Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[CH:3]=1.OS(O)(=O)=O.[BrH:15].N(C(C)(C)C#N)=NC(C)(C)C#N.OO>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:15])=[C:4]([F:9])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1F
Reactant: Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: OO
Solvent: Clc1ccccc1
Product: Fc1cc(Cl)ccc1CBr

Procedure:
361.5 g of 4-chloro-2-fluorotoluene, 520 g of chlorobenzene, 6 g of conc. H2SO4, 467 g of 47% strength hydrobromic acid and 2.7 g of 2,2'-azobis(2-methylpropionitrile) were mixed at 70° C. in a 4 l stirred apparatus. 620.5 g of a 10% strength aqueous hydrogen peroxide solution and a solution of 16.5 g of 2,2'-azobis(2-methylpropionitrile) in 270 g of chlorobenzene were simultaneously added dropwise over the course of 1.5 hours. The mixture was then stirred at 70° C. for 1 hour. GC analysis of the org. phase:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7](O)[CH2:6][C@H:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2].CS(Cl)(=O)=O>ClCCl.C(N(CC)CC)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H](O)C[C@H]1c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C=CC1c1ccccc1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
6.0 g (17.9 mmol) of rel-(7S,9S)-10-acetyl-7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (racemic) are dissolved in 100 ml of dichloromethane and 20 ml of triethylamine. A solution of 2.9 g (25 mmol) of methanesulphonyl chloride in 5 ml of dichloromethane is then added dropwise with ice cooling within 30 min. After 2 h, hydrolysis is effected using water and extraction using dichloromethane. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized using diethyl ether. 4.8 g (85%) of the title compound are isolated as a pale brown solid (m.p. 170° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[C:11]1([CH2:17][C:18]#[CH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:19]#[C:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: C#CCc1ccccc1
Reactant: Cc1nc(N)nc(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N)c1C#CCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.3 %

Procedure:
A reaction vessel containing 0.8 gram (0.0032 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 0.5 mL (0.0042 mole) of 3-phenyl-1-propyne, 0.2 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, 0.05 gram (catalyst) of copper iodide, and 8 mL of triethylamine is evacuated and refilled with dry nitrogen gas three times. The reaction mixture is then stirred at ambient temperature for about 60 hours. After this time, the reaction mixture is diluted with 100 mL of water. The mixture is then extracted with three 75 mL portions of ethyl acetate. The combined extracts are washed with three 75 mL portions of an aqueous 5% lithium chloride solution. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 5-15% methanol methylene chloride mixtures as eluants. The appropriate product-containing fractions are combined and concentrated under reduced pressure, yielding 0.3 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine. The NMR spectrum is consistent with the proposed structure. Other fractions containing less pure product are combined and concentrated under reduced pressure to a residue. This residue is subjected to column chromatography on neutral alumina, using 2.5-10% methanol in methylene Chloride mixtures as eluants. The product-containing fractions are combined and concentrated under reduced pressure, yielding an additional 0.2 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine. The NMR spectrum is consistent with the proposed structure. The two solids are combined, yielding about 0.5 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine, mp 145°-149° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([CH3:32])([OH:31])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.CN(C=O)C.[H-].[Na+]>O>[CH3:32][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([N:19]=[CH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[O:31][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCN(N=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 2.5 h
Yield: 66.6 %

Procedure:
To a mixture of (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-{4-[(4-trifluoromethylbenzylidene)amino]piperazin-1-yl}propan-2-ol prepared in Example 496 (847 mg, 0.85 mmol) and DMF (4 ml), sodium hydride (69 mg, 1.73 mmol) was added followed by stirring for 2.5 hours with cooling on ice-bath. To the reaction mixture, water was added, and the precipitates were filtered off. The resulting solid was washed with methanol and recrystallized from acetone/water to afford (S)-N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethylbenzylidene)amine (248 mg, yield 69%) as a light yellow powder.
Reaction SMILES: C([O:8][C:9](=[O:30])[C@@H:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:11]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH2:24]([O:23][C:21]([CH2:20][CH2:19][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[C@@H:10]([C:9]([OH:30])=[O:8])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:22])[CH3:25]
Reactant: [H][H]
Reactant: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CC(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CC(C)C)C(=O)O
Yield: 93 %

