Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].[OH:36][CH:37]([CH:48]([OH:59])[C:49]([O:51]N1C(=O)CCC1=O)=O)[C:38]([O:40]N1C(=O)CCC1=O)=O.[CH2:60]([N:62]([CH2:65][CH3:66])[CH2:63][CH3:64])C>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:38](=[O:40])[CH:37]([OH:36])[CH:48]([OH:59])[C:49]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:64]3[C:32]4[C:66](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:65][N:62]([CH3:60])[CH2:63]3)[CH:18]=2)(=[O:16])=[O:15])=[O:51])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Reactant: CCN(CC)CC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (compound 28) (1.2 g, 2.28 mmol, 1.00 equiv) in DMF (8 mL) was added bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (intermediate 168.1) (393 mg, 1.14 mmol, 0.50 equiv) and triethylamine (1.5 g, 14.82 mmol, 6.50 equiv) and the resulting solution was stirred overnight at room temperature. The mixture was concentrated under vacuum and the crude product was purified by Flash-Prep-HPLC with the following conditions: Column, silica gel; mobile phase, methanol:water=1:9 increasing to methanol:water=9:1 within 30 min; Detector, UV 254 nm. This resulted in 591 mg (43%) of N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide as a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.92 (d, J=7.8 Hz, 2H), 7.81 (m, 2H), 7.67 (t, J=7.8 Hz, 2H, 7.57 (m, 2H), 7.55 (d, J=6.9 Hz, 2H), 6.85 (m, 2H), 4.78 (s, 2H), 4.77 (s, 2H), 4.54 (d, J=40.2 Hz, 2H), 4.48 (s, 2H), 3.92 (m, 2H), 3.53 (m, 30H), 3.18 (s, 6H), 3.07 (t, J=5.4 Hz, 4H). MS (m/z): 603 [½M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.C(O)C.C1CCCCC=1>[Pd].O>[CH3:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: Cc1cc([N+](=O)[O-])cc2[nH]ccc12
Agent: [Pd]
Solvent: O
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1cc(N)cc2[nH]ccc12

Procedure:
4.3 g of nitro derivative prepared in stage 3, 20 ml of ethanol, 9 ml of cyclohexene, 3 ml of water and 2.2 g of 10% palladium on carbon are mixed and are then heated to reflux for 2 hours.
Reaction SMILES: [CH2:1]([CH:4]([C:19]([O:21]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[C:5]([O:7]C1C(Cl)=C(Cl)C(Cl)=C(Cl)C=1Cl)=O)[CH:2]=[CH2:3].C(N(CC)CC)C.[NH2:40][C:41]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[CH:43][N:42]=1>CC(C)=O>[CH2:1]([C:4]1[C:5](=[O:7])[N:42]2[CH:43]=[CH:44][C:45]([O:47][CH3:48])=[CH:46][C:41]2=[N:40][C:19]=1[OH:21])[CH:2]=[CH2:3]
Reactant: COc1ccnc(N)c1
Reactant: C=CCC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CCc1c(O)nc2cc(OC)ccn2c1=O
Reaction time: 16 h
Yield: 64.8 %

Procedure:
Bis(pentachlorophenyl) allylmalonate (905 mg, 1.412 mmol) and triethylamine (0.359 ml, 2.58 mmol) were added to a slurry of 2-amino-4-methoxypyridine (160 mg, 1.289 mmol) in acetone (6.5 ml). The slurry was stirred for 16 hours, filtered, and washed with acetone to yield the title compound as a white solid (194 mg, 65%). LCMS (ES+) m/z 233.0 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH:5]1[C:10]([OH:11])=[CH:9][C:8]2[O:12][C:13]([S:15][C:7]=2[CH:6]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:11][C:10]1[CH:5]=[CH:6][C:7]2[S:15][C:13](=[O:14])[O:12][C:8]=2[CH:9]=1)[CH:2]=[CH2:3]
Reactant: O=c1oc2cc(O)ccc2s1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2sc(=O)oc2c1
Yield: 77.4 %

