Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14]([C:16]1[N:17]=[CH:18][NH:19][C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:24]([O:23][C:21]([C:20]1[N:19]=[CH:18][N:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[C:16]=1[C:14]([O:13][CH2:11][CH3:12])=[O:15])=[O:22])[CH3:25]
Reactant: CCOC(=O)c1nc[nH]c1C(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(-c2ccccc2[N+](=O)[O-])c1C(=O)OCC
Yield: 81.7 %

Procedure:
To a solution of o-fluoronitrobenzene (106 g) and imidazole 4,5-dicarboxylic acid diethyl ester (106 g) in one liter of N,N-dimethyl formamide (DMF) was added anhydrous potassium carbonate (200 g). The reaction mixture was stirred vigorously for at least four hours. After removal of solvent under oil pump vacuum, the residue was treated with water, then extracted with chloroform (300 ml×3). The combined chloroform extracts were washed with water, dried by magnesium sulfate, then concentrated under vacuum to an oil. Upon treatment with ether, the oil was solidified and the product was obtained as a white solid (136 g, 81% yield). Recrystallized from chloroform-hexane, m.p. 93°-95° C.
Reaction SMILES: [C:1](=O)([O:27]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C@@H:4]([N:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=2)[C:9]1=[O:26])[CH:5]1[CH2:7][CH2:6]1.[CH2:38]([O:40][C:41]1[N:46]=[C:45]([CH3:47])[C:44]([NH2:48])=[CH:43][C:42]=1[CH3:49])[CH3:39].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl>C1COCC1>[CH2:38]([O:40][C:41]1[N:46]=[C:45]([CH3:47])[C:44]([NH:48][C:1](=[O:27])[O:2][CH2:3][C@@H:4]([N:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]3[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=3)[C:9]2=[O:26])[CH:5]2[CH2:7][CH2:6]2)=[CH:43][C:42]=1[CH3:49])[CH3:39]
Reactant: CCOc1nc(C)c(N)cc1C
Reactant: COc1nc(C)c(Nc2nc(Cl)cn([C@H](COC(=O)Oc3ccc([N+](=O)[O-])cc3)C3CC3)c2=O)cc1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1nc(C)c(NC(=O)OC[C@H](C2CC2)n2cc(Cl)nc(Nc3cc(C)c(OC)nc3C)c2=O)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.5 %

Procedure:
To a solution of (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl 4-nitrophenyl carbonate (30 mg, 0.057 mmol) from Part A, 6-ethoxy-2,5-dimethylpyridin-3-amine (17 mg, 0.100 mmol), HOBt (9 mg, 0.063 mmol) and 4 Å molecular sieves (60 mg) in THF (1 mL) at room temperature was added triethylamine (23 μL, 0.17 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was transferred to a separatory funnel containing 1 N HCl (5 mL) and the aqueous layer was extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by HPLC (MeCN/H2O with 0.1% TFA, C18 column) to afford (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl 6-ethoxy-2,5-dimethylpyridin-3-ylcarbamate (10 mg, 32% yield) as a yellow amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 6.80 (s, 1H), 6.13 (s, 1H), 4.61-4.58 (m, 1H), 4.43 (dd, JAB=11.6, JAX=7.5 Hz, 1H), 4.31 (q, J=6.8 Hz, 2H), 4.26-4.21 (m, 1H), 3.92 (s, 3H), 2.41 (s, 3H), 2.29 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.25-1.19 (m, 1H), 0.88-0.81 (m, 1H), 0.65-0.55 (m, 2H), 0.38-0.34 (m, 1H); HRMS (ESI) m/e 557.2269 [(M+H)+, calcd for C27H34N6O5Cl 557.2279].
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].Cl[CH2:11][C:12]([NH:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])=[O:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[CH3:9][O:8][C:1](/[CH:2]=[CH:3]/[C:4]([O:6][CH2:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[O:5])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)(C)OC(=O)CNC(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)NCC(=O)O
Yield: 12.1 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.68 g, 5.26 mmol) dissolved in NMP was reacted at ca. 55° C. with tert-butyl 2-(2-chloroacetylamino)acetate (0.91 g, 4.38 mmol) in the presence of CsHCO3 (1.19 g, 6.13 mmol) of the tert-butyl-protected intermediate and then purified by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:2 to 2:3 to 1:1) as eluent. The purified product was treated with 50% trifluoroacetic acid (TFA) in dichloromethane (DCM). Removal of solvents afforded 0.13 g (12% yield) of the title compound (6). 1H NMR (CD3OD, 400 MHz): δ 6.96-6.93 (m, 2H), 4.74 (s, 2H), 3.98-3.95 (m, 2H), 3.81 (s, 3H). MS (ESI): m/z 246.00 (M+H)+, 244.02 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]3[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]3[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cn2c(n1)sc1cc(OC)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc2c(c1)sc1nc(CO)cn12
Yield: 39.3 %

