Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Na+].[Na+].O[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-:18])=[O:17])[C:9]=1[O:19][CH3:20].S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:20][O:19][C:9]1[C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:14]=[CH:15][C:8]=1[O:4][CH3:1])[CH:12]=[O:13]
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C=O)c([N+](=O)[O-])c1OC
Yield: 78 %

Procedure:
Anhydrous sodium carbonate (957 g., 9.03 moles), toluene (5 liters), 4-hydroxy-3-methoxy-2-nitrobenzaldehyde (1424 g., 7.22 moles) and dimethyl sulfate (810 ml., 8.67 moles) were refluxed for 4 hours. Toluene was removed in vacuo and the residual solid dissolved in 5 liters of ethyl acetate and 3 liters of water. The organic layer was separated, washed with 2 liters of 1 N NaOH and 6 liters of brine, decolorized with charcoal, dried over magnesium sulfate and filtered. Hexane (7.6 liters) was added slowly. After cooling in an ice bath, 1527 g. product was obtained by filtration. The crude material was recrystallized from ethanol to yield 1187 g. (78%) of the title compound as a pale yellow solid, 60°-62° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:5][CH2:6][C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH:9]([O:12][CH2:13][CH2:14][OH:15])[C:10]=2[N:11]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.O>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:9]2[C:8]3[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=3[CH2:6][CH2:5][C:4]3[O:3][C:2]([CH3:1])=[N:11][C:10]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: Cc1nc2c(o1)CCc1ccccc1C2OCCO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CCc3oc(C)nc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
Under a nitrogen atmosphere, 2-(2-methyl-9,10-dihydro-4H-1-oxa-3-aza-benzo[f]azulen-4-yloxy)-ethanol (400 mg, 1.6 mmol), tributylphosphine (480 mg, 2.4 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (380 mg, 1.6 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (480 mg, 2.4 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and, the stirring was continued for 16 h. The mixture was added water and the product extracted with ethyl acetate. The combined organic phases was dried (MgSO4), and concentrated in vacuo. The residue was purified chromatography eluting with petroleum ether/ethyl acetate (1:1) to give 300 mg (40%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H). 1.20 (t, 3H), 22.38 (s, 3H), 2.60-2.85 (m, 2H), 2.90-3.05 (m, 3H), 3.25-3.38 (m, 1H), 3.52-3.65 (m, 1H), 3.65-3.75 (m, 1H). 3.75-3.90 (m, 2H), 3.95 (t, 1H), 4.05 (t, 2H), 4.15 (q, 2H), 5.25 (s, 1H), 6.75 (d, 2H), 7.10 (d, 2H), 7.13-7.30 (m, 4H).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([NH:13][OH:14])=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH2:15][OH:16])[CH:3]=1.CC(O[CH2:21][C:22]1[CH2:31][S:30][C@@H:25]2[C@H:26]([NH2:29])[C:27](=[O:28])[N:24]2[C:23]=1[C:32]([OH:34])=[O:33])=O.B(F)(F)F.CCOCC.ClCCl>S1(CCCC1)(=O)=O.ClCCl>[NH2:29][C@@H:26]1[C:27](=[O:28])[N:24]2[C@@H:25]1[S:30][CH2:31][C:22]([CH2:21][S:1][C:2]1[N:7]3[N:8]=[C:9]([C:11](=[O:12])[NH:13][OH:14])[N:10]=[C:6]3[N:5]=[C:4]([CH2:15][OH:16])[CH:3]=1)=[C:23]2[C:32]([OH:34])=[O:33]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(NO)c1nc2nc(CO)cc(S)n2n1
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(CO)nc4nc(C(=O)NO)nn34)CS[C@H]12
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
7-Mercapto-N-hydroxy-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidine-2-carboxamide (300 mg) (1.24 mmol) and 305 mg (1.12 mmol) of 7-aminocephalosporanic acid are suspended in 50 ml of sulpholane/dichloromethane (1:1 v/v). 5 ml of boron trifluoride diethyl etherate are added thereto at 0° C. The reaction mixture is stirred at 0° C. for 21/2 hours and at room temperature for 24 hours. After the addition of 30 ml of dichloromethane the mixture is stirred for 15 minutes and subsequently filtered. The suction filter material is dissolved in water and adjusted to pH 5 with saturated aqueous sodium hydrogen carbonate solution. The precipitated product is filtered off under suction and washed in succession with water, dichloromethane and diethyl ether. There are obtained 340 mg of (6R,7R)-7-amino-3-[[[2-(hydroxycarbamoyl)-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:20][N:21]([CH3:23])[CH3:22])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Cc1ccc(Cl)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C(C(=O)C(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorophenyl)-3,3-dimethyl-butan-2-one (30 mmol) and tert-butoxybis-(dimethylamino)methane (31.5 mmol) are heated together at reflux overnight. The reaction mixture is then cooled to RT and the excess tert-butoxybis(dimethylamino)methane removed under reduced pressure to give 2-(4-chlorophenyl)-1-dimethylamino-4,4-dimethyl-pent-1-en-3-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16](Cl)[N:15]=[C:14]([CH3:28])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[NH2:29][CH2:30][CH2:31][OH:32]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:32][CH2:31][CH2:30][NH2:29])[N:15]=[C:14]([CH3:28])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C)cn1
Reactant: NCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCN

