Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[C:19]([CH3:30])[CH:18]=1)[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[N:6]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.ClCl>ClCCl.ClCCl.C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([C@@H:4]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[N:6][C:7]=2[CH:13]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CS(=O)(=O)Cl
Agent: ClCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](CCNS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 37 %

Procedure:
Prepared analogously to Example 125 from N-[(1S)-3-amino-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, methanesulfonic acid chloride, and triethylamine in dichloromethane. Yield: 37%; Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C24H28ClN5O4S (518.04); mass spectrum: (M+H)+=518/520 (chlorine isotope) and (M−H)−=516/518 (chlorine isotope).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([Li])C=CC=CC=1.BrC1C=CC=CC=1.[Li].[Li][CH:27]1C2N=CC=CC=2CCC1.[C:37](=[O:39])=[O:38]>CCOCC>[CH3:27][O:38][C:37]([CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)=[O:39]
Reactant: [Li]C1CCCc2cccnc21
Reactant: O=C=O
Reactant: c1cnc2c(c1)CCCC2
Agent: [Li]
Agent: [Li]c1ccccc1
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: COC(=O)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline (14 g.) in dry ether (100 ml.) was added dropwise over 1/2 hour to an ethereal solution of phenyl lithium (prepared from bromobenzene (42 g.) and lithium (3.7 g.) in dry ether (300 ml.) and the reaction mixture stirred at room temperature for a further one hour. The cooled reaction mixture containing 8-lithio-5,6,7,8-tetrahydroquinoline was saturated with dry CO2 gas, evaporated in vacuo and the residue treated with methanol previously saturated with dry HCl (500 ml.) giving methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate as described in our copending U.S. Ser. No. 460,265.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]([C:14]1[C:15]2[CH2:23][CH2:22][CH2:21][CH2:20][C:16]=2[S:17][C:18]=1[NH2:19])=O)[CH:2]=[CH2:3].[O:24]=[C:25]([CH2:31][C:32](=O)[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([Cl:38])(=O)C>C(O)C>[ClH:38].[CH2:29]([O:28][C:26](=[O:27])[C:25]([C:31]1[C:12]([C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])=[C:14]2[C:15]3[CH2:23][CH2:22][CH2:21][CH2:20][C:16]=3[S:17][C:18]2=[N:19][C:32]=1[CH3:33])=[O:24])[CH3:30]
Reactant: CC(=O)Cl
Reactant: C=CCOc1cc(C)ccc1C(=O)c1c(N)sc2c1CCCC2
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Product: C=CCOc1cc(C)ccc1-c1c(C(=O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Product: Cl
Temperature: 50 °C
Yield: 76.5 %

Procedure:
To a stirred solution of (2-allyloxy-4-methyl-phenyl)-(2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-methanone (882 mg, 2.69 mmols) in ethanol (30 mL) was added ethyl 2,4-dioxopentanoate (426 mg, 378 μL, 1 eq) followed by acetyl chloride (846 mg, 766 μL, 4 eq), and the reaction was heated to 50° C. for 1 hour. The reaction was then concentrated in vacuo to give [4-(2-allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-oxo-acetic acid ethyl ester hydrochloride as a pale yellow oil 1 g (86% yield). LCMS (2 min acidic) 1.70 min 54-100% pure by UV, ES+/AP+ 450. HNMR (CDCl3)>90% pure 6.95 (d, J=7.0 Hz, 1 H) 6.87 (d, J=7.0 Hz, 1 H) 6.76 (s, 1 H) 5.82 (m, 1 H) 5.09-5.20 (m, 2 H) 4.39-4.51 (m, 2 H) 3.84-3.94 (m, 2 H) 2.95 (s, 3 H) 2.87-2.93 (m, 2 H) 2.43 (s, 3 H) 1.92-2.08 (m, 2 H) 1.78-1.89 (m, 2 H) 1.55-1.70 (m, 2 H) 1.12 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O-])([O-])=O.[Cs+].[Cs+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:29][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[CH:18][CH:17]=2)[C:13]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:14]1
