
Reaction time: 24 h
Yield: 68.3 %

Procedure:
To a stirred solution of 1-(5-(dimethoxymethyl)pyridin-3-yl)ethanone (214 mg, 1.1 mmol) in CH2Cl2 (5 mL) was added TFA (2 mL). The resulting mixture was stirred for 24 h and the solvent was removed. The residue was dissolved in CHCl3 and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed to provide 5-acetylnicotinaldehyde (112 mg) as a yellow solid.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]1[O:15][C:16]3[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)=[CH:9][CH:8]=[CH:7]2.O>C(O)(=O)C>[Br:1][C:5]1[C:4]([OH:3])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]1[O:15][C:16]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Oc1ccc2c(-c3nc4ccc(O)cc4o3)cccc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2nc(-c3cccc4c(Br)c(O)ccc34)oc2c1
Reaction time: 2 h

Procedure:
Bromine (86 mg, 0.54 mmol) in acetic acid (2 mL) was added dropwise into solution of 2-(6-hydroxy-1-naphthyl)-1,3-benzoxazol-6-ol (0.15 g, 0.54 mmol) and acetic acid (9 mL). The reaction mixture was stirred for 2 h, poured into water and the precipitated solid filtered and dried. The product was recrystallized from acetone/EtOAc to give a yellow solid, m.p. 221-223° C.; MS m/e 354 (M−H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:27]([CH:24]5[CH2:26][CH2:25]5)=[O:28])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)C1CC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CC4)nc3cc21

Procedure:
Cyclopropanecarboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.48 mmol) and cyclopropanecarbonyl chloride (152 mg, 1.45 mmol). The title compound was obtained as white powder (23 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:11]1[CH3:20].N[C:22](N)=[O:23]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH:11]3[CH3:20])[C:22](=[O:23])[NH:1][C:2]=2[CH:7]=1
Reactant: NC(N)=O
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)C(C)C1
Product: COC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)C(C)C1

Procedure:
A mixture of 30 parts of methyl 4-(2-amino-4-chlorophenylamino)-3-methyl-1-piperidinecarboxylate and 10 parts of urea is stirred and heated at 160°-180° C (oil-bath) for 3h. 30. The reaction mixture is cooled and the product is extracted with methylbenzene. The extract is washed successively with water, with a diluted hydrochloric acid solution and again with water, dried, filtered and evaporated. The oily residue is crystallized from a warm mixture of 2,2'-oxybispropane and a small amount of 2-propanol. After cooling, the product is filtered off and dried, yielding methyl 4-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)-3-methyl-1-piperidinecarboxylate; mp. 196.2° C.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[CH3:18][C:14]1[N:13]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc(C)n2)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)n1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(6-methyl-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.62 g, 2.5 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.48 g, 86%) as white solid, which was used in the next step without further purification. MS m/e: 250 (M+H+)
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][S:15][C:16]([S:18][C@H:19]2[NH:22][C:21](=[O:23])[C@@H:20]2[O:24][CH3:25])=[S:17])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:28]([C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38](OCC)[OH:39])=[CH:33][CH:32]=1)([O-:30])=[O:29]>C1(C)C=CC=CC=1.CN(C)C=O>[N+:28]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][O:36][C:37](=[O:43])[CH:38]([N:22]2[C@H:19]([S:18][C:16]([S:15][CH2:14][CH2:13][NH:12][C:10]([O:9][CH2:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:27][CH:26]=3)=[O:11])=[S:17])[C@@H:20]([O:24][CH3:25])[C:21]2=[O:23])[OH:39])=[CH:44][CH:45]=1)([O-:30])=[O:29]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CO[C@H]1C(=O)N(C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(=S)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
Analogously to Example 23, 646 mg (1.5 mmole) of (3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthiothiocarbonylthio)-3-methoxy-2-oxoazetidine in 22 ml of absolute toluene and 5.5 ml of absolute dimethylformamide are reacted with 848 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in the presence of freshly dried molecular sieves. After working up and chromatography over silica gel the title compound is obtained.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[H-].[Na+]>CN(C=O)C>[F:6][C:7]([F:17])([F:18])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:5][CH2:4][CH:2]2[CH2:1][O:3]2)=[CH:11][CH:10]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(COCC2CO2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
A mixture of glycidol (115) (303 mg, 4.09 mmol) and 4-(trifluoromethoxy)benzyl bromide (0.810 mL, 5.06 mmol) in anhydrous DMF (6 mL) under N2 at 0° C. was treated with 60% NaH (246 mg, 6.15 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 7 h, the mixture was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to water (100 mL) and extracted with EtOAc (4×100 mL). The extracts were washed with brine (100 mL) and evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-5% Et2O/petroleum ether firstly gave foreruns, and then further elution with 5-10% Et2O/petroleum ether gave 2-({[4-(trifluoromethoxy)benzyl]oxy}methyl)oxirane (116) (625 mg, 62%) as an oil; 1H NMR (CDCl3) δ 7.38 (dt, J=8.7, 2.3 Hz, 2H), 7.20 (br dd, J=8.7, 0.7 Hz, 2H), 4.62 (d, J=12.0 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 3.82 (dd, J=11.5, 2.8 Hz, 1H), 3.43 (dd, J=11.5, 6.0 Hz, 1H), 3.21 (m, 1H), 2.82 (dd, J=4.9, 4.2 Hz, 1H), 2.63 (dd, J=5.0, 2.7 Hz, 1H); HRESIMS calcd for C11H11F3NaO3 m/z [M+Na]+ 271.0552. found 271.0557.
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:23][O:24][C:25]1[C:26]([NH2:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>COCCO>[CH3:23][O:24][C:25]1[C:26]([NH:31][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccccc1N
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: COCCO
Product: COc1ccccc1Nc1cccc2c1C(=O)c1cc([N+](=O)[O-])ccc1C2=O

