Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Reaction time: 4 h

Procedure:
2′,4′-Dichloro-biphenyl-4-carboxylic acid methyl ester (3 g) was dissolved in a mixture of THF (25 mL) and methanol (25 mL). 1 M NaOH (50 mL) was added and the mixture stirred for 4 hours by which stage a clear solution had formed. Conc. HCl was added and the precipitate was collected as a white solid. Toluene was added and the mixture was evaporated to dryness to give the title compound as a white solid. 1H NMR (CDCl3): δ 7.20 (2H, m), 7.52 (2H, m), 7.64 (1H, s) and 8.12 (2H, m).
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH3:24])[NH:5][C:6](=[O:23])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].S(OCC)(O[CH2:35][CH3:36])(=O)=O.CN(C)C=O>C(OCC)(=O)C>[CH2:35]([O:1][C:2]1[N:3]=[C:4]([CH3:24])[NH:5][C:6](=[O:23])[C:7]=1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1)[CH3:36]
Reactant: Cc1nc(O)c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A mixture of 4′-[(4-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), cesium carbonate (3.01 g), diethyl sulfate (0.41 mL) and N,N-dimethylformamide (20 mL) was stirred at 0° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.17 g, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:19][NH2:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:20][CH3:19])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.8 %

Procedure:
To a solution of 2,4-dichloro-5-nitrobenzoic acid (8 g, 33.9 mmol) in toluene (200 ml) was added thionyl chloride (12.4 ml, 169 mmol) at room temperature. The mixture was stirred at 80° C. for 5 h. The solvent was removed and the residue was dissolved with tetrahydrofurane (60 ml). The mixture was added 40% methylamine (1.4 ml, 33.9 mmol) at 0° C. and the mixture was stirred at room temperature for 2.5 h. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (100 ml), brine (100 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2:1/1:1/1:2) to afford 5.3 g (63%) of the title compound as pale yellow solids.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[C:29]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:28][NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[OH:33][C:30]([C:29]1[C:25]([C:24]([F:35])([F:34])[F:23])=[N:26][N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[CH:28]=1)([CH3:32])[CH3:31]
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Reactant: CC(C)(O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3cc(C(C)(C)O)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (30 mg, 0.11 mmol) was dissolved in DCM (5 mL) and thionyl chloride (66 mg, 0.57 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) and 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)propan-2-ol (21.6 mg, 0.11 mmol) was added followed by potassium carbonate (30.8 mg, 0.22 mmol). The reaction mixture was stirred at room temperature overnight before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative basic HPLC gave (R)—N-(5-((4-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (9.6 mg, 0.022 mmol, 19.4%). MS (ESI): m/z [M+H]+ 446.5
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([CH3:22])[CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[CH3:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A 100 mL round-bottom flask was charged tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate (1.90 g, 5.14 mmol, 1.00 equiv), (3-methylphenyl)boronic acid (2.12 g, 15.6 mmol, 3.00 equiv), potassium carbonate (2.15 g, 15.6 mmol, 3.00 equiv), Pd(PPh3)4 (0.600 g, 0.520 mmol, 0.10 equiv), dioxane (25 mL), water (2.5 mL) with an inert atmosphere of nitrogen. The resulting solution was stirred overnight at 80° C., diluted with water (50 mL), extracted with dichloromethane (3×40 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide in 2.00 g (95% yield) of tert-butyl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 381 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][O:30][CH3:31])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:27][CH2:26]1
Reactant: COCCC1CCN(CCCCl)CC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCC1CCN(CCCOc2ccc(C3(CN(C)C)CCOCC3)cc2)CC1
Yield: 45.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-4-(2-methoxy-ethyl)-piperidine (466 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (409 mg, 46%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.41 (t, 2H), 3.33 (s, 3H), 2.97-2.86 (m, 2H), 2.49 (t, 2H), 2.40 (s, 2H), 2.15-1.78 (m, 8H), 1.97 (s, 6H), 1.74-1.17 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:35][CH3:36])=[CH:29][N:28]=1>>[C:40]([O:39][C:37]([N:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[N:28][CH:29]=1)[CH2:34][CH2:35][CH3:36])=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: CCCN(C(=O)OC(C)(C)C)c1ccc(N)nc1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Product: CCCN(C(=O)OC(C)(C)C)c1ccc(NC(=O)Cc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)nc1

Procedure:
Using a similar procedure to that described in Example 6, 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid was reacted with 2-amino-5-(N-tert-butoxycarbonyl-N-propylamino)pyridine to give N-[5-(N-tert-butoxycarbonyl-N-propylamino) pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetamide; Mass Spectrum: M+H+ 574.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:44])[N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([C:35](C)(C)[O:36][SiH2]C(C)(C)C)[CH:29]=1)[CH3:26])([CH3:22])([CH3:21])[CH3:20].CCOC(C)=O>C1COCC1>[C:19]([O:23][C:24](=[O:44])[N:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([CH2:35][OH:36])[CH:29]=1)[CH3:26])([CH3:22])([CH3:20])[CH3:21]
Reactant: CN(Cc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.1 %