Procedure:
Allyl bromide (28.3 ml, 0.327 mol) was added to a mixture of tioxolone (50 g, 0.297 mol) and potassium carbonate (82 g, 0.595 mol) in acetone (300 ml), and the resultant suspension stirred at RT overnight. After removal of the solvent in vacuo, the residue was partioned between EtOAc (700 ml) and water (500 ml). The aqueous phase was removed, extracted with further EtOAc (2×300 ml), and the combined organics dried over MgSO4 and concentrated to an off-white solid (66.6 g). Purification by flash column chromatography on silica eluting with EtOAc:pentane (1:39 to 1:9) gave the title compound as a white solid (48.3 g, 0.23 mol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[CH3:12].[C-:13]#[N:14].[Na+].CCOCC>CN(C)C=O.[I-].[Na+]>[CH3:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:13]#[N:14]
Reactant: Cc1c(CCl)cccc1[N+](=O)[O-]
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(CC#N)cccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 70.9 %

Procedure:
1-Chloromethyl-2-methyl-3-nitro-benzene (25 g) was dissolved in 125 ml of N,N-dimethylformamide. To this mixture was added 10.89 g of sodium cyanide (Mallinckrodt, Paris, Ky.) and 0.4 g of sodium iodide (Mallinckrodt) and the heterogeneous mixture was heated to 80° C. for 21 hr. The reaction mixture was cooled to room temperature, poured into ether, washed several times with water, dried, and evaporated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane, giving 16.83 g of (2-methyl-3-nitro-phenyl)-acetonitrile as a cream solid. ##STR118##
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[F:50][C:51]1[CH:59]=[CH:58][C:54]([CH:55]([OH:57])[CH3:56])=[CH:53][CH:52]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:39](=[O:41])[O:57][CH:55]([C:54]1[CH:58]=[CH:59][C:51]([F:50])=[CH:52][CH:53]=1)[CH3:56]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC(C)c4ccc(F)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 35.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (85 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (114 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-fluoro-α-methylbenzyl alcohol (54 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (45 mg, yield 35%).
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]([N:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]3\[C:26](=[O:37])[NH:27][C:28]4[C:33]\3=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH3:10])=[O:8])C(=O)C2=CC=CC=C12.ClCCl.O.NN>C(O)C>[NH2:5][CH2:6][C:7]([N:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[CH3:10])=[O:8]
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: NN
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CN(C(=O)CN)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
287 mg (0.5 mmol) of (Z)-3-{1-[4-(N-phthalimidomethylcarbonyl-N-methylamino)phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone are suspended in 20 ml of ethanol and 20 ml of dichloromethane and after the addition of 0.3 ml of 80% hydrazine hydrate solution stirred for 18 hours at 50° C. The mixture is then cooled to ambient temperature, the insoluble matter is suction filtered and the mother liquor is concentrated by evaporation. The residue is chromatographed on silica gel (dichloromethane/methanol/ammonia=92:8:0.8) and the product is again triturated with methanol, suction filtered and dried.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[CH2:18][OH:19].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[CH2:18][OH:19]
Reactant: OCc1cc(O)ccc1Br
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(Br)c(CO)c2)cc1
Temperature: 80 °C
Yield: 99 %

