Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([C:6]([Br:14])=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:15].[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28](O)=O)=[CH:26][C:25]([O:31][CH3:32])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Br:14][C:6]1[C:5]2=[CH:4][C:3]([Cl:15])=[C:2]3[C:10]([C:11](=[O:13])[O:12][C:28]([C:27]4[N:23]([C:18]5[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=5)[N:24]=[C:25]([O:31][CH3:32])[CH:26]=4)=[N:1]3)=[C:9]2[NH:8][N:7]=1
Reactant: Nc1c(Cl)cc2c(Br)n[nH]c2c1C(=O)O
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
To a suspension of 400 mg (1.38 mmol) of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid in 16 mL of anhydrous tetrahydrofuran at 10° C., is added 349 mg (1.38 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid followed by 499 μL (6.20 mmol) of pyridine. Then the suspension is cooled to 0° C. and 376 μL (4.82 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature over the night. The reaction is not complete and therefore 166 μL (2.07 mmol) of pyridine are added followed by 349 mg (1.38 mmol) of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid. The reaction is stirred again at ambient temperature for 5 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated and washed with cold water. The pale yellowish product obtained is purified by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 200 mg (0.47 mmol, 34%) of the product as a solid; LC/MS:509/511 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:24](=[O:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(N(CC)CC)C.CC1C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:20]2[O:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][N:22]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CCOC(=O)C(=O)NNC(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a stirred solution of ethyl 2-(2-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carbonyl)hydrazinyl)-2-oxoacetate (1.1894 g, 2.731 mmol) was in CH2Cl2 (23.78 mL) was added triethylamine (552.7 mg, 761.3 μL, 5.462 mmol), followed by 4-methylbenzenesulfonyl chloride (520.7 mg, 2.731 mmol) and the resulting solution stirred at room temperature for 3 h. The reaction mixture is diluted with CH2Cl2 and washed with water (1×20 mL), saturated aqueous sodium hydrogen carbonate solution (1×20 mL) and brine (1×20 mL). The organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with acetonitrile to give the product as a yellow solid (1.03 g, 90%); 1H NMR (400 MHz, DMSO) d 1.37 (m, 6H), 1.54 (m, 3H), 3.25 (m, 1H), 4.64 (m, 2H), 8.00 (m, 2H), 8.20 (m, 2H) and 8.83 (s, 1H) ppm; MS (ES+) 418.19
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C2CCN(CCCCc3ccccc3)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C2CCN(CCCCc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from BBr3 in CH2Cl2 (1 M, 3.75 mL) and 4-(4-methoxyphenyl)-1-(4-phenylbutyl)piperidine (323 mg, 1.00 mmol) in dry CH2Cl2 (20 mL) as a colorless crystalline solid (85 mg, 26%): mp 210-211° C., 1H NMR (CD3OD) 1.66-2.12 (m, 8H), 2.66-2.87 (m, 3H), 3.00-3.20 (m, 4H), 3.54-3.66 (m, 2H), 6.75 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.14-7.32 (m, 5H).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:20][CH:9]2[CH2:10][O:11][C:12]3[C:17]([C:8]2([S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:7][CH2:6]1)=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[CH:2]=C.[O:31]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:8]23[CH2:7][CH2:6][CH:5]([O:4][CH2:1][CH2:2][OH:31])[CH2:20][CH:9]2[CH2:10][O:11][C:12]2[C:17]3=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:23])=[O:22])=[CH:29][CH:28]=1
