Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](O)=O.Cl.CN(C)CCCN=C=NCC.N1C=CC=CC=1.[F:28][C:29]([F:64])([F:63])[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[N:41]=C(C3C=CC=CN=3)[NH:43][C:39]=2[CH:38]=1)=[O:31]>C(OCC)(=O)C>[F:64][C:29]([F:28])([F:63])[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]1[C:51]([O:52][C:53]2[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=2)=[CH:50][C:40]2[N:41]=[C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[NH:43][C:39]=2[CH:38]=1)=[O:31]
Reactant: O=C(O)c1cnccn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2C2CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
14.5 mg of pyrazine-2-carboxylic acid and 27.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride were added in order to a pyridine (1 ml) solution of 53 mg of 1-(2-(4,5-diamino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone obtained in Example 162 (step 6), and the reaction liquid was stirred at room temperature for 3 hours. The reaction liquid was diluted with saturated saline, and extracted with ethyl acetate. The organic layers were combined, washed with aqueous saturated ammonium chloride and aqueous saturated sodium bicarbonate in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was dissolved in 1 ml of toluene. 9.9 mg of p-toluenesulfonic acid monohydrate was added to it, and the reaction liquid was stirred at 120° C. for 6 hours. After cooled, the reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as an oily substance.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=O)[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH2:13]([NH2:17])[CH2:14][CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:13]([N:17]1[C:1](=[O:12])[CH2:2][C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7])[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCCN
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCCN1C(=O)Cc2ccccc2C1=O
Temperature: 160 °C
Yield: 37.7 %

Procedure:
Homophthalic anhydride (1.5 g, 9.25 mmol), 3-buten-1-amine (1.129 ml, 11.10 mmol), and 4 A molecular sieves (300 mg) were combined in toluene (15 ml) and heated to 160° C. in a microwave for 40 minutes. The reaction mixture was diluted with CH2Cl2 and the slurry was filtered over CELITE. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (gradient elution, 10-20% EtOAc/Hexane) to afford the title compound (0.75 g, 36%) as an oil. LCMS (ES+) m/z 216.03 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[Cl:24][C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:30]([C:28]2[S:29][C:25]([Cl:24])=[CH:26][CH:27]=2)=[O:31])[S:3][CH:4]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc(Cl)s1

Procedure:
37.5 Using general procedure D, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone was coupled with 5-chlorothiophene-2-carboxylic acid to give 5-chloro-thiophene-2-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. Light yellow amorphous solid. MS 482.4 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C([O-])([O-])=O.[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Cl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH:32]3[CH2:33][O:34]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: ClCC1CO1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.100 g, 0.316 mmol) in DMF (5 ml) was added K2CO3 (0.066 g, 0.474 mmol). The resulting mixture was stirred at room temperature for 30 minutes, after which time epichlorohydrin (0.044 g, 0.474 mmol) was added. The reaction was heated to 100° C., stirred at this temperature for 2 h and then diluted with EtOAc before being washed with water and brine. Drying over Na2SO4 and removal of solvent under vacuum gave 2-(2,6-difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4-carboxamide (0.102 g, 0.274 mmol, 87%) as a golden oil. LCMS (1) 2.00 min; m/z (ES+) 374.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][C:12](=O)[NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.[Na]>O1CCOCC1>[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: [Na]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CCNCC2