Procedure:
TBAF (1M in THF, 2.25 mL, 2.25 mmol) was added to a sol. of [3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzyl]-methyl-carbamic acid tert-butyl ester (450 mg, 1.13 mmol) in THF (11 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. EtOAc (50 mL) was added, and the resulting mixture was washed with aq. sat. NH4Cl (2×) and brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 40:60) yielded the title compound (110 mg, 34%). LC-MS: tR=0.91 min; ES+: 271.10.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]([C@H:16]1[CH2:20][CH2:19][NH:18][C@H:17]1[CH3:21])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([N:18]2[CH2:19][CH2:20][C@H:16]([C:13]([OH:12])([CH3:15])[CH3:14])[C@@H:17]2[CH3:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(Cl)c1Cl
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)c(Cl)c1Cl

Procedure:
Using 2,3-dichloro-4-fluorobenzonitrile (334 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (397.3 mg) and lithium carbonate (312 mg), the title compound was obtained as white crystals (yield: 427 mg) by an operation similar to that in Example 3.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31])#[N:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:31])#[N:25]
Reactant: N#Cc1ccccc1C=CC(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccccc1C#N
Yield: 86.3 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2-cyanocinnamic acid (2.1 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.2 g, 86%) as crystals.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=2)=[CH:9][C:8]=1[CH2:33][CH3:34])(=O)=O.C([Sn](CCCC)(CCCC)[C:42]1[N:43]=[CH:44][S:45][CH:46]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=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>[CH2:33]([C:8]1[CH:9]=[C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=3)[N:16]=[C:15]([C:29]([F:32])([F:31])[F:30])[CH:14]=2)[CH:11]=[CH:12][C:7]=1[C:42]1[N:43]=[CH:44][S:45][CH:46]=1)[CH3:34]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: CCc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(C)(=O)=O)c(F)c2)ccc1-c1cscn1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a stirred solution of 2-ethyl-4-[1-[3-fluoro-4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl trifluoromethanesulfonate (183 mg, 0.33 mmol) in dioxane (5 ml) was added 4-(tributylstannyl)thiazole (135 mg, 0.36 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol), lithium chloride (35 mg, 0.82 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:2) to give title compound (25 mg, 15% yield). mp: not detected.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14](=[O:15])[N:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:25])[C:7]3[C:14]([OH:15])=[N:13][N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:12](=[O:24])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1ccc(NN2C(=O)c3[nH]c4cc(Cl)ccc4c(=O)c3C2=O)cc1
Agent: CS(=O)(=O)O
Solvent: CO
Product: Cc1ccc(-n2nc(O)c3c(=O)c4ccc(Cl)cc4[nH]c3c2=O)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 37.1 %

Procedure:
A stirred suspension of 6-chloro-2-(4-methylanilino)-2,3,4,9-tetrahydro-1H-pyrrolo[3,4-b]quinoline-1,3,9-trione (1.60 g, 4.53 mM) in a solution of methanol (128 mL) and methanesulfonic acid (32 mL) was refluxed for 4 hours and cooled to room temperature. The resulting yellow suspension was stirred at room temperature for five days and then filtered (the filtrate was saved for use in Example 19). The collected solids were washed with methanol and then ether to give the title compound (0.594 g, 37%) as a yellow powder, mp >400° C.; MS(CI): 354 (M+H). Analysis for C18H12 ClN3O3 ·0.4 H2O: Calculated: C, 59.89; H, 3.57; N, 11.64; Found: C, 59.47; H, 3.14; N, 11.57; NMR: 13.34 (s, 1H exchangeable), 12.48 (s, 1H, exchangeable), 8.30 (d, J=8.75 Hz, 1H), 8.22 (br s, 1H), 7.62 (d, J=8.75 Hz, 1H), 7.55 (d, J=8.01 Hz, 2H), 7.33 (d, J=8.01 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8].C1C=CC=CC=1.C(Cl)([Cl:24])=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([Cl:24])=[O:8]
Reactant: O=C(Cl)Cl
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)Cl
Temperature: 35 °C

Procedure:
71.8 g. (0.288 moles) of α-(3,5-dichlorophenoxy) butyric acid and 75 ml. of benzene are placed in a 500 ml. flask to which a dropping funnel with dry-ice condenser is attached. The slurry is stirred and the 0.2 ml. dimethyl formamide is added. The mixture is heated to 35° C. and 10 g. of phosgene is condensed into the mixture to initiate reaction. The start of the reaction is evidenced by HCl evolution and foaming. 26.0 g. more phosgene is added in 5 gm. increments. At the conclusion of the reaction (HCl evolution ceasing), the reaction mixture is evaporated leaving a residual liquid α-(3,5-dichlorophenoxy) butyryl chloride 77.6 g., ND20 = 1.5345
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23](Cl)(=[O:25])=[O:24].[CH3:27][NH:28][CH3:29]>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23](=[O:25])(=[O:24])[N:28]([CH3:29])[CH3:27]
Reactant: CNC
Reactant: Nc1c(S(=O)(=O)Cl)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Product: CN(C)S(=O)(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 0 °C