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccc(S(=O)(=O)c3ccccc3)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1cc(CCNC(=O)OC(C)(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
A solution of tert-butyl 2-[5-(phenylsulfonyl)-1H-indol-3-yl]ethylcarbamate (0.58 g, 1.46 mmol) in acetone (25.0 mL) was treated with Cs2CO3 (1.85 g, 5.68 mmol) and dimethyl sulfate (0.80 mL, 8.45 mmol). The reaction was stirred at room temperature for 3.5 hours then filtered. The filtrate was concentrated in vacuo and subjected to column chromatography (silica gel, 30% EtOAc/hexane) to give 0.41 g (68%) of a colorless solid as the title compound: mp 127.4-130.6° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.93 (d, J=7.1 Hz, 1H), 7.65-7.55 (m, 5H), 7.35 (s, 1H), 6.93 (br, 1H), 3.77 (s, 3H), 3.20-3.18 (m, 2H), 2.86-2.82 (m, 2H), 1.37 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 155.5, 142.7, 138.3, 132.8, 130.5, 130.0, 129.4, 127.0, 126.7, 119.7, 119.3, 113.4, 110.7, 77.4, 41.1, 32.5, 28.1, 24.9; IR (diffuse reflectance) 1676, 1531, 1450, 1366, 1316, 1303, 1286, 1177, 1152, 1144, 1103, 797, 726, 692, 626 cm−1; HRMS (FAB) calcd for C22H26N2O4S+H 414.1613, found 414.1619; Anal. Calcd for C22H26N2O4S: C, 63.74; H, 6.32; N, 6.76. Found: C, 63.78; H, 6.39; N, 6.80.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11](SC)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1C=CC=C(C(OO)=O)C=1.[S:36]([O-:39])(O)=[O:37].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11]([S:36]([CH3:26])(=[O:39])=[O:37])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(SC)cc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(-c2noc(C)n2)c(S(C)(=O)=O)cc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 3-(4-benzyloxy-5-methoxy-2-methylsulfanyl-phenyl)-5-methyl-[1,2,4]oxadiazole, m-chloroperbenzoic acid (60%, 1.43 g) and methylene chloride (30 mL) was stirred overnight. An aqueous solution of sodium hydrogen sulfite and methylene chloride were added to the mixture. The separated organic layer was washed with a 2 mol/L aqueous solution of sodium hydroxide and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-(4-benzyloxy-2-methanesulfonyl-5-methoxyphenyl)-5-methyl-[1,2,4]oxa-diazole.
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:11][C:12]1[C:16]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:15][S:14][N:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CC(C)=O>[I-:2].[CH2:3]([O:11][C:12]1[C:16]([C:17]2[CH:18]=[N+:19]([CH3:1])[CH:20]=[CH:21][CH:22]=2)=[N:15][S:14][N:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CI
Reactant: CCCCCCCCOc1nsnc1-c1cccnc1
Solvent: CC(C)=O
Product: CCCCCCCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(3-octyloxy-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.81 g (62%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CCN(CC)CC.[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][S:26](Cl)(=[O:28])=[O:27].O>O1CCOCC1>[I:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][S:26]([NH:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:28])=[O:27]
Reactant: COC(=O)c1scnc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1scnc1NS(=O)(=O)Cc1ccccc1I