Procedure:
A solution of glacial acetic acid (1.8 g) in dioxan (10 ml) is added dropwise to a suspension of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.3 g, 6 mmol) and sodium borohydridel (1 g, 3 mmol) in dioxan (20 ml), refluxed for 3 hours, concentrated by evaporation and decomposed with water. The mixture is extracted twice with methylene chloride, the extract is concentrated by evaporation and the residue is taken up in ether. After filtration the ether is eliminated in vacuo.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[C:21]=1F.C(O[K])(C)(C)C.O>CN(C)C(=O)C>[F:19][C:20]1[CH:21]=[C:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:24][C:25]=1[O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: CS(=O)(=O)c1cccc(F)c1F
Agent: CC(C)(C)O[K]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(S(C)(=O)=O)cc4F)cc23)n1
Temperature: 77 °C
Reaction time: 12 h
Yield: 28.1 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (250 mg; 1.033 mmol) and 424 mg (2.219 mmol) of the above-prepared sulfone compound were added to a solution of 320 mg (2.857 mmol) of tert-butoxy potassium in 24 ml of N,N-dimethylacetamide and the mixture was stirred at 77° C. for 12 hours. To the reaction solution was added water followed by extracting with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a reversed phase preparative HPLC (0.1% TFA-containing water:acetonitrile=90:10→10:90) to give 120 mg (yield: 28%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:21])[CH:3]=1.[F-].[NH4+].[CH2:24](OCC)[CH3:25]>C1(C)C=CC=CC=1>[CH:19]([O:18][C:16]([C:8]1[CH:9]([C:12]([F:15])([F:14])[F:13])[O:10][C:11]2[C:2]([CH:24]=[CH2:25])=[CH:3][C:4]([Cl:21])=[CH:5][C:6]=2[CH:7]=1)=[O:17])=[CH2:20]
Reactant: CCOCC
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=COC(=O)C1=Cc2cc(Cl)cc(C=C)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
In a 100 mL round bottomed flask under N2, ethyl 8-bromo-6-chloro-2-trifluoromethyl-2H-benzopyran-3-carboxylate (Example 74, Step 1)(2.21 g, 5.73 mmol) was dissolved in toluene (30 mL of anhydrous reagent). Tetrakis (triphenylphosphine)palladium(0) (0.132 g, 0.115 mmol) was added, followed by tributylethyenylstannane (2.0 g, 6.31 mmol). The resulting solution was heated to reflux for 5 hours. The reaction mixture was allowed to cool to room temperature, was poured into 50 mL of 20% ammonium fluoride solution and stirred for one hour. Diethyl ether (100 mL) was added and the mixture was washed with water (2×50 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield a yellow oil. The crude material was purified by flash chromatography (0.5% ethyl acetate in hexanes) to afford the ester as a yellow solid (0.86 g, 45%): mp 75.9–77.2° C. 1H NMR (CDCl3/300 MHz) 7.64 (s, 1H), 7.45 (d, 1H, J=2.5 Hz), 7.12 (d, 1H, J=2.6 Hz), 6.92 (dd, 1H, J=17.7 Hz, 11.3 Hz), 5.81 (d, 1H, J=17.7 Hz), 5.76 (q, 1H, J=6.8 Hz), 5.41 (d, 2H, J=11.1 Hz), 4.36–4.29 (m, 2H), 1.36 (t, 3H, J=7.3 Hz). FABLRMS m/z 350.1 (M+NH4+). ESHRMS m/z 350.0796 (M+NH4+, Calc'd. 350.0771). Anal. Calc'd. for C15H12ClF3O3+4.07% H2O: C, 51.95; H, 3.94. Found: C, 51.67; H, 3.69.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[N+](=[CH2:11])=[N-]>CCOCC.C(O)(=O)C>[CH3:11][O:7][C:1](=[O:8])[CH2:2][C:3]#[C:4][CH2:5][CH3:6]
Reactant: CCC#CCC(=O)O
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCC#CCC(=O)OC

Procedure:
A solution of 5.9 g of 3-hexynoic acid in 50 ml of ether is treated with a slight excess of ethereal diazomethane solution. A few drops of glacial acetic acid are added to the mixture, the mixture is concentrated in vacuo and then distilled. 5.65 g of the title compound are obtained: b.p. 62° C. (5 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28])([O-:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:27]([C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:25])([F:26])[F:24])=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:28])=[O:29])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: COc1ccc(N)c2ncccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2[N+](=O)[O-])c2ncccc12
Yield: 73.1 %

Procedure:
In a similar fashion using route 18 general procedure 27, 5-methoxy-quinolin-8-ylamine 586 (280 mg, 1.6 mmol), 2-nitro-4-(trifluoromethyl) benzenesulfonyl chloride (600 mg, 2.0 mmol), pyridine (0.39 ml, 4.8 mmol) DMAP (cat.) and DCM (15 ml) gave the title compound (500 mg, 73%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:34][N:35]([CH3:54])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:47]=[C:48]([CH2:52]O)[CH:49]=[CH:50][CH:51]=2)=[N:44][CH:45]=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[CH3:54][N:35]([CH3:34])[CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[N:44][C:43]([C:46]2[CH:47]=[C:48]([CH:49]=[CH:50][CH:51]=2)[CH2:52][N:6]2[C:5]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=3[O:3][C:2]2=[O:1])=[N:42][CH:41]=1
Reactant: CN(C)CCCOc1cnc(-c2cccc(CO)c2)nc1
Reactant: COC(=O)c1ccc2oc(=O)[nH]c2c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2oc(=O)n(Cc3cccc(-c4ncc(OCCCN(C)C)cn4)c3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.84 g (9.5 mmol) of methyl 2-oxo-2,3-dihydrobenzoxazole-5-carboxylate and 4.75 g (14.25 mmol) of polymer-bound triphenylphosphine (3 mmol/g) are added to a solution of 3.03 g (10.45 mmol) of {3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}methanol in 40 ml of THF. The suspension is shaken at room temperature for 30 min. The suspension is cooled in an ice bath, and 3.35 g (14.25 mmol) of di-tert-butyl-azodicarboxylate are added in portions. After the mixture has been stirred at room temperature for 24 h, a further 4.75 g (14.25 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 3.35 g (14.25 mmol) of di-tert-butyl azodicarboxylate are added, and the mixture is shaken at room temperature for a further 24 h. The reaction mixture is filtered, the filtrate is evaporated to dryness, and the residue is purified by column chromatography on silica gel, giving 947 mg of “A64”; m.p. 125° C., ESI: 463 (M+H); Rt=3.07 min (method C);
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[O:21][CH2:20][C:19]([F:23])([F:22])[F:18])[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: OCC(F)(F)F
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1OCC(F)(F)F