Procedure:
According to the procedure described in Example 4b) 1.00 g 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with 2-aminoethanol to give 1.05 g 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=2.93 min, [M+1]+=446.51, [M−1]−=444.53.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[C:3]1SC.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH2:21][CH2:20]1>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=[C:3]1[NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)[CH2:21][CH2:20]1
Reactant: NCCCN1CCN(c2ccc3ccccc3n2)CC1
Reactant: CSc1nc2c(c(=O)n1C)CCCC2
Product: Cn1c(NCCCN2CCN(c3ccc4ccccc4n3)CC2)nc2c(c1=O)CCCC2
Temperature: 140 °C
Reaction time: 6 h
Yield: 48.6 %

Procedure:
A mixture of 420 mg of 3-methyl-2-methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one as synthesized in Step 7-29-A and 540 mg of 2-[4-(3-aminopropyl)piperazin-1-yl]quinoline as synthesized in above Step 7-29-B was heated under stirring at 140° C. for 6 hours. The residue was purified on silica gel column chromatography (chloroform:methanol=10:1) to provide 420 mg (48%) of 3-methyl-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylamino]-5,6,7,8-tetrahydro-3H-quinazolin-4-one.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[CH:23]=[CH:24][C:25]([F:30])=[C:26]([CH:29]=3)[C:27]#[N:28])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)ccc1F
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-2-fluorobenzonitrile generally according to the procedures described in examples 82 and 1. An off-white solid: mp 197-199° C.; 1H NMR (DMSO-d6): δ 10.09 (s, 1H), 8.25 (dd, J=6.35, 2.44 Hz, 1H), 8.02-8.05 (m, 1H), 7.68 (dd, J=8.3, 1.95 Hz, 1H), 7.61 (d, J=1.95 Hz, 1H), 7.7 (dd, JHF=9.28 Hz, JHH=9.28 Hz, 1H), 7.56 (dd, J=5.37, 1.47 Hz, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.0 (dd, J=4.88, 3.42 Hz, 1H), 6.95 (dd, J=3.9, 1.47 Hz, 1H), 4.08 (d, J=15.62 Hz, 1H), 3.94 (d, J=15.13 Hz, 1H), 2.46-2.57 (m, 2H), 0.76 (t, J=6.83 Hz, 3H); MS (ESI) m/z 393 ([M+H]+); MS (ESI) m/z 391 ([M−H]−); Anal. calcd for C22H17FN2O2S: C, 67.33; H, 4.37; N, 7.14. Found: C, 67.26; H, 4.38; N, 6.90.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C@H:6]([NH:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=2)[CH2:12][CH2:11]1.[CH2:34](Cl)[CH2:35]Cl.[CH:38]1[CH:39]=C[C:41]2[N:46](O)N=[N:44][C:42]=2[CH:43]=1>CN(C=O)C>[N:46]12[CH2:35][CH2:34][CH:43]([CH2:38][CH2:39]1)[C@H:42]([NH:44][C:26](=[O:28])[CH2:25][CH2:24][C:23]([NH:22][C@@H:6]([CH2:5][C:4]1[CH:30]=[C:31]([F:33])[CH:32]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:21])[CH2:8][NH:9][C:10]1([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[CH:14]=3)[CH2:12][CH2:11]1)=[O:29])[CH2:41]2.[CH:26]([OH:28])=[O:27]
Reactant: ClCCCl
Reactant: On1nnc2ccccc21
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCC(=O)O)CC2)c1
Solvent: CN(C)C=O
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)CCC(=O)N[C@@H]3CN4CCC3CC4)CC2)c1
Product: O=CO
Temperature: 45 °C
Reaction time: 8 h
Yield: 149.9 %