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2 g (12.64 mmol) of methyl 4-amino-1,3-thiazole-5-carboxylate were dissolved together with 5.1 ml (63.2 mmol) NEt3 in 20 ml of dioxane, and 4.4 g (13.9 mmol) of (2-iodophenyl)methanesulfonyl chloride were added at room temperature. The reaction mixture was stirred at RT for 5 h. Then 40 ml of water were added and the mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed with 2N HCl, dried and concentrated. The residue was purified by means of column chromatography (SiO2, gradient ethyl acetate/n-heptane 10:90 to 75:25). This gave 4.3 g of methyl 4-{[(2-iodobenzyl)sulfonyl]amino}-1,3-thiazole-5-carboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][C:28]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:29])[CH:22]=1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: O=C(O)Cc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 109 mg 3-pyridylacetic acid, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. The residue is purified by silica gel flash chromatography. 146 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]2[C:11]=1[CH2:12][CH2:13][NH:14]2>C(Cl)Cl.CO>[Br:8][C:18]1[C:10]([F:9])=[C:11]2[C:15](=[C:16]([C:19]([OH:21])=[O:20])[CH:17]=1)[NH:14][CH2:13][CH2:12]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1ccc(F)c2c1NCC2
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cc(Br)c(F)c2c1NCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NBS (40 mg, 0.23 mmol) was added to a solution of 4-fluoro-2,3-dihydro-1H-indole-7-carboxylic acid (36 mg, 0.14 mmol) in DCM (3 mL) and MeOH (1 mL). The reaction was stirred at room temperature overnight and filtered. The filtrate was evaporated, and the residue was purified by flash chromatography, giving the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14]([CH2:18][O:19][CH2:20][CH3:21])[C:13]([SH:22])=[N:12][C:11]=2[N:10]([CH3:23])[C:8]1=[O:9].[C:25](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH2:20]([O:19][CH2:18][N:14]1[C:15]2[C:16](=[O:17])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([OH:1])[CH3:24])[C:8](=[O:9])[N:10]([CH3:23])[C:11]=2[N:12]=[C:13]1[S:22][CH3:25])[CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CCOCn1c(S)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOCn1c(SC)nc2c1c(=O)n(CCCC[C@@H](C)O)c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a stirring suspension of (R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine (62.0 mg, 0.174 mmol) and potassium carbonate (42 mg, 0.30 mmol) in acetonitrile (3.4 ml) was added methyl iodide (44 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. After evaporation of the solvent under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (3:1) to provide (R)-7-ethoxymethyl-1-(5-hydroxyhexyl)-3-methyl-8-methylsulfanylxanthine (58 mg, 89% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[CH2:37][C:38]#[N:39])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[C:37]([C:38]#[N:39])=[CH:44][CH:41]4[CH2:43][CH2:42]4)[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
Into a 10-mL round-bottom flask, was placed (R)-N-(4-[4-amino-1-[1-(2-cyanoacetyl)piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-4-(trifluoromethyl)-benzamide (65 mg, 0.12 mmol, 1.00 equiv), cyclopropanecarbaldehyde (16.6 mg, 0.24 mmol, 2.00 equiv), piperidine (10 mg, 0.12 mmol, 0.99 equiv), methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum and the residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50:1) to give 43 mg (60%) of (R)-N-[4-(4-amino-1-[1-[2-cyano-2-(cyclopropylmethylidene)acetyl]piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-4-(trifluoromethyl)benzamide as a white solid. MS (ESI, pos. ion) m/z: 601 (M+1), 1HNMR (300MHz, CDCl3, ppm), 8.6(1H, s), 8.348 (1Hs), 8.065˜8.038 (2H, d,J=8.1),7.880˜7.852 (1H, d,J=8.4), 7.768˜7.659 (4H,m), 6.532˜6.496 (1H, d,J=10.8), 5.949 (2H,s), 4.976˜4.907 (1H,m), 4.638˜3.218 (4H,m), 2.436˜1.818 (5H,m),1.221˜1.198 (2H,m), 0.89˜0.772 (2H,m).