Procedure:
A mixture of 5-amino-4-chlorosulphonyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (1.2 g) and dimethylamine (17.6 ml of a 40% aqueous solution) was heated on a steambath for 1 hour, cooled, and poured onto crushed ice (50 g) to give a brown solid. This solid was filtered, dried, and recrystallized from toluene to give 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(N,N-dimethylsulphamoyl)-3-trifluoromethylpyrazole (0.8 g) as light brown crystals, m.p. 177.6°-178.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH3:20][NH:21][NH2:22]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([N:21]([CH3:20])[NH2:22])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: CNN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CO
Product: CN(N)C1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
A suspension of 8.6 g. (0.03 mole) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (I) (prepared as in U.S. Pat. No. 3,422,091) in 600 ml. of methanol; is treated with 5.53 g. (0.12 mole) of methylhydrazine (II) and stirred at room temperature for about 2.5 hours. A vigorous stream of nitrogen is bubbled through the mixture during this period to remove liberated hydrogen sulfide. The mixture is concentrated under vacuum to a small volume, diluted with ice water and extracted with chloroform. The extract is washed with cold, dilute sodium chloride solution, dried with sodium sulfate and concentrated under vacuum. The residue is chromatographed on 400 g. of silica gel with a mixture of 1.5% methanol-98.5% chloroform. The product is crystallized on a rotary evaporator at about 25° C. by replacing the chloroform of a methanolchloroform solution, first with ethyl acetate and then with Skellysolve B. The yields of 7-chloro-2-(1-methylhydrazino)-5-phenyl-3H-1,4-benzodiazepine (III) are 5.07 g. having a melting point of 166.6° to 173° C. and 0.52 g. having a melting point of 175° to 176° C. The analytical sample is recrystallized from ethyl acetate-Skellysolve B having a melting point of 178.5° to 179.5° C.; ultraviolet (EtOH) end absorption, λmax. 232mμ (ε=21,400), 269 (18,300), 352 (2920); infrared absorption (Nujol) 3290, 3180 cm-1 (NH), 1645, 1590, 1575, 1565 (C=N/C=C).
Reaction SMILES: C([O:3][C:4](=[O:42])[C:5]([N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])=[CH:23][CH:22]=1)[CH:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6])C.O.[OH-].[Li+]>C1COCC1.O>[CH2:30]([NH:29][C:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:7]([C:5](=[O:6])[C:4]([OH:42])=[O:3])[CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH3:9])=[CH:26][CH:25]=1)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)OCC)C(C)c2cccc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)O)C(C)c2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The resin-bound ethyl{{4-[(dodecylamino)carbonyl]benzyl}[1-(1-naphthyl)ethyl]amino}-(oxo)acetate (described in step d, 0.0426 mmol) was swelled in THF (0.300 mL) for 15 min at rt. Lithium hydroxide monohydrate (36 mg, 0.852 mmol) diluted in H2O (0.060 mL) was added and the resulting reaction mixture was shaken 14 h at rt. The resin was washed successively with THF (1×15 min), H2O (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound {{4-[(dodecylamino)carbonyl]benzyl}[1-(1-naphthyl)-ethyl]amino}(oxo)acetic acid which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:11])[CH:9]=[CH2:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH:9]=[CH2:10]
Reactant: C=CC(O)c1ccccc1Br
Reactant: C1=COCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CC(OC1CCCCO1)c1ccccc1Br

Procedure:
To 1-(2-bromophenyl)prop-2-en-1-ol) (31.0 g; 0.145 mol) in 150 ml of dry THF (tetrahydrofuran) was added 20 ml of 3,4-dihydro-2H-pyran and then 1 ml of POCl3 and the mixture stirred over the weekend at room temperature. The reaction mixture was neutralized with saturated NaHCO3 and concentrated down. The resulting material was partitioned between water and diethyl ether and the aqueous layer extracted again with diethyl ether. The organics were combined and washed with water and then brine and dried over K2CO3 and concentrated. The crude subtitle compound was chromatographed by HPLC using a solvent gradient from pure hexane to 5% ethyl acetate in hexane to afford the subtitle compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](Cl)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C([N+:25]([O-])=O)=CC=C(O)C=1.N1C=CC=CC=1>C(Cl)Cl>[NH2:25][C:13]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9](=[O:18])(=[O:17])[N:10]=[C:11]([O:15][CH3:16])[N:12]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(N)=N1

Procedure:
A solution of 2-benzyl-3-chloro-5-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide (3.8 g) in methylene chloride (10 ml) is added dropwise to a stirred mixture of p-nitrophenol (1.7 g) and pyridine (2.4 g) in methylene chloride (20 ml). The reaction mixture is heated to reflux for 3 hours, cooled, washed with 3N aqueous HCl and saturated aqueous Na2CO3. The methylene chloride layer is dried over MgSO4, filtered and evaporated in vacuo yielding the desired product as an oil.