Procedure:
50 g of 1,7-dinitro-anthraquinone and 150 ml of o-anisidine are stirred for 9 hours at 120° - 125° C and then diluted with 150 ml of ethylene glycol monomethyl ether, the mixture is stirred until cold and stirred for several hours longer in an ice bath, and the product is filtered off and successively washed with a little ethylene glycol monomethyl ether, methanol and water. 40.4 g of 1-o-anisidino-7-nitro-anthraquinone are obtained.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[NH:8][CH2:9][CH3:10])([O-:5])=[O:4].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:3]([C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[N:8]([CH2:9][CH3:10])[S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([O-:5])=[O:4]
Reactant: CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.12 g (3.00 mmol)) in DMF (4.0 ml), 2,4-dinitro-N-ethylaniline (0.42 g (1.99 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.57 g (2.99 mmol)) was added. After two hours' stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:2) as eluent, to give 0.47 g (65%) of the title compound as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:27])[O-:26])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]3[N:43]=[CH:42][NH:41][C:40]=3[CH:44]=2)O1>>[NH:41]1[C:40]2[CH:44]=[CH:36][C:37]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][C:6]([C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[C:5]4[NH:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:27])[O:26][C:4]([CH3:9])([CH3:5])[CH3:3])[CH2:22][CH2:23]3)=[CH:38][C:39]=2[N:43]=[CH:42]1
Reactant: O=C([O-])N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2ccc3nc[nH]c3c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc5[nH]cnc5c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl [trans-4-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (49 mg, 0.200 mmol) to afford the desired product (45.3 mg, 86%) as an off-white solid: ESI MS m/z 526 [C31H35N5O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1>CC#N>[NH2:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of 4-methoxybenzoyl chloride (1.03 g, 6.02 mmol) in CH3CN (6 ml) was added drop wise to a solution of methyl 3,4-diaminobenzoate (106) (1.00 g, 6.02 mmol) and pyridine (0.49 ml, 6.02 mmol) in CH3CN (25 ml) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and the solvent was evaporated. Ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 1-3% MeOH in DCM), 1.03 g (56%) of compound 107 was obtained as a off white solid. 1H NMR: (DMSO) δ(ppm): 9.51 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.75 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 5.80 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H). MS: (calc.) 300.1; (obt.) 301.1 (MH)+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([CH2:9][NH2:10])[OH:8].O>ClCCl>[OH:8][CH2:7][CH2:9][NH:10][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: NCCO
Reactant: C=C1CC(=O)O1
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC(=O)NCCO
Reaction time: 2 h

Procedure:
To a solution of diketene (42.1 g, 0.5 mol) in dichloromethane (100 ml), ethanolamine (30.5 g, 0.5 mol) was added dropwise at 10°-20.C with stirring, and the reaction was carried out at room temperature for 2 hrs. After pouring H2O (200 ml) into the reaction solution, an aqueous layer was separated, washed thrice with dichloromethane and was obtained N-(2-hydroxyethyl)-3-oxobutanamide as an aqueous solution.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([CH2:15][C:16]([NH2:18])=[NH:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[C:19]([O:23][C:24]([C:26]1[C:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:30]([OH:40])N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:33]([O:32][C:31]1[C:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[N:17][C:16]([CH2:15][C:10]2([C:5]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:3]([Cl:2])[CH:4]=3)[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:18][C:30]=1[OH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N=C(N)CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
tert-Butyl 5-(benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylate (487) was synthesized as a white solid from 2-(1-(3,4-dichlorophenyl)-cyclopentyl)-acetamidine hydrochloride (486) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (243)
Reaction SMILES: [Cl-].[CH2:2]([CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH3+:23])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][N:10]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN(C1C=CC=CN=1)C.[CH3:38][N:39]1[CH:43]=[C:42]([S:44](Cl)(=[O:46])=[O:45])[N:41]=[CH:40]1>ClCCl.C(OCC)(=O)C>[CH2:2]([CH:9]1[C:15]2[CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][S:44]([C:42]3[N:41]=[CH:40][N:39]([CH3:38])[CH:43]=3)(=[O:46])=[O:45])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12][CH2:11][N:10]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)N1CCCc2ccc(OCC[NH3+])cc2C1Cc1ccccc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1CCCc2ccc(OCCNS(=O)(=O)c3cn(C)cn3)cc2C1Cc1ccccc1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of 0.12 mmol 2-(1-benzyl-2-(ethoxycarbonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yloxy)ethanaminium chloride in 3 ml dichloromethane were added 0.33 mmol dimethylaminopyridine and 0.17 mmol 1-methyl-1H-imidazole-4-sulfonyl chloride. The mixture was stirred at room temperature over night. The mixture was diluted with ethyl acetate and washed with NH4Cl solution (2×), water (1×), and brine (1×). The organic layer was dried over MgSO4 and filtered. Evaporation of the solvent gave 66 mg of crude material that was purified by flash chromatography to yield 60 mg of ethyl 1-benzyl-8-(2-(1-methyl-1H-imidazole-4-sulfonamido)ethoxy)-4,5-dihydro-1H-benzo[c]azepine-2(3H)carboxylate (95%).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[OH:33][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:4]=1
Reactant: CSc1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1nc(O)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reaction time: 2 h