Procedure:
To a solution of R-aminoquinuclidine (0.086 g, 0.434 mmol) TEA (0.302 ml, 2.17 mmol), and anhydrous DMF (2.5 ml) was added 4-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)amino]-4-oxobutanoic acid (0.200 g, 0.434 mmol), EDC (0.125 g, 0.651 mmol), and HOBT (0.088 g, 0.651 mmol) under nitrogen, with stirring at 45° C. overnight. Reaction mixture was quenched with 10% sodium bicarbonate (aq.) then extracted with ethyl acetate then concentrated in vacuo, yielding product (0.200 g). Prep-HPLC yielded the product as its formate salt. (ES+: 569.3)
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][C:24]1([OH:28])[CH2:27][NH:26][CH2:25]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:26]2[CH2:27][C:24]([OH:28])([CH3:23])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC1(O)CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1.38 g, 3.5 mmol) and 3-methyl-azetidin-3-ol (HCl salt, 519 mg, 4.2 mmol) were dissolved in iPrOH (3.5 mL). DIPEA (1.4 mL, 8 mmol) was added and the RM mixture was heated at 140° C. for 4 h in a pressure safe vial. After cooling at RT, the RM was dissolved in EtOAc, washed with 0.5 M. HCl and brine. The organic phase was dried over Na2SO4 and the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, n-hexane/EtOAc, from 50 to 100% EtOAc) to afford the title compound as a white crystalline solid. HPLC (Condition 4) tR=5.59 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=448.1 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:24][N:23]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:30]2[CH2:29][CH2:28][N:27]([C:25]3[S:24][N:23]=[C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[N:26]=3)[CH2:32][CH2:31]2)=[O:15])[CH:2]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)nc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccn3)ns2)CC1
Yield: 38.6 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (297 mg, 1.10 mmol), 1-(3-pyridin-2-yl-1,2,4-thiadiazol-5-yl)piperazine (300 mg, 1.21 mmol) and diisopropylethylamine (0.211 ml, 1.21 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, followed by ethyl acetate:methanol=9:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 156 mg (38.5%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.C([Li])CCC.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1>CCOCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][OH:24])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(CCCO)c1cccnc1
Yield: 76.5 %

Procedure:
A solution of 10.0 g (63.3 mmol) of 3-bromopyridine in 100 ml of ether was cooled to -78° C., to which 40 ml (64 mmol) of 1.6M n-butyllithium hexane solution was added dropwise with stirring. After completion of the addition, the mixture was stirred for further 15 minutes, to which the solution of 5.45 g (63.3 mmol) of γ-butyrolactone in 15 ml of ether was added dropwise, and stirred for further 1 hour at -78° C.-room temperature. To the reaction mixture an aqueous solution of ammonium chloride, and the resultant substance was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was evaporated off. The residue was purified with silica gel column chromatography (CHCl3 -MeOH (9:1)) and recrystallized from ethyl acetate-isopropyl ether, to give 8.0 g (77%) of 4-(3-pyridyl)-4-oxobutanol. m.p. 36°-37° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[S:23])=[CH:3][CH:2]=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[ClH:24].[ClH:24].[N:33]1[CH:34]=[CH:35][C:30]([S:29][CH2:28][CH2:27][CH2:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[S:23])=[CH:31][CH:32]=1
Reactant: ClCCCCSc1ccncc1
Reactant: O=c1c2ccccc2[nH]c(=S)n1CCCCSc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: O=c1c2ccccc2n(CCCCSc2ccncc2)c(=S)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 515 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2(1H)-thion-4(3H)-one and 332 mg (1.65 mmol) of 4-(4-chlorobutylthio)pyridine in 15 ml of dimethylformamide, 0.25 ml (1.65 mmol) of 1,8-diazabicyclo-[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent:ethyl acetate/ethanol=25:1 to 10:1) to give 0.694 mg of the desired product (97.1% yield; colorless oil).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)(Cl)Cl.[N+:16]([O-])([OH:18])=[O:17]>O>[N+:16]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1cccc2ccccc12
Yield: 74 %