Procedure:
To a solution of 4-fluoro-benzaldehyde (5.4 mL, 50.0 mmol, 1.0 eq.), 4-bromo-3-hydroxymethyl-phenol (10.6 g, 50.0 mmol, 1.0 eq.) in DMF (140.0 mL) was added K2CO3 (8.3 g, 60.0 mmol, 1.2 eq.) under nitrogen atmosphere. The mixture was heated at 80° C. overnight. After cooling to room temperature, the mixture was poured into EtOAc (10 mL) and sat. H2O (100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×100 mL). Combined organic extracts was washed with brine (100 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give 4-(4-bromo-3-hydroxymethyl-phenoxy)-benzaldehyde as a yellow oil. 1H NMR (CHLOROFORM-d) δ: 9.93 (s, 1H), 7.80-7.89 (m, 2H), 7.55 (d, J=8.6 Hz, 1H), 7.27 (d, J=3.1 Hz, 1H), 7.06 (d, J=8.7 Hz, 2H), 6.89 (dd, J=8.6, 2.9 Hz, 1H), 4.74 (s, 2H). Amount obtained, 15.2 g, 99% yield.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH:19]([NH2:26])[CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][C:12]=2[Cl:28])[N:3]=[CH:2]1.N1C=CC=CC=1.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:32]=[CH:31][CH:30]=[CH:29][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:27])[CH:19]([NH:26][C:39](=[O:41])[CH3:40])[CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:13][C:12]=2[Cl:28])[N:3]=[CH:2]1
Reactant: NC(C(=O)Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)c(Cl)c1)C1CCOCC1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC(C(=O)Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)c(Cl)c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
To a solution of N-(4-(2-(2-(1H-imidazol-4-yl)phenoxy)ethyl)-3-chlorophenyl)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetamide (40 mg, 0.088 mmol) in dichloromethane (3 mL) was added pyridine (29 μL, 0.352 mmol) and acetyl chloride (29 μL, 0.264 mmol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5%-10% MeOH/DCM as eluent) to afford the desired product as a white solid (27 mg, 0.054 mmol, 61%). 1H NMR: 1.42-1.58 (m, 3H), 1.68 (d, 1H, J=12.8 Hz), 2.03-2.07 (m, 1H), 2.08 (s, 3H), 3.24-3.31 (m, 4H), 3.94 (t, 2H, J=11.2 Hz), 4.39 (t, 2H, J=6 Hz), 4.61 (t, 1H, J=8.4 Hz), 6.81 (d, 1H, J=8.4 Hz), 6.99 (d, 2H, J=8 Hz), 7.18-7.24 (m, 3H), 7.37 (dd, 1H, J=8 Hz, 1.6 Hz), 7.60 (s, 1H), 7.77 (s, 1H),
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[C:11](Cl)(=O)C(Cl)=O.CN(C=O)C.CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 123 %

Procedure:
To a solution of 4-chloronicotinic acid (0.5 g, 3.17 mmol) in CH2Cl2 (60 mL) was added oxalyl chloride (1.007 g, 7.93 mmol) dropwise at room temperature followed by the addition of DMF (0.4 mL). The solution was stirred at room temperature for 3 h. Methanol (1.9 mL, 46.8 mmol) was added dropwise and the clear solution was further stirred for 30 min. The solvent was evaporated under reduced pressure to yield methyl 4-chloronicotinate (0.67 g, 3.90 mmol, 50% yield). LCMS (ESI) m/e 172.5 [(M+H)+, calcd for C7H7ClNO2 172.0]; LCMS retention time (Method D): tR=1.15 min.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[C:11]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[CH:15][CH:14]=[C:13]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:12]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc(-c2cccc(-c3cccc4[nH]ccc34)c2)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-bromoindole (2.1 g, 10 mmol), and 3-biphenylboronic acid (2.2 g, 10 mmol) in THF (34.5 mL) were added Palladium catalyst Pd(PPh3)4 (0.35 g, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.21 g, 30 mmol in 14 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified on a silica gel column to give 4-biphenyl-3-yl-1H-indole.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]([OH:16])=O)=[O:10].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>ClCCl.CN(C)C=O>[N:28]1([C:14]([C:13]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([CH:12]=2)[C:9]([O:8][CH3:7])=[O:10])=[O:16])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.61 ml, 6.99 mmol) was added dropwise to a stirred solution of 3-[(methyloxy)carbonyl]-4-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 49; 400 mg, 1.40 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 h. The solvent was removed. The residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of morpholine (609 mg, 6.99 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 h. Water (60 ml) was added and the mixture was extracted with dichloromethane (3×60 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product as colourless oil. The crude product was loaded onto a silica gel column and was eluted with dichloromethane/methanol=20:1 to yield the title compound as a colourless oil. 450 mg.
Reaction SMILES: C([N:8]([CH3:41])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[NH2:42][C:43]1[N:48]=[C:47]([CH3:49])[C:46](Br)=[CH:45][CH:44]=1>>[ClH:27].[ClH:27].[NH2:42][C:43]1[N:48]=[C:47]([CH3:49])[C:46]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH2:36][CH3:37])=[C:29]([CH:30]=2)[CH2:28][N:15]([CH:12]2[CH2:11][CH2:10][CH:9]([NH:8][CH3:41])[CH2:14][CH2:13]2)[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])=[CH:45][CH:44]=1
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)ccc1Br
Product: CCOc1ccc(-c2ccc(N)nc2C)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound was prepared from boronic acid (12) (25 mg, 42 μmol) and 6-amino-3-bromo-2-methylpyridine (6.5 mg, 41 μmol) in accordance with Method L2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)pyridine-2-sulfonamide (983 mg, 3.14 mmol) synthesized in Example (120a) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (132 mg, 3.30 mmol) was added. After ice cooling, p-methoxybenzyl chloride (1.02 mL, 3.37 mmol) was added, and the temperature was raised to room temperature, followed by stirring for 2 hours. Water (20 mL) was added to the reaction solution, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-100%) to afford the desired compound (1.14 g, yield 84%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+]([O-])=O)[CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1cccc(N)c1
Solvent: CCO
Product: Cc1cccc(Nc2cc(Cl)ccc2[N+](=O)[O-])c1
Reaction time: 72 h