Procedure:
7-methoxy imidazo[2,1-b]-benzthiazole-2-methanol was prepared according to the procedure outlined in Example 1, (Step 2). Starting from ethyl 7-methoxyimidazo[2,1-b]-benzthiazole-2-carboxylate (12.5 g, 43.5 mmol) and LiAlH4 solution (43.5 ml, 0.5 M solution in THF), 4.0 g (40% yield) of the alcohol derivative was isolated as a brown solid. (M+H) 235.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]=O)[C:27]3[C:26](=[O:37])[N:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:40])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH:35]=[CH2:1])[C:27]3[C:26](=[O:37])[N:25]([CH3:38])[C:24](=[O:39])[N:23]([CH3:40])[C:22]=3[N:21]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:9])([CH3:10])[CH3:8]
Reactant: Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2C=O)n(C)c1=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200.8 %

Procedure:
Potassium tert-butoxide (9 mg) was dissolved in tetrahydrofuran (1 ml), and methyl triphenyl phosphonium bromide (31 mg) was added thereto. The reaction mixture was stirred at room temperature for 30 minutes, and a solution of 4-[7-(2-formylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (20 mg) in tetrahydrofuran (1 ml) was added thereto. The reaction solution was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 40 mg of 4-[7-(2-vinylphenyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. This product (12 mg) was dissolved in trifluoroacetic acid, and the solution was concentrated. The residue was purified by reversed phase high performance liquid chromatography to give 4.38 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:21]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:14][CH:13]=1)[C:20]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:19]=1[Cl:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Product: Clc1ccc(C(c2c[nH]c3ccc(OCc4ccccc4)cc23)c2c[nH]c3ccc(OCc4ccccc4)cc23)c(Cl)c1