Procedure:
N-[2-(ethoxycarbonyl)ethyl]-N-t-butyloxycarbonyl-D-leucine benzyl ester (837 mg) was dissolved in methanol (25 ml), and 10% palladium-carbon (90 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless oil (612 mg, 93%), which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=O.Cl.[NH2:21][OH:22].O>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[N:21][OH:22]
Reactant: NO
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: ON=CC1=C(Cl)c2ccccc2OC1c1ccccc1

Procedure:
A solution of 27 g 4-chloro-3-formyl-flav-3-ene in 25 ml dimethylformamide is refluxed. To this solution one adds 7.7 g hydroxylamine hydrochloride dissolved in 60 ml dimethylformamide. After two hours reflux, the solution is cooled at room temperature before the addition of 400 ml water. The precipitate is formed, filtered, washed with water and dried. The solid is crystallized in diisopropylether. Pure 4-chloro-3-hydroxyiminomethyl-flav-3-ene is obtained as pale yellow crystals; m.p. 199°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[C:13]([NH2:20])[CH:12]=3)=[CH:7][CH:6]=1)=[O:4].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([NH:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17](=[O:19])[CH:18]=[C:9]([C:8]3[CH:21]=[CH:22][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[O:10]2)=[CH:15][CH:14]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2cc(=O)c3ccc(N)cc3o2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2cc(=O)c3ccc(NC(C)=O)cc3o2)cc1
Yield: 56 %

Procedure:
The mixture consisting of 2 g of 7-amino-4'-flavonecarboxylic acid methyl ester thus prepared, 30 cc of pyridine, 15 cc of acetic anhydride is heated at 40° for 2 hours with stirring. Completion of the reaction is verified by thin-layer chromatography (benzene (90)-dioxane (25)-acetic acid (4) elution solvent). The reaction mixture is poured in 500 cc of ice water. The solid that is formed is filtered, washed with water and dried by formation of an azeotropic system with benzene. Yield 56%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:17]1(=[O:36])=[O:35])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([N:16]1[C:20](=[O:21])[C:19]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[O:8])[CH2:25][CH2:24]2)=[C:18]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:17]1(=[O:36])=[O:35])([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)c3ccc(C#N)cc3)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 11 %

Procedure:
The title compound was prepared as described for Example 105 from 4-cyanobenzoyl chloride and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) using DMF as solvent. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 50% EtOAc in petroleum ether 40-60° C. as eluent. The product containing fractions were evaporated, dissolved in DCM, washed through a cation exchange column and evaporated to give the title compound (0.015 g, 11%). 1H NMR (500 MHz CDCl3): δ 7.70 (d, 1H), 7.55-7.50 (m, 2H), 7.49-7.40 (m, 5H), 5.21 (d, 1H), 4.52-4.40 (m, 1H), 3.50-3.36 (m, 1H), 3.24-3.14 (m, 2H), 2.62-2.44 (m, 2H), 1.92-1.78 (m, 1H), 1.74 (s, 9H), 1.67-1.54 (m, 2H), 1.48-1.16 (m, 2H); 13C NMR (125 MHz CDCl3): δ 168.5, 159.7, 140.1, 133.9, 132.7, 131.8, 130.3, 129.0, 127.7, 125.2, 118.2, 113.9, 107.9, 61.9, 50.1, 46.0, 40.9, 32.9, 32.1, 27.8; M+H+ 493.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]([C:25](=O)[CH3:26])=[CH:16][C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([CH2:31][CH2:32][O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])#[N:30]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:15]2[CH:16]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[C:35]([C:34]([O:33][CH2:32][CH2:31][C:29]#[N:30])=[O:39])=[C:36]([CH3:37])[NH:38][C:25]=2[CH3:26])=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C/C(N)=C/C(=O)OCCC#N
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC#N)C(c2cc(Cl)cc(Cl)c2)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.66 g (3.88 mmol) of 4-[2-acetyl-3-(3,5-dichlorophenyl)-2-propenoyl] piperazine-1-carboxylic acid t-butyl ester and 598 mg (3.88 mmol) of 3-aminocrotonate 2-cyanoethyl ester were stirred in 30 ml of 2-propanol at 80° C. overnight and then stirred at 120° C. for 2 hours. After concentration under reduced pressure, ethyl acetate was added and the residue was washed with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1 to 30/1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:29])[CH3:22]
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(C)CCCCN
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-dimethylbutane-1,4-diamine (29.1 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light salmon solid, 65.5 mg, (73% yield) MS (ES+): 366.2, (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:4][CH2:3]1>CCOC(C)=O.CO>[CH3:20][O:19][C:12]1[CH:11]=[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:15]=[CH:14][C:13]=1[NH2:16]
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCN2CCN(C)CC2)ccc1N
Reaction time: 8 h
Yield: 85.6 %