Reactant: C=CCOC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C12CCC(OCCO)CC1COc1c(F)ccc(F)c12
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 8-allyloxy-10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromene (1.55 g, 3.41 mmol) in 1:1 MeOH/CH2Cl2 (30 mL) at −78° C. was purged with O3 until a blue color persisted. The reaction mixture was then purged with nitrogen until the blue color dissipated, NaBH4 (0.39 g, 10.2 mmol) was added and the reaction mixture was warmed slowly to ambient temperature, After 18 h, the reaction mixture was quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was diluted with water and extracted with CH2Cl2 (3×). The combined organic extracts were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo to afford the title compound (1.46 g, 93%): 1H NMR (CDCl3 400 MHz) δ 7.60 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.06 (m, 1H), 6.41 (m, 1H), 5.23 (dd, J=11.7, 3.7 Hz, 1H), 4.13 (d, J=11.7 Hz, 1H), 3.76 (t, J=5.1 Hz, 2H), 3.56-3.50 (m, 3H), 2.99 (m, 1H), 2.40-2.30 (m, 2H), 1.96-1.84 (m, 2H), 1.60 (br s, 1H), 1.54 (m, 1H), 1.16 (m, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].S(OC)(=O)(=O)[CH3:12]>C1(C)C=CC=CC=1>[CH3:12][N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10]
Reactant: O=C1CCCCCN1
Reactant: COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCCCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A suspension of 8.42 g of 57% NaH-mineral oil (4.8 g, 0.2 mole of NaH) was washed with 2 × 400 ml portions of dry toluene (distilled from CaH2). After the washing was completed, 350 ml of dry toluene was added and the suspension mechanically stirred while a solution of 20 g (0.177 mole) of azacycloheptan-2-one in 50 ml of dry toluene was added dropwise over 1 hour. After the addition was completed, the mixture was refluxed with stirring for 1 hour, then cooled to 25° C and 22.0 g (0.2 mole) of methyl mesylate was added dropwise over 1 hour. After the addition was complete, the mixture was warmed with stirring to 50° for 1 hour. The mixture was cooled, filtered and the solid was resuspended in 100 ml toluene and filtered. The combined filtrates were concentrated and the residue was distilled at 85°-87°/0.1mm to yield 20 g (88.85%) of product. On 5% SE-30 column it showed one peak.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]1[C:12]([NH2:13])=[CH:11][CH:10]=[N:9]1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].[Cl-].[NH4+]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([NH:13][C:12]2[N:8]([CH3:7])[N:9]=[CH:10][CH:11]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Cn1nccc1N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nccc1Nc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 80.6 %

Procedure:
Potassium tert-butoxide (1.16 g, 10.3 mmol) was added to a solution of 2-methyl-2H-pyrazol-3-ylamine (0.50 g, 5.15 mmol) in THF (10 mL) at 0° C. under nitrogen and the resultant mixture stirred for 15 min. 2,4-difluoro-1-nitrobenzene (0.98 g, 6.18 mmol) in THF (5 mL) was added and stirring continued for 2 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with EtOAc (×3). The combined EtOAc extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-2% methanol in DCM) to give the title compound as a yellow/brown crystalline solid (0.98 g, 80%). LCMS (Method C): RT 2.98 min [M+H]+ 237.0