Procedure:
The compound Bis(5-benzyloxyindol-3-yl)-(2,4-dichlorophenyl)methane was prepared following procedure A, starting from 5-benzyloxy indole and 2,4 dichloro benzaldehyde. LC: Tr 2.89 min, MS: 603 (M+H)+
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](Cl)=[O:36]>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:35]([C:31]3[S:30][CH:34]=[CH:33][N:32]=3)=[O:36])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1nccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4nccs4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.57 g, 1.75 mmol) in CH3CN (10 ml), were added triethyl amine (0.61 mL, 4.4 mmol) and 1,3-thiazole-2-carbonyl-chloride (1.07 g, 4.5 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford thiazole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.52 g, 74%): mp, 189-191° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=5.9 min (97%); 1H NMR (DMSO-d6): δ 2.05-2.12 (m, 1H), 2.53-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.94 (d, J=6.2 Hz, 2H), 5.18 (dd, J=5, 11 Hz, 1H), 7.68-8.10 (m, 5H), 9.50 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 38.32, 48.88, 121.98, 125.99, 127.17, 131.56, 132.92, 134.85, 138.43, 143.98, 159.59, 163.18, 166.93, 167.51, 169.81, 172.73. Anal Calcd for C18H14N4O5S: C, 54.27; H, 3.54; N, 14.06; S, 8.05. Found: C, 53.98; H, 3.49; N, 13.75; S, 8.22.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18](=O)[CH2:19]Br.CN(C)C=O>O>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:19]=1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(-c3ccccc3C(F)(F)F)cs2)cc1
Temperature: 125 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
A mixture of methyl 4-thiocarbamoylbenzoate (1.00 g), 2-trifluoromethyphenacyl bromide (1.50 g) and N,N-dimethylformamide (3 ml) was stirred at 120 to 130° C. for 3 hours. The reaction mixture was poured into water, and precipitated crystals were collected by filtration and then subjected to a silica gel column chromatography. From a fraction eluted with ethyl acetate-hexane (1:4, v/v), methyl 4-[4-(2-trifluoromethylphenyl)-2-thiazolyl]benzoate (1.01 g, yield: 54%) was obtained. The product was recrystallized from hexane-toluene to obtain colorless prisms. Melting point: 122 to 123° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7].[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][CH2:22][CH2:23][CH2:24][N:34]2[CH2:35][CH2:36][N:31]([C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)[CH2:32][CH2:33]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7]
Reactant: O=C(NCc1ccc(F)cc1F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCc1ccc(F)cc1F)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-2,4-difluoro-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24](O)[CH2:23][CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(S(F)(F)F)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC(O)CC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC=CCC1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(7-chloro-4-quinolinyl)-N-(4-hydroxycyclohexyl)-1-piperazinecarboxamide (100 mg) in CH2Cl2 at −78° C. was added DAST (100 mg). The reaction was warmed to rt overnight, and quenched with NaOH (sat.). The reaction mixture was extracted with EtOAc, and dried. Concentration in vacuo followed by flash chromatography with CH2Cl2-MeOH afforded the title product. 1H NMR (DSMO-d6) 61.03 (m, 1H), 1.4 (m, 1H), 1.7 (m, 1H), 1.9 (m, 1H), 2.05 (m, 1H), 2.1 (m, 1H), 3.1 (br. s, 4H), 3.6 (br. s, 4H), 3.65 (m, 1H), 5.6 (m, 2H), 6.4 (d, 1H), 7.0 (d, 1H), 7.6 (m, 1H), 8.0 (s, 1H), 8.1 (d, 1H), 8.7 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.[Mg].O1CCCC1>O>[C:10]12[CH2:9][C:13](=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=1
Reactant: C1=CCC=C1
Reactant: Brc1ccccc1I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C1=C2CC(=C1)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Bromo-2-iodobenzene (1 ml) was combined with cyclopentadiene (1.5 ml) and added dropwise to a mixture of magnesium (0.25 g) and tetrahydrofuran (25 ml) which had been heated to reflux. After the addition, heating was continued for 1 hour. The mixture was cooled to room temperature, treated with water (50 ml), and extracted with ether (3×30 ml). The combined organic layers were dried over magnesium sulfate and the solvents removed on a rotary evaporator. The residue was distilled on a Kugelrohr apparatus (40° C. at 0.1 mm Hg) to provide the product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=O)[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[S:30])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C
Yield: 38.6 %