Procedure:
81 ml of m-toluidine is added to a solution of 50 g of 1-chloro-3,4-dinitrobenzene in 250 ml of ethanol, and the solution was allowed to stand for 72 hours. The reaction mixture was filtered, and the crystallizate was washed with cold ethanol and 2N aqueous hydrochloric acid. It was purified by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][OH:23])=[N:12][C:11]=2[CH:24]([CH3:26])[CH3:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])N.[C:31]([N:34]=[C:35]=[O:36])(=[O:33])[CH3:32]>>[C:31]([NH:34][C:35](=[O:36])[O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:24]([CH3:26])[CH3:25])[N:12]=1)(=[O:33])[CH3:32]
Reactant: CC(C)c1nc(CO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)N=C=O
Agent: NC(=O)[O-]
Product: CC(=O)NC(=O)OCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1Cc1ccncc1
Yield: 76 %

Procedure:
5-(3,5-Dichlorophenylthio)-4-isoproyl-1-(4-pyridylmethyl)-2-hydroxymethyl-1H-imidazole (89) (245 mg, 0.6 mmol) prepared in accordance with the method as described in WO 96/10019 was converted to the carbamate with acetyl isocyanate (5 eq.) in the same manner as the example 66 to give the compound 90 (225 mg, 76%) as crystals. Mp. 135-137° C. Rf 0.32 (10:1 EtOAc - CH3OH).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[N:7]=3.CO[C:21](OC)([N:23]([CH3:25])[CH3:24])[CH3:22]>C1(C)C=CC=CC=1>[CH3:24][N:23]([CH3:25])/[C:21](=[N:16]/[C:14]([C:8]1[N:7]=[C:6]2[N:10]([CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=32)[CH:9]=1)=[O:15])/[CH3:22]
Reactant: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: COC(C)(OC)N(C)C
Solvent: Cc1ccccc1
Product: C/C(=N\C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)N(C)C
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a solution of 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (0.280 g, 0.000909 mol) in toluene (5 mL) was added dimethylacetamide-dimethylacetal (0.405 mL, 0.00273 mol). The solution was stirred at 95° C. for 4 h. The toluene was removed in vacuo to give 8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid [1-dimethylamino-eth-(E)-ylidene]-amide. MS (ESI+) 377.1/379.1.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[S:15][C:14]([NH:16][C:17](=[O:40])[CH:18]([C:26]3[CH:27]=[N:28][C:29]([S:32]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:34])=[O:33])=[CH:30][CH:31]=3)[O:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:13][CH:12]=2)[CH:5]=1.[Li+].[OH-]>O.C1COCC1.CO>[CH:35]1([S:32]([C:29]2[N:28]=[CH:27][C:26]([CH:18]([O:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:17]([NH:16][C:14]3[S:15][C:11]([O:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:41])=[O:2])=[CH:12][N:13]=3)=[O:40])=[CH:31][CH:30]=2)(=[O:33])=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COC(=O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CCCC4)nc3)s2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(Oc2cnc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CCCC4)nc3)s2)c1
Yield: 73.3 %

Procedure:
The compound of example B8 was obtained by similar method described in example B1 using 3-[2-[[2-(6-cyclopentylsulfonyl-3-pyridyl)-2-tetrahydropyran-4-yloxy-acetyl]amino]thiazol-5-yl]oxybenzoic acid methyl ester (Example A10; 0.140 g, 0.232 mmol), LiOH (0.049 g, 1.16 mmol) in Water:THF:MeOH (2:1:0.2 8 mL) to provide the title compound (0.100 g).