Procedure:
To a solution of sodium β,β,β -trifluoroethoxide in β,β,β-trifluoroethanol (prepared by dissolving 2.1 g of sodium in 45 ml of β,β,β-trifluoroethanol), 4-chloro-3-nitro-5-sulphamyl-benzoic acid (4.2 g) was added, and the resulting solution was refluxed for 5 days. After evaporation of the reaction mixture in vacuo, water (50 ml) was added, and the aqueous solution was acidified with 4N hydrochloric acid. After standing in a refrigerator, the precipitate was collected by suction. After several recrystallizations from aqueous ethanol, the 3-nitro-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoic acid was obtained with a melting point of 195°-197° C.
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:33])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=2)=[C:9]([N:11](C(=O)C)C(=O)C)[N:10]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[NH:6][C:7](=[O:33])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[C:9]([NH2:11])[N:10]=1
Reactant: CCOC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N)c(CCCNc2ccc(C(=O)O)cc2)c(=O)[nH]1
Temperature: 70 °C
Yield: 77.2 %

Procedure:
To a solution of 0.22 g (0.47 mmol) of ethyl 4-[3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propylamino]benzoate in 7.0 ml of 95% ethyl alcohol was added 15 ml of 1.0 N NaOH. The reaction was heated at 70° C. for 20 hours. The mixture was reduced by spin evaporation in vacuo to a 10-ml volume and adjusted to pH 5 with 1.0 N HCl. The precipitate was collected by filtration, washed with water, and dried in vacuo to yield 0.11 g (71% of theory) of 4-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propylamino]benzoic acid one-half sodium salt as a white solid, mp 273°(dec.); HPLC on Versapack C-18 (10 micron; 4.6×250 mm) with aqueous 60% methanol containing 0.2% trifluoroacetic acid gave one major peak, k1 =0.58; NMR (DMSO-d6)δ1.58 (m, 2H, CCH2C), 2.24 (t, 2H, Het-CH2), 3.02 (m, 2H, CH2N), 5.77 (br s, 2H, NH2), 5.94 (br s, 2H, NH2), 6.46 (t, 1H, NH-Ar), 6.54 (d, 2H, Ar), 7.65 (d, 2H, Ar), 9.80 (br s, 1H, NH), 11.95 (br s, 0.5 H, CO2H). Elemental analysis. Calculated for C14H16N5O3Na0.5.0.75 H2O (MW 327.82); C, 51.29; H, 5.53; N, 21.36; Na, 3.51. Found: C, 51.34; H, 5.39; N, 21.32; Na, 3.33.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:41]([N:45]1[C:50]2=[N:51][NH:52][C:53]([NH:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[C:49]2[C:48](=[O:61])[N:47]([CH3:62])[C:46]1=[O:63])[CH:42]([CH3:44])[CH3:43].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:41]([N:45]1[C:50]2=[N:51][N:52]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH2:14][CH2:13][CH2:12][CH2:11][N:10]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=3)[C:53]([NH:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[C:49]2[C:48](=[O:61])[N:47]([CH3:62])[C:46]1=[O:63])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(CO)cc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)[nH]nc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(C4CCCCN4C(=O)OC(C)(C)C)cc3)nc21
Temperature: -78 °C
Yield: 81 %