Procedure:
3-[4-(2,6-Dioxo-3-propyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (250 mg, 0.64 mmol) was dissolved in 8 mL of pyridine. P4S10 (430 mg, 1.5 eq) was added and the reaction mixture was stirred under reflux for 3 h. It was then cooled to rt and quenched with 3 mL of H2O and then with enough 6 N HCl to bring the pH to 3. The resulting reaction mixture was extracted with CHCl3. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford 100 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:24]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N:18]([CH3:24])[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A mixture of 4-bromo-1-acetylaminoanthraquinone (purity 98%, 35.1 g), monochlorobenzene (420 g), tetra-n-butyl ammonium bromide (0.3 g) and 96% potassium hydroxide (12.0 g) was stirred for 1 hour, while being maintained at 30° C. Then, methyl iodide (28.4 g) was dropped at 30° C. over 2 hours. The mixture was stirred at 30° C. for 30 minutes and 40° C. for 3 hours, successively. Then the same procedure as in Example 3 was applied to obtain 4-bromo-N-acetyl-1-methylaminoanthraquinone (35.1 g, purity 94.4%, yield 92.6%).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]1[CH2:11][NH:10][C:9](=O)[CH2:8][O:7]1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:13]1([C@H:5]([O:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[C@H:6]2[O:7][CH2:8][CH2:9][NH:10][CH2:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1COC(C(Oc2ccccc2Br)c2ccccc2)CN1
Product: c1ccc([C@H](Oc2ccccc2-c2ccncc2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-Phenyl-(2-pyridin-4-yl-phenoxy)-methyl]-morpholine was synthesized from 6-[(2-Bromo-phenoxy)-phenyl-methyl]-morpholin-3-one and 4-pyridineboronic acid according to general procedures A and B and was isolated as a thick viscous gum. 1H NMR (CDCl3) δ: 8.65 (d, 2H), 7.60 (d, 2H), 7.32-7.18 (m, 7H), 6.96 (m, 1H), 6.90 (d, 1H), 5.10 (d, 1H), 3.93 (d, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 2.75 (m, 2H), 2.48 (m, 2H), 1.80 (br s, 1H). MS (ES) m/z 347.08 [C22H22N2O2+H]+. Analysis: Calcd for C22H22N2O2:0.5H2O: C, 74.34; H, 6.52; N, 7.88. Found: C, 74.15; H, 6.84; N, 7.37.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[C:23]1(=[O:38])[N:27]([CH2:28][C:29](=[O:32])[CH2:30][NH2:31])[C:26](=[O:33])[C:25]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:24]12>C(O)C>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[C:11]([NH:31][CH2:30][C:29]([CH2:28][N:27]3[C:23](=[O:38])[C:24]4=[CH:37][CH:36]=[CH:35][CH:34]=[C:25]4[C:26]3=[O:33])=[O:32])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: NCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCC(=S)N2
Solvent: CCO
Product: O=C(CNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1)CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in example 12, 7-trifluoromethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione is heated with (3-phthalimidoacetonyl)amine, ethylene ketal in ethanol to give 7-trifluoromethyl-5-phenyl-2-[(3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:27]([F:38])([F:37])[F:26])[CH:33]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 95 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
To a stirred solution of 100 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone dissolved in 15 ml toluene and 5 ml ethanol, were added 30 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate, and 100 mg of 3-(trifluoromethyl)benzeneboronic acid. Then the mixture was stirred at 95° C. for 24 hours. The reaction mixture was purified according to a procedure similar to Step 4 of Example 22 to yield 35 mg of 5-{4-(aminosulfonyl)phenyl}2,2-dimethyl-4-{3-(trifluoromethyl)phenyl}-3(2H)-furanone. mp: 129-130° C. NMR: δ1.59 (s, 6H), 4.93 (br, s, 2H), 7.48 (m, 2H), 7.59 (m, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.93 (d, J=9.0 Hz, 2H). IR (cm−1): 3343, 3265, 1691, 1593, 1329, 1262.
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[CH2:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Br[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.ClCCl.CN(C)C=O>[N:28]1[CH:29]=[CH:30][C:25]([CH2:23][CH:20]2[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]2)=[CH:26][CH:27]=1
Reactant: Brc1ccncc1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccncc2)CC1
Temperature: 25 °C

Procedure:
9-borabicyclo[3.3.1]nonane (101.5 ml of a 0.5M solution in tetrahydrofuran) was added to a degassed sample of N-(tert-butoxycarbonyl)-4-methylene piperidine (may be prepared as described in A. Palani et al., J. Med. Chem., 2002, 45: 3145) (10 g) and the resultant solution heated at reflux for 1 h. After cooling to room temperature the reaction mixture was then added to a mixture of 4-bromopyridine (7.23 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.14 g), K2CO3 (8.42 g), N,N-dimethylformamide (100 ml) and water (10 ml), and the resultant mixture heated at 60° C. for 3 h. After cooling to room temperature, another charge of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (1.14 g) was added to the reaction and heated at 60° C. overnight. The mixture was cooled to room temperature and poured into water, the pH was adjusted to 11 by the addition of 10% aqueous sodium hydroxide and extracted into ethyl acetate. Combined organic extracts were dried (Na2SO4) and evaporated to give the crude pyridine as a brown viscous oil. Chromatography [silica gel, eluting with ethyl acetate in hexanes, 0-100%] gave the title compound (D1) as a pale yellow oil (7.5 g).