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1I)=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([Mg]Cl)(C)C.[Li+].[Cl-].Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].[NH4+].[Cl-]>CN1C(=O)N(C)CCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:19][CH:18]=2)[C:8]2[C:13]([C:14]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:12][C:11]([Br:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c(I)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)c1c(C(=O)OCC)n(-c2ccc(OC(C)C)cc2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-3-iodo-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (1.0 g, 1.89 mmol; see step (b) above) in anhydrous DMPU (4 mL) was rapidly added to i-PrMgCl.LiCl (1.0 M in THF, 4.2 mmol, 4.2 mL) at −65° C. After 30 min at −65° C., ethyl chloroformate (720 mL, 7.56 mmol) was added and the mixture was allowed to warm to rt and poured into NH4Cl (aq, sat, 200 mL). The mixture was extracted with EtOAc (3×50 ml-L) and the combined extracts were washed with brine, dried (Na2SO4), concentrated and purified by chromatography to afford the sub-title compound. Yield 650 mg (72%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH3:22])[O:16][C:15]=3[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)=[O:11])=[CH:6][C:5]=1[CH3:27].C(N(CC)CC)C.[CH3:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([C:45](O)=[O:46])[CH2:41][CH2:40]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:27][C:5]1[CH:6]=[C:7]([C:10]([N:12]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([CH3:22])[O:16][C:15]=3[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)=[O:11])[CH:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:45]([CH:42]1[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][C:36]([CH3:49])([CH3:48])[CH3:35])[CH2:40][CH2:41]1)=[O:46]
Reactant: CC(C)(C)CCN1CCC(C(=O)O)CC1
Reactant: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2c(o1)-c1ccccc1N(C(=O)c1ccc(CNC(=O)C3CCN(CCC(C)(C)C)CC3)c(C)c1)CC2
Yield: 69 %

Procedure:
(4-Aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-1-oxa-3,6-diaza-benzo[e]azulen-6-yl)-methanone hydrochloride from Example E119.2 (89 mg, 0.225 mmol) was dissolved in dichloromethane (10 ml) and triethylamine (to pH9) at room temperature. 1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid (53 mg, 0.25 mmol), DMAP (27 mg, 0.225 mmol) and PyBroP (165 mg, 0.36 mmol) were added and the mixture was heated at reflux for 18 h. The solution was diluted with EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:9% methanol:90% dichloro-methane) to give a white solid identified as the title compound (84 mg, 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([N+:13]([O-])=O)[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>C(O)(=O)C.O1CCCC1.[Fe]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[C:6]([NH2:13])[C:5]=1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1SCc1ccccc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)cc(N)c1SCc1ccccc1

Procedure:
17.7 g of iron turnings are heated to 66° C. in 80 ml of acetic acid (5%) with thorough stirring. A solution of 12.0 g (0.034 mol) of 2-benzylthio-3,5-dinitrobenzoic acid methyl ester in 20 ml of tetrahydrofuran is then slowly added dropwise. After cooling, the batch is neutralised with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The extracts are washed with water, dried over magnesium sulfate, filtered and concentrated. Crystallisation from diethyl ether gives 8.1 g (82% of the theoretical yield) of product; m.p. 80°-82° C.
Reaction SMILES: [CH2:1]([N:6]1[CH:10]=[CH:9][N:8]=[N:7]1)[CH2:2][CH2:3][C:4]#[CH:5].[N:11]([CH2:14][C:15]([CH3:23])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:12]=[N-:13]>>[CH3:23][C:15](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:11]1[CH:5]=[C:4]([CH2:3][CH2:2][CH2:1][N:6]2[CH:10]=[CH:9][N:8]=[N:7]2)[N:13]=[N:12]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCCCn1ccnn1