Procedure:
tert-butyl 2-(4-(hydroxymethyl)phenyl)piperidine-1-carboxylate (47 mg, 0.16 mmol) is dissolved in 1 mL of anhydrous THF, and then triphenylphosphine (42 mg, 0.16 mmol) is added, followed by 7-isobutyl-5-methyl-3-(phenylamino)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (50 mg, 0.16 mmol). The mixture is cooled to −78° C., and then DIAD (95%, 50 μL) is added slowly. After the reaction is complete, the mixture is purified on a basic alumina column to give 76 mg of product (yield: 81%). MS (ESI) m/z 587.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[CH3:13][S-:14].[Na+]>O1CCCC1>[F:9][C:7]1[CH:6]=[CH:5][C:4]([N+:10]([O-:12])=[O:11])=[C:3]([CH2:2][S:14][CH3:13])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSCc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10.0 g (42.7 mmol) of the compound from Example 1A were introduced into 100 ml of tetrahydrofuran at RT, 3.29 g (47.0 mmol) of sodium methanethiolate were added, and the mixture was stirred at RT for 4 h. It was filtered with suction through kieselguhr and washed with tetrahydrofuran, and the filtrate was concentrated to result in 9.00 g (100% of theory) of the title compound which were reacted without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.CO>O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 320 g of polyphosphoric acid (111.8% phosphoric acid) heated at 80°-95° C. was added 0.72 g (5.1 mmole) of sodium sulfate followed by 72 g (0.1915 mole) of essentially salt-free 2,5-di(4-methylanilino)terephthalic acid. The mixture was heated at 120°-125° C. for two hours. The viscous solution was cooled to 90°-95° C. and then slowly poured into a mixture of 468 g of methanol and 52 g of water (i.e., 90% aqueous methanol) at 40° C. The temperature of the resultant slurry was allowed to rise during the addition to about 64° C., with the temperature being controlled during addition by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour, cooled to 60° C., and diluted with 600 g of water. After the slurry was stirred at 60° C. for 30 minutes, the solid component was collected by filtration and washed with water until acid-free. The resultant presscake was reslurried in 800 g of aqueous sodium hydroxide, then heated at about 90°-95° C. The slurry was cooled, filtered, and washed with water until free of alkali, then reslurried in water. The resultant slurry was heated at 140°-145° C. in a closed system (e.g., a pressure reactor), cooled, acidified to pH 3.5 with phosphoric acid, treated with an aqueous emulsion of sodium dioctyl sulfosuccinate and VM&P Naphtha (available from Unocal Chemicals), and stirred. The solid component was collected by filtration and washed with water. The wet cake can be oven dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give about 60 g of 2,9-dimethylquinacridone as a brilliant magenta solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[C:10]3[C:5]2=[C:6]([CH:22]=1)[C:7](=[O:21])[N:8]([OH:20])[C:9]3=[O:19].C1C(=O)N([Cl:30])C(=O)C1.O>C(O)(=O)C>[Br:1][C:2]1[CH:22]=[C:6]2[C:5]3=[C:10]([CH:11]=[C:12]([Cl:30])[C:13]([N:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:4]3[CH:3]=1)[C:9](=[O:19])[N:8]([OH:20])[C:7]2=[O:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1c2ccc(N3CCCC3)c3cc(Br)cc(c23)C(=O)N1O
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(Br)cc3c(N4CCCC4)c(Cl)cc(c23)C(=O)N1O
Yield: 43.3 %

Procedure:
A mixture of 5-bromo-2-hydroxy-7-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.15 g, 0.42 mmol, from Example 59) and NCS (0.072 g, 0.54 mmol) in acetic acid (12 mL) was reacted at 100° C. for 3 hours. The reaction mixture was cooled and poured into water. The resulting precipitate was collected by filtration, washed with water, and dried to give 0.072 g of the title compound.
Reaction SMILES: [NH3:1].[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:14](Cl)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1>>[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:14]([NH2:1])(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
An aqueous solution of NH3 (32%) is added at room temperature to a solution of 3,5-bis-(trifluoromethyl)benzene-sulfonylchloride in EtAc. The mixture obtained is stirred and two phases obtained are separated, the organic layer obtained is washed with 1 N HCl and H2O, and dried. Solvent of the organic solution obtained is evaporated. 3,5-Bis-trifluoromethyl-benzene sulfonamide is obtained.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Br:17])=[C:9]([O:14][CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)NC(C)(C)C)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C(=O)NC(C)(C)C)ccc1CBr
Temperature: 30 °C
Reaction time: 48 h

Procedure:
A mixture of 3 g of N-tert-butyl-4-methyl-3-methoxybenzamide, 2.4 g of N-bromosuccinimide, 0.16 g of benzoyl peroxide in 40 ml of carbon tetrachloride is stirred at 30° C., under irradiation with visible light for 48 hours. The solvent is evaporated off, then in succession 25 ml of water is added, the mixture is extracted with diethyl ether, dried over magnesium sulfate, the solvent is evaporated off and the residue is chromatographed on silica gel, eluting with an 8/2 cyclohexane/ethyl acetate (v/v) mixture. The expected reactant is isolated after crystallisation from isopropyl ether; M.p.=114° C.