Procedure:
1-Methyl-4-{2-[3-(methyloxy)-4-nitrophenyl]ethyl}piperazine (0.6 g, 2.15 mmol) was placed in a 100 mL high pressure vessel and dissolved in 30 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.42 g, 0.107 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (50 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step D (0.460 g, 1.84 mmol, 86%). 1H NMR (400 MHz, CDCl3) δ ppm 6.60-6.64 (m, 3H), 3.82 (s, 3H), 3.64 (bs, 2H), 2.64-2.73 (m, 2H), 2.38-2.63 (m, 10H), 2.29 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([CH:19]([F:21])[F:20])[CH:15]=[CH:16][CH:17]=3)[C:12]([N:22]([S:32]([C:35]3[S:36][C:37]([Cl:40])=[CH:38][CH:39]=3)(=[O:34])=[O:33])[S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[Cl:31][C:28]1[S:27][C:26]([S:23]([N:22]([S:32]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)(=[O:33])=[O:34])[C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH:19]([F:20])[F:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:48](=[O:50])[CH3:49])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCc1cccc(Cn2nc(N(S(=O)(=O)c3ccc(Cl)s3)S(=O)(=O)c3ccc(Cl)s3)c3c(C(F)F)cccc32)c1
Reaction time: 1 h

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-4-(difluoromethyl)-1H-indazol-3-yl]-5-chloro-N-[(5-chloro-2-thienyl)sulfonyl]-2-thiophenesulfonamide (for a preparation see Intermediate 70) (26 mg, 0.039 mmol) was suspended in dichloromethane (0.5 mL) and triethylamine (0.055 mL, 0.39 mmol) and then acetic anhydride (0.004 mL, 0.043 mmol) was added to the suspension. The mixture was stirred for 1 h, and concentrated under a stream of nitrogen to give N-[(3-{[3-{Bis[(5-chloro-2-thienyl)sulfonyl]amino}-4-(difluoromethyl)-1H-indazol-1-yl]methyl}phenyl)methyl]acetamide, which was used without further purification. The residue was dissolved in methanol (2 mL) and treated with NaOH (0.553 mL, 1.105 mmol) and the reaction mixture was stirred at 60° C. for 3 h. LCMS showed the reaction had gone to completion so the mixture was concentrated in vacuo and acidified with 5% citric acid. The solution was extracted with ethyl acetate and the organic layer was washed twice with water (25 mL) and once with brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo to give a yellow residue which was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (7 mg, 36%). LCMS (System A) RT=1.02 min, ES+ve m/z 525/527 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:12][C:11]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:10]=2[CH3:9])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: Clc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1

Procedure:
4,6-Dichloropyrimidine (5.37 g, 36.0 mmol) and 2-methyl-5-nitroaniline (5.48 g, 36.0 mmol) are heated in n-butanol (58 mL) with diisopropylethylamine (4.66 g, 36 mmol) for 3 days at 110° C. The mixture is evaporated and the product is purified by standard methods.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([Cl:19])=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(O)c2C(=O)c2c(Cl)ccc(Cl)c21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2cccc(OCc3ccccc3)c2C(=O)c2c(Cl)ccc(Cl)c21
Yield: 86.8 %