Product: CC(=Cc1ccccc1)Cn1cc(CCCn2ccnn2)nn1
Yield: 99.6 %

Procedure:
1-Pent-4-ynyl-1H-[1,2,3]triazole (0.100 g, 0.739 mmol) was reacted with (3-Azido-2-methylpropenyl)-benzene (0.154 g, 0.889 mmol) following the general procedure for click reactions outlined above to produce 1-(2-Methyl-3-phenyl-allyl)-4-(3-[1,2,3]triazol-1-yl-propyl)-1H-[1,2,3]triazole (0.227 g, Quantitative) as a white solid. 1H NMR (300 MHz, DMSO) δ 7.91 (s, 1H), δ 7.77 (s, 2H), δ 7.40-7.25 (m, 5H), δ 6.47 (s, 1H), δ 5.05 (s, 2H), δ 4.48 (t, 2H), δ 2.62 (t, 2H), δ 2.50 (t, 2H), δ 2.21 (m, 2H), δ 1.74 (s, 3H) ppm; 13C (75 MHz, DMSO) δ 146.4, 137.1, 134.8, 133.6, 132.8, 129.4, 129.3, 129.2, 128.9, 127.6, 123.0, 57.9, 54.0, 32.9, 29.6, 22.7, 16.2 ppm; HRMS (ESI) calcd for C17H21N6 (M+) 309.1822. Found 309.1821.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([O:37][S:38](=[O:43])(=[O:42])[N:39]([CH3:41])[CH3:40])[C:34]([CH3:44])=[CH:33][C:32]=1[S:45]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([C:31]1[C:32]([S:45][C:3]2[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)[CH2:7][C:2]=2[OH:1])=[CH:33][C:34]([CH3:44])=[C:35]([O:37][S:38](=[O:42])(=[O:43])[N:39]([CH3:40])[CH3:41])[CH:36]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(CCc2cccc(O)c2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)N(C)C)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(CCc3cccc(O)c3)OC2=O)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C

Procedure:
The compound was synthesized following General Method 9 and using 77 mg (0.2 mmol) of 4-hydroxy-6,6-bis-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example XX), 100 mg (0.2 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-dimethylsulfamoyloxy-5-methyl-phenyl) ester (prepared in Example UUU), 18 mg (0.8 mmol) of K2CO3 and 5 mL of DMF. The reaction was worked up as described and chromatographed on silica gel, eluting with (1:1 CH2Cl2 :EtOAc+2% MeOH), to give the title compound. 1H NMR (DMSO-d6) δ 1.45 (s, 9 H), 1.9 (s, 3 H), 2.95 (m, 4 H), 2.6 (m, 4 H), 2.95 (s, 6 H), 3.35 (m, 2 H), 6.60 (m, 6 H), 6.8 (s, 1 H), 7.05 (t, 2 H), 7.15 (s, 1 H), 9.25 (s, 2 H).
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)[CH:26]=[N:25][CH:24]=1>C1COCC1>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]2)[CH:26]=[N:25][CH:24]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(Cl)n2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.1 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (1.53 g, 7.6 mmol) in DMF (76 mL) was added Et3N (22 mmol) stirred for 15 min. 2-6-Dichloro pyrazine (1.14 g, 76 mmol) was added at RT and the reaction mixture was stirred at 100° C. overnight. The resulting reaction mixture was quenched with ice cold water and precipitate was formed. The precipitate was collected by filtration, washed with ice cold water and dried to obtain (R)-tert-butyl 3-(6-chloropyrazin-2-ylamino)piperidine-1-carboxylate (1.1 g, 43%). MS (ESI, pos. ion) m/z: 313 (M+1). To a solution of tributyltin hydride (1.39 g, 4.8 mmol) in THF (25 mL) at 0° C. was added LDA (1.8 M; 0.5 mL, 4.8 mmol) and stirred at the same temperature for 10 min. (R)-tert-butyl 3-(6-chloropyrazin-2-ylamino)piperidine-1-carboxylate (1.1 g) was added at 0° C. and the reaction mixture was stirred at RT for an additional 3 h. The resulting mixture was quenched with 10% KF aqueous solution and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography, using basic alumina, and eluting with 10% EtOAc/hexane to obtain pure (R)-tert-butyl 3-(6-(tributylstannyl)pyrazin-2-ylamino)piperidine-1-carboxylate (0.8 g, 48%). MS (ESI, pos. ion) m/z: 569.2 (M+1).