Reaction SMILES: CCO[C:4]([C:6]([O:8]CC)=O)=[O:5].[CH2:11]([NH:13][CH2:14][CH2:15][NH2:16])[CH3:12]>C(O)C>[CH2:11]([N:13]1[CH2:14][CH2:15][NH:16][C:6](=[O:8])[C:4]1=[O:5])[CH3:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCNCCN
Solvent: CCO
Product: CCN1CCNC(=O)C1=O
Yield: 76.1 %

Procedure:
Into a mixture comprising 8 g of a diethyl ester of oxalic acid and 8 ml of ethanol was dropped at room temperature 4.4 g of N-ethyl ethylenediamine. The resulting mixture was allowed to react for 3 hours, and then heated to remove the ethanol. Subsequently, the residue was recrystallized from 10 ml of dioxane to obtain 5.4 g of 1-ethyl-2,3-dioxo-piperazine, m.p. 124° C., yield 76.0%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1Cc2cc(OCc3ccccc3)ccc2CC1C(=O)O
Yield: 19.2 %

Procedure:
2.0 g, (6.8 mmol) of (3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester was reacted with 2.56 g (15.0 mmol) of benzyl bromide as described in general procedure H. The resulting crude product was subjected to hydrolysis as described in general procedure C. The crude product was purified by column chromatography using 1:1 ethyl acetate and hexane as eluent to afford 0.5 g of 7-benzyloxy-3,4-dihydro-1H-isoq uinoline-2,3-dicarboxylic acid 2-tert-butyl ester.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH:6]1[C:5]2[C:10](=[CH:1][C:2]3[C:3]([CH:4]=2)=[CH:3][CH:2]=[CH:1][CH:10]=3)[CH:9]=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 60 °C
Yield: 456.3 %

Procedure:
The resultant compound was dissolved in toluene (1 L) under a nitrogen atmosphere, and 2-naphthalenyl boronic acid (51.6 g, 0.3 mol), tetrakistriphenylphosphine palladium (9.3 g, 8.1 mmol), sodium carbonate (31.4 g, 0.3 mol), and water (300 ml) were added thereto. The reaction mixture was stirred under reflux for three hours. The reaction solution was cooled to about 60° C., filtered on silica gel, and extracted with toluene. The extracted solution was concentrated to remove an organic solvent, and methanol was added thereto. The resultant solid was filtered. The resultant yellowish brown matter was dissolved in methylene chloride, and methanol was dropwise added thereto to give an anthracene derivative (Cpd 1, 122 g, yield 85%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.Cl>O1CCCC1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[OH:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ccccn2)C1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
2-Bromopyridine (6.50 g, 40 mmol) was added to isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 20 mL, 40 mmol) at room temperature. The mixture was stirred for 10 minutes then warmed to 30° C. and stirred for 105 minutes. The mixture was cooled to −10° C. and a solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (5.5 g, 10 mmol) in tetrahydrofuran (9 mL) was added dropwise. The reaction mixture was stirred for 15 minutes at −10° C. followed by stirring at room temperature for 1 hour. The reaction mixture was cooled and treated with water (20 mL) followed by aqueous hydrochloric acid (1.0 M, 40 mL). The mixture was stirred for 10 minutes then extracted with dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (gradient: 20-80% ethyl acetate in cyclohexane) to afford the diastereoisomeric (2:1) mixture (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol as an off-white foam (3.25 g). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J=4.8 Hz, 1 H); 8.00 (d, J=8.2 Hz, 2 H); 7.84-7.86 (m, 3 H); 7.44-7.46 (m, 1 H); 7.29-7.30 (m, 1.5 H); 7.09-7.10 (m, 3.5 H); 6.95-6.97 (m, 2.5 H); 6.41 (s, 0.5 H); 6.18 (s, 1 H); 5.11 (s, 0.5 H); 5.04 (s, 1 H); 4.87 (s, 1 H); 4.50 (d, J=11.8 Hz, 1 H); 4.10 (d, J=13.3 Hz, 2.5 H); 3.80 (d, J=12.1 Hz, 0.5 H); 3.69 (s, 0.5 H); 3.24 (d, J=16.6 Hz, 1 H); 3.09-3.13 (m, 1.5 H); 2.54-2.58 (m, 2.5 H); 2.25-2.27 (m, 1 H); 2.11 (d, J=16.6 Hz, 1 H); 1.43 (s, 0.5 H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:11](=[O:13])[CH3:12])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.OO.[OH2:17].C(O)(=[O:20])C>>[CH3:1][C:2]([CH3:14])([C:11](=[O:13])[CH3:12])[CH2:3][S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:20])=[O:17]
Reactant: CC(=O)C(C)(C)CSc1ccccc1
Reactant: O
Reactant: CC(=O)O
Agent: OO
Product: CC(=O)C(C)(C)CS(=O)(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
40.6 g (0.2 mole) of 2,2-dimethyl-1-phenylmercapto-butan-3-one (Example 4) were dissolved in 300 ml of glacial acetic acid, and 30.4 g (0.89 mole) of hydrogen peroxide were added. The reaction mixture was stirred at 50° C. for 8 hours. It was then poured into 250 ml of water and extracted with ether. The ether phase was washed with sodium bicarbonate solution, and with water, until neutral, and dried over sodium sulphate and concentrated. 40.4 g (84.2% of theory) of 2,2-dimethyl-1-phenylsulphonyl-butan-3-one of melting point 56°-58° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=[C:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:15][S:18][C:5]=1[CH3:6])=[O:16]
Reactant: COC(=O)C(C(C)=O)=C(N)c1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)nsc1C
Temperature: 25 °C
Yield: 42.6 %

Procedure:
A mixture of 2-(amino-phenyl-methylene)-3-oxo-butyric acid methyl ester (4.48 mmol), phosphorus pentasulfide (13.43 mmol), chloranil (4.48 mmol), and toluene was refluxed for 15 minutes before it was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography with a gradient of ethyl acetate and hexanes on silica gel (40 g) to give the title compound as a red oil (445 mg); 1H NMR (CDCl3, 200 MHz): δ=7.51 (m, 2H), 7.42 (m, 3H), 3.75 (s, 3H), 2.74 (s, 3H); MS: (+) m/z 224.32 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27](=[O:32])[CH2:26]5)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH:40]=O>C(O)C.N1CCCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27](=[O:32])[C:26]5=[CH:40][C:36]4[NH:35][CH:39]=[CH:38][CH:37]=4)[CH:17]=3)=[O:14])=[CH:33][CH:34]=2)[CH2:6][CH2:7]1
Reactant: O=Cc1ccc[nH]1
Reactant: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)CC(=O)N5)c3)cc2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)C(=Cc4ccc[nH]4)C(=O)N5)c3)cc2)CC1

Procedure:
To a solution of 4-(4-methyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-phenyl]-benzamide (23 mg, 0.05 mmol) in ethanol (2 ml) is added 1H-pyrrole-2-carbaldehyde (16 mg, 0.17 mmol) and 2 drops of piperidine. The reaction is refluxed for 12 hours and then concentrated. The desired compound after HPLC purification: 1H NMR (DMSO-d6) δ 2.44-2.52 (m, 2H), 2.79 (s, 3H), 2.98-3.10 (m, 2H), 3.18-3.22 (m, 2H), 3.38-3.42 (m, 2H), 3.77 (s, 2H), 6.32-6.36 (m, 1H), 6.61-6.69 (m, 111), 6.81-6.82 (m, 2H), 6.92 (dd, 1H, J=8.8 Hz, J2=1.6 Hz), 7.12-7.18, (m, 2H), 7.34 (s, 1H), 7.46 (dd, 2H, J=4.8 Hz, J2=1.6 Hz), 7.48 (s, 2H), 7.69 (s, 1H), 7.93 (d, 2H, J=8.0 Hz), 8.01 (s, 1H), 10.09 (s, 1H), 10.78 (s, 1H), 13.39 (s, 1H); LC-MS: 533.2 (MH+).