Procedure:
Naphthalene (13.62 g), Zn2+ montmorillonite (0.25 g) and CCl4 were stirred in 50 ml two-necked round-bottomed flask equipped with Dean-Stark apparatus. Fuming nitric acid (5 ml) was added dropwise into the reaction mixture. The reaction mixture was heated to reflux where upon the required amount of liberated water is collected in the Dean-Stark apparatus which usually takes 1 hr. Later on, the catalyst was filtered and the organic layer is concentrated to obtain 1-nitronaphthalene.
Reaction SMILES: [H-].[Na+].[CH:3]([Si:6]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[SH:7])([CH3:5])[CH3:4].[H][H].I[C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=1)[O:20][CH2:21][CH2:22][C:23]1[N:28]=[C:27]([CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=1>C1COCC1.C1(C)C=CC=CC=1.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>[CH3:12][CH:11]([Si:6]([CH:3]([CH3:5])[CH3:4])([S:7][C:17]1[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=1)[O:20][CH2:21][CH2:22][C:23]1[N:28]=[C:27]([CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=1)[CH:8]([CH3:10])[CH3:9])[CH3:13]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: [H][H]
Reactant: NCc1cccc(CCOc2cccc(I)c2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[Si](Sc1cccc(OCCc2cccc(CN)n2)c1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 94.6 %

Procedure:
To a suspension of sodium hydride (128 mg, 5.1 mmol) in THF (30 ml) was added triisopropylsilanethiol (1.1 ml, 5.1 mmol) dropwise. After the evolution of hydrogen ceased, a solution of {6-[2-(3-Iodophenoxy)ethyl](2-pyridyl) }methylamine (1.2 g, 3.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (390 mg, 0.3 mmol) in toluene (30 ml) was added. After refluxing for 16 h under argon, the reaction mixture was cooled to room temperature and evaporated under vacuum. The residue was dissolved in ethyl acetate and washed with 1N NaOH and brine. The organic layer was dried with sodium sulfate, filtered, and evaporated. The crude product was chomatrographed over silica gel to yield 1.34 g (95%) of [6-(2-{3-[1,1-bis (Methylethyl)-2-methyl-1-silapropylthio]phenoxy}ethyl)(2-pyridyl)]methylamine. NMR 1H Cl3CD δ: 7.38 (dd, 1H, J=7.2, 8.0 Hz), 7.04 (m, 3H), 6.77 (m, 1H), 6.52 (d, 1H, J=8.0 Hz), 6.25 (d, 1H, J=4.0 Hz), 4.29 (t, 2H, J=6.8 Hz), 3.06 (t, 2H, J=6.8 Hz), 2.90 (d, 3H, J=8Hz), 1.85 (m, 3H), 1.09 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:12]1[CH:30]=[CH:29][C:15]([CH:16]=[CH:17][C:18]([NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:23]([OH:24])[C:22]=2[OH:28])=[O:19])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:31][O:32][C:33](=[O:38])[CH:34]=[CH:35][CH2:36]Br.O>CC(C)=O>[CH3:31][O:32][C:33](=[O:38])[CH2:34][CH:35]1[O:28][C:22]2[C:21]([NH:20][C:18](=[O:19])[CH:17]=[CH:16][C:15]3[CH:14]=[CH:13][C:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:30][CH:29]=3)=[CH:27][CH:26]=[CH:25][C:23]=2[O:24][CH2:36]1
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc(O)c2O)cc1
Reactant: COC(=O)C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(=O)OC)CO3)cc1