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][C:14]=1[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N:21]([C:23]1[CH:29]=[CH:28][C:26]([OH:27])=[CH:25][C:24]=1O)=O>S(=O)(=O)(O)O>[CH2:1]([C:13]1[C:14](=[O:20])[CH:15]=[C:16]2[C:18](=[N:21][C:23]3[C:29]([O:17]2)=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=3)[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccc(O)cc1O
Reactant: O=Nc1ccc(O)cc1O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCc1cc2nc3ccc(O)cc3oc-2cc1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.9 %

Procedure:
A solution of 4-dodecylresorcinol (8.5 g, 30.53 mmole) (Aldrich Chemical Company) and 4-nitrosoresorcinol (5.0 g, 35.9 mmole) (Aldrich) in concentrated sulfuric acid (100 mL) is heated to 67° C. with stirring for 5 hours. The reaction mixture is allowed to cool to room temperature, poured into ice-water (1800 mL) and filtered. The resulting precipitate is washed with water until the filtrate is neutral to pH paper. This precipitate is dissolved in chloroform and the combined aqueous filtrates are back-extracted with chloroform (6×250 mL) to recover additional product. The combined chloroform layers are dried over anhydrous sodium sulfate and evaporated to a dark purple solid (2.55 g), homogenous by SiO2 -t.l.c. (45:5:1 chloroform:methanol:triethylamine) Rf =0.69. An additional 5.58 g of product is obtained by neutralization of the aqueous filtrates above with 8M KOH and extraction with chloroform (total yield=8.13 g, 68%). 1H NMR (d6 -DMSO) δ:7.57(d,1H); 7.27(s,1H); 6.79(D,1H); 6.66(s,1H); 6.23(s,1H); 4.14(c,1H); 2.46(t,2H); 1.52(c,2H); 1.23(c,18H); 0.85(c,3H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])=[CH:14][CH:13]=1)(=[O:11])=[O:10].B(Br)(Br)Br.CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23])=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: COc1ccccc1S(=O)(=O)c1ccc(NC(=O)C(C)(O)C(F)(F)F)cc1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a stirred suspension of N-[4-(2-methoxyphenylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.14 g, 2.8 mmol) in dry methylene chloride (30 mL) was added boron tribromide (8.5 mL of a 1.0M solution of boron tribromide in methylene chloride, 8.5 mmol). The resulting solution was stirred at room temperature for 3 hours, diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to yield an off-white solid which was dissolved in ethyl acetate (10 mL) and dropped into hexane (300 mL). Collection of the precipitate by filtration yielded the title propanamide as a white solid (0.84 g, 77%); mp 184°-186° C. 1H-NMR (250 MHz, d6-DMSO): 1.57 (s, 3H, CH3) 6.90 (d, 1H, J=8.3 Hz, aromatic) 7.01 (t, 1H, J=7.5 Hz, aromatic) 7.50 (m, 1H, aromatic) 7.56 (s, 1H, OH) 7.85-7.97 (m, 5H, aromatic) 10.37 (s, 1H, NH) 10.74 (s, 1H, OH). MS (CI, CH4): 390 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:4](=[O:22])[C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)=[O:9])=[N:6][CH:7]=1.[Br:33]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:33][C:7]1[N:6]=[C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][N:13]=2)=[O:9])[C:4](=[O:22])[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[CH:24]=2)[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Br)nc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
5-Methyl-N-{[5-(methylsulfonyl)-pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.097 g, 0.21 mmol) was dissolved in DMF (2 ml) in a vial. To this mixture was added N-bromosuccinimide (0.055 g, 0.31 mmol), and the vial was sealed and the mixture was heated at 50° C. with stirring for 1 h. The crude mixture was added dropwise to water (40 ml) under magnetic stirring. The precipitate was isolated by filtration to give 0.105 g (92%) of 6-bromo-5-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[CH2:7]([O:14][N:15]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([OH:29])[CH:28]=[C:21]3[C:22]=2[C:17](=[CH:18][CH:19]=[CH:20]3)[C:16]1=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>CN(C=O)C.O>[CH3:1][N:2]([CH3:6])[C:3]([O:29][C:27]1[CH:28]=[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]2=[C:23]([CH:26]=1)[C:24](=[O:25])[N:15]([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:16]3=[O:30])=[S:4]
Reactant: CN(C)C(=S)Cl
Reactant: O=C1c2cccc3cc(O)cc(c23)C(=O)N1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1cc2c3c(cccc3c1)C(=O)N(OCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of excess dimethylthiocarbamoyl chloride in DMF (20 mL) was added to a mixture of 2-benzyloxy-5-hydroxy-benzo[de]isoquinoline-1,3-dione (3.5 g, 11.0 mmol) and sodium hydroxide (0.9 g, 22 mmol) in water (50 mL) at 0° C. The mixture was stirred vigorously at room temperature for 2 hours. The solid formed was filtered, washed with water, and dried. The crude product (0.5 g) was purified by column chromatography (silica gel using 2% methanol in chloroform). Fractions containing the target compound were combined, concentrated, and recrystallized from chloroform:ether mixture to give 0.3 g of the title compound, mp 211-214° C.;