Procedure:
A mechanically stirred mixture of 177.2 g (0.605 mol) of 1,4-dichloro-5-hydroxy-9,10-anthracenedione (1, British Pat. No. 1,029,448), 83.5 g (0.605 mol) of powdered anhydrous potassium carbonate, 79 ml (0.675 mol) of benzyl bromide, and 1.7 l of dry acetone was heated at reflux for three days. The initial dark brown suspension changed to an olive green color signaling the end of the reaction. The mixture was filtered hot and the salts were washed with hot acetone. The cooled filtrate was concentrated to ~1/2 of its volume. The yellow precipitate was collected by filtration, washed with acetone and methanol, and dried at 200 mm/50° C./12 hr to leave 201.2 g (87%) of 2, mp 122°-126° C.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]1([N:14]2[C:18](Cl)=[N:17][N:16]=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:20]1[O:22][CH:21]1[CH2:23][OH:24]>CCCCCC>[O:22]1[CH2:20][CH:21]1[CH2:23][O:24][C:18]1[N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=[N:16][N:17]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: c1ccc(-n2nnnc2OCC2CO2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium hydride (11.9 g., 0.050 mole), washed free of mineral oil with hexane, was stirred in 1.8 l. of DMF at ice-water temperature while a solution of 72.3 g (0.40 mole) of 1-phenyl-5-chlorotetrazole and 29.6 g. (0.04 mole) of glycidol in 1.8 l. of DMF was added dropwise during 4 hours. The solution was allowed to stand at 25° overnight (16 hours), diluted with 12 l. of H2O and extracted with ethyl acetate. The extracts were washed with water, dried (Na2SO4), and evaporated to give 75.7 g. of product, m.p. 77°-81°. Recrystallization from MeOH-i-PrOH gave 55.8 g., m.p. 83°-84°.
Reaction SMILES: Cl.C(N[CH2:7][C:8]1[C:9]([OH:30])=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH:13]=1)(C)(C)C.BrC1C=C(Br)C=C(C=[O:36])C=1O>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:13]=[C:8]([CH:7]=[O:36])[C:9]([OH:30])=[C:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:11]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: CC(C)(C)NCc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Product: O=Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
3,3″,4,4″-Tetrachloro-4′-hydroxy-[1,1′:3′,1″-terphenyl]-5′-carbaldehyde was prepared using the procedure described in Intermediate 5 from 3,5-dibromosalicylaldehyde and 3,4-chlorophenylboronic acid.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH2:8][N:9]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:10]2[N:15]=[C:14]3[N:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[C:18]([CH3:19])[C:13]3=[CH:12][C:11]=2[CH:24]=O)[CH2:7][CH2:6]1.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH2:42][NH2:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.C([BH3-])#N.[Na+]>CO>[F:30][C:31]([F:44])([F:45])[C:32]1[CH:33]=[C:34]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:42][NH:43][CH2:24][C:11]1[CH:12]=[C:13]2[C:18]([CH3:19])=[N:17][N:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]2=[N:15][C:10]=1[N:9]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[CH2:8][CH:5]1[CH2:7][CH2:6]1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(C=O)cc12
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Reaction time: 0.33 h

Procedure:
Acetic acid (2.82 g, 46 mmol) was added to a mixture of 6-(bis(cyclopropylmethyl)amino)-1-(tert-butyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (8 g, 23 mmol) and (3,5-bis(trifluoromethyl)phenyl)methanamine (5.7 g, 23 mmol) in methanol at 0° C. The resulting mixture was stirred continuously for 20 min. Sodium cyanoborohydride (4.5 g, 70 mmol) was added portion wise to the reaction mixture at 0° C. and the mixture was stirred for 1 h. After which the mixture was quenched with water, organic layer was separated, washed with brine, dried and evaporated to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1>[CH3:20][S:21]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCOCc1ccccc1

Procedure:
The 3-benzyloxypropanol (Aldrich, 0.28 g, 1.7 mmol), triethylamine (0.67 mL, 5.0 mmol), and methanesulfonyl chloride (0.19 mL, 2.5 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [CH:1]1[C:6]2C(OC(=O)[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=O)=O.O[C:18]1[C:19]([CH3:31])=[N:20][C:21]2[C:26]([C:27]=1C(O)=O)=[CH:25][CH:24]=[CH:23][CH:22]=2.[N+](C1C=CC=CC=1)([O-])=O>>[CH:24]1[CH:25]=[C:26]2[CH:27]=[CH:18][C:19]([CH:31]3[C:15](=[O:16])[C:2]4[C:3](=[CH:4][CH:5]=[CH:6][CH:1]=4)[C:12]3=[O:14])=[N:20][C:21]2=[CH:22][CH:23]=1
Reactant: Cc1nc2ccccc2c(C(=O)O)c1O
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)C1c1ccc2ccccc2n1
Reaction time: 1 h

Procedure:
65.4 Parts of pyromellitic acid dianhydride and 61 parts of 3-hydroxy-2-methyl-quinoline-4-carboxylic acid are heated under reflux at 205° in 1000 parts of nitrobenzene for 1 hour, distilling off the water produced by the reaction. The mixture is held at this temperature for 31/2 hours. The mixture is then cooled to 10° and after stirring at this temperature for 1 hour, is filtered and the product is washed in toluene and ethanol. 93 parts of a dark brown quinophthalone intermediate result.