Procedure:
To a 10 mL round bottom flask fitted with a magnetic stirrer bar was added 2-methylthio-4-hydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 11 (40 mg, 0.1 mmol) and 1.0 mL DCM. The reaction flask was cooled in an ice bath and mCPBA (70%, 50mg, 0.22 mmol) was added all at once. After 2 h, two new products were observed by LC. The product eluting at Rt=3.38 min was 2-methylsulfonyl-4-hydroxy-5-(4-chlorophenyl)-6-(2, 4-dichlorophenyl)pyrimidine, m/e=431 (M++1) and that at Rt=2.91 min is 2,4-dihydroxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: m/e=367 (M+). The mixture was poured into 2 N NaOH and heated briefly. The precipitate that formed was filtered, washed with water and dried under reduced pressure. The title product was recovered. m/e=367 (M+). Rt=2.91 min; 1H-NMR 500 MHz (CDCl3): δ 6.98 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 3H), 7.38 (d, J=2 Hz, 1H), 9.8 (bs, 1H), 10.1 (bs 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].Cl>C1COCC1.CCOCC>[CH2:11]([C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1)[CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: Brc1ccc(Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Mg (8.76 g, 360 mmol) is suspended in THF (90 mL) under nitrogen in a three-necked flask equipped with a condenser and a dropping funnel. The dropping funnel is filled with 1,4-dibromobenzene (77.3 g, 327 mmol) in THF (40 mL). About 5% of the 1,4-dibromobenzene sol. is added carefully to the Mg-suspension and the reaction is started with the help of a heat gun. When the reaction starts, the 1,4-dibromobenzene sol. is added to such a speed so that the reaction mixture is refluxing gently (about 20 min). The mixture is stirred for further 30 min, and is cooled to 0° C. THF (100 mL) is added and the dropping funnel is filled with a sol. of allyl bromide (30.5 mL, 360 mmol) in THF (50 mL). The allyl bromide sol. is added slowly, maintaining the reaction temperature below 20° C. When the addition is complete, the mixture is stirred for further 30 min, while being cooled to 0° C. Aq. 1M HCl is added. The mixture is diluted with Et2O, and washed with aq. 1M HCl and brine. The combined aq. extracts are extracted back with Et2O. The combined org. extracts are dried over MgSO4, filtered, and the solvents are removed under reduced pressure. Distillation of the residue (11 mbar, 88-92° C.) yields the title compound (39.3 g, about 61%), together with another, unidentified impurity.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C>[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:28]2[CH2:29][CH2:30][CH:25]([NH:24][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:26][CH2:27]2)=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: CC(=O)Nc1ccc(OCC(O)CN2CCC(NC(=O)c3ccccc3)CC2)cc1

Procedure:
A solution of 2,3-epoxy-1-(4-acetamidophenoxy)-propane (5.18 g. and 4 -benzamidopiperidine (6.13 g.) in isopropanol (250 ml.) was refluxed for 24 hours, cooled and a white crystalline solid was filtered off (8.90 g.). This was recrystallised from isopropanol to give 7.41 g. of the title compound as a quarter hydrate, m.p. 226°-8° C. (Found: C, 66.35; H, 7.1; N, 10.1. C23H29N3O4.1/4H2O requires C, 66.4; H, 7.15; N, 10.1%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C:12](=[O:20])[O:11]1>C(O)(=O)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([N:5]2[C:12](=[O:20])[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]2=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Cc1c(N)cccc1Br
Solvent: CC(=O)O
Product: Cc1c(Br)cccc1N1C(=O)Cc2ccccc2C1=O
Temperature: 100 °C
Yield: 35.5 %

Procedure:
Step 1 A mixture of 3-bromo-2-methylaniline (1 g, 5.37 mmol) and isochroman-1,3-dione (0.872 g, 5.37 mmol) in acetic acid (15 mL) was heated overnight at 100° C. in a sealed tube. The mixture was cooled to rt and concentrated, and the residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to give 2-(3-bromo-2-methylphenyl)isoquinoline-1,3(2H, 4H)-dione as a tan solid (630 mg, 36%). Mass spectrum m/z 330, 332 (M+H)+.