Procedure:
Potassium carbonate (509 mg) was added to a solution of 3- (p-pentylcinnamoyl) aminopyrocatechol (300 rag; synthesized by the same procedure as reference example 1) and 4-bromo-2-butenoic acid methyl ester in acetone (10 ml), and the mixture was refluxed for 10 min. The reaction mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was purified by column chromatography on silica gel (hexane: ethyl acetate=5:1) to give the title compound (341 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][C:27]([F:33])([F:32])[S:28]([NH2:31])(=[O:30])=[O:29]>>[ClH:1].[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][S:28]([C:27]([F:33])([F:32])[F:26])(=[O:30])=[O:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NS(=O)(=O)C(F)(F)F)c2c1
Product: Cl

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,1,1-trifluoromethanesulfonamide. MS obsd. (ESI+) [(M+H)+] 486, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99-7.92 (m, 2 H), 7.85-7.80 (d, J=7.2 Hz, 1 H), 7.78-7.73 (d, J=2 Hz, 1 H), 7.72-7.65 (t, J=7.6 Hz, 1 H), 7.62-7.51 (m, 2 H), 7.13 (s, 1 H), 5.07 (s, 2 H), 4.60-4.40 (m, 2 H), 3.98-3.91 (t, J=2.8 Hz, 2 H), 2.39 (s, 3 H).
Reaction SMILES: [CH3:1]C(C)=O.[S:5]([O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[CH:12][C:11]=1[CH3:20])(=[O:8])(=[O:7])[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O>O>[S:5]([O:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([O:19][CH3:1])=[CH:12][C:11]=1[CH3:20])(=[O:7])(=[O:8])[CH3:6]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1OS(C)(=O)=O
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1cc(C)c(OS(C)(=O)=O)cc1[N+](=O)[O-]
Yield: 77 %

Procedure:
To 200 ml of acetone, were added 19.1 g (77.3 mmol) of 2-methyl-4-hydroxy-5-nitrophenyl mesylate, 31.2 g of sodium carbonate and 19.2 g of dimethyl sulfate. The obtained mixture was heated under reflux for 3 hours. The reaction mixture was cooled and 700 ml of water was poured thereto. Then the mixture was extracted with 700 ml of chloroform, and the extract was washed with water and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the residue was recrystallized from a solvent mixture (hexane/acetone (2:1, by volume)) to thereby give 15.4 g (59.1 mmol) of 2-methyl-4-methoxy-5-nitropheyl mesylate. The yield was 77%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[C:19]([CH2:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1O)[CH3:9].Cl.[CH3:26][N:27]([CH2:29][C:30]([OH:32])=[O:31])[CH3:28]>C(Cl)Cl>[CH3:26][N:27]([CH2:29][C:30]([O:32][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]([O:22][CH3:23])=[C:19]([CH2:20][CH3:21])[C:10]=1[CH2:8][CH3:9])=[O:31])[CH3:28]
Reactant: CN(C)CC(=O)O
Reactant: CCc1c(CC)c(OC)c2ccccc2c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1c(CC)c(OC(=O)CN(C)C)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.2 %

Procedure:
Triethylamine (3 eq) and dry methylene chloride (150 ml) are introduced to a mixture of 2,3-diethyl-4-methoxynaphthol (1.59 g, 6.5 mmole), dimethylamino acetic acid hydrochloride (2 eq, 1.8 g, 13.0 mmole), dicyclohexylcarbadiimide (2 eq, 2.7 g, 13.0 mmole) and 4-dimethylaminpyridine (1 eq, 2.7 ml, 19.5 mmole), prepared under an argon atmosphere, at room temperature under argon. The resulting suspension is stirred at room temperature for 20 hours under argon, then diluted with 300 ml of methylene chloride. The methylene chloride extracts are washed thoroughly with saturated aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is chromatographed through a silica gel (200 g) flash column and eluted by ether to give 1.48 g (72.2%) of N,N-dimethylamino acetic acid, 2,3-diethyl-4-methoxynaphth-1-yl ester as a yellowish brown oil.