Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1)=[O:18])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
(2S,4S)-1-Boc-4-azidopyrrolidine-2-carboxylic acid (9.5 g, 35 mmol) obtained in Step A was dissolved in DMF (30 mL). After DIPEA (1.15 mL, 6.70 mmol) was added thereto, 1-methylpiperazine (5.81 mL, 52.5 mmol), HOBT (7 g, 52.5 mmol) and EDC (10.2 g, 52.5 mmol) were added thereto, in turn. The reaction solution was stirred for 12 hours at room temperature and concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution, water and 1N HCl. The extracted organic solution was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent: MC/MeOH=10/1) to give the title compound (11.67 g, 93%).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])[C:6]=1B(O)O)C(C)C.Br[C:23]1[CH:34]=[CH:33][C:26]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:25][CH:24]=1.[OH-].[Na+].[C:37]1([CH3:43])[CH:42]=CC=C[CH:38]=1>C(OCC)(=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.C(O)C>[N:28]1([CH2:27][C:26]2[CH:33]=[CH:34][C:23]([C:6]3[CH:5]=[C:10]([CH2:38][CH:37]([CH3:43])[CH3:42])[CH:9]=[CH:8][C:7]=3[S:11]([NH:14][C:15]([CH3:16])([CH3:17])[CH3:18])(=[O:12])=[O:13])=[CH:24][CH:25]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: Cc1ccccc1
Reactant: Brc1ccc(Cn2ccnc2)cc1
Reactant: CC(C)Cc1cccc(S(=O)(=O)NC(C)(C)C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(Cn3ccnc3)cc2)c1
Yield: 53 %

Procedure:
The crude product from step (b) above (1.2 g, 3.83 mmol), 1-(4bromo-benzyl)-1H-imidazole (98.8 mg, 0.416 mmol, see Example 1(d) above), Pd(PPh3)4 (29 mg, 0.25 mmol), NaOH (3 mL, 1M, 3 mmol), toluene (15 mL) and ethanol (3 mL) were mixed under N2 (g). The mixture was heated to reflux for 2 h. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. Purification using column chromatography with CHCl3:MeOH (20:1) as eluent yielded the sub-title compound (93.7 mg, 0.220 mmol) in 53% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([CH3:18])=[C:5]2[CH2:19][C:20]([NH2:22])=[O:21].[H-].[Na+].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.C(OCC)(=O)C.Cl>[CH3:18][C:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]2[C:4]([C:5]=1[CH2:19][C:20]([NH2:22])=[O:21])=[CH:3][C:2]([O:1][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:10][CH:9]=2
Reactant: Ic1ccccc1
Reactant: Cc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(CC(N)=O)c2cc(Oc3ccccc3)ccc2n1Cc1ccccc1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
5-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide (1.2 g, 4.1 mmol) was dissolved in 40 mL of pyridine, 90 mg (2.2 mmol) of 60% NaH/mineral oil added, stirred 0.17 hours, 315 mg of CuO added, stirred 0.17 hours and 0.5 (4.1 mmol) mL of iodobenzene added. The mixture was heated to maintain reflux for 24 hours, cooled, and diluted with ethyl acetate and 1N HCl. The mixture was filtered thru a celite pad and the organic material separated, washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was chromatographed on silica gel and eluted with 1% MeOH/methylene chloride→3% MeOH/methylene chloride to give 40 mg (3% yield) of 2-methyl-5-phenoxy-1-(phenylmethyl)-1H-indole-3-acetamide.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].I[C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>CO.O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:12][C:16]2[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:4]=1
Reactant: COC(=O)c1ccccc1I
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccccc1Nc1cc(C(F)(F)F)ccc1C(=O)O
Yield: 43 %

Procedure:
Reaction of 4-trifluoromethylanthranilic acid and methyl 2-iodobenzoate by the reported method [Rewcastle and Denny, Synth, Comm 1987, 17, 309 gave 4-trifluoromethyl-2-(2-methoxycarbonylphenyamino)benzoic acid (43%), mp (MeOH/H2O) 206-207° C. 1H NMR [(CD3)2SO] δ 3.87 (s, 3 H, CO2CH3), 7.12 (ddd, J=8.0, 6.1, 2.1 Hz, 1 H., H-5'), 7.23 (dd, J=8.3, 1.0 Hz, 1 H, ArH), 7.55-7.62 (m, 3 H, 3×ArH), 7.95 (dd, J=8.0, 1.3 Hz, 1 H, ArH), 8.12 (d, J=8.2 Hz, 1 H, ArH). Formation of the corresponding imidazolide and immediate reduction of this as above gave methyl-2-[N-(5'-trifluoromethyl-2'-hydroxymethyl)phenyl-amino]benzoate (86%), mp (hexane) 86-87° C. 1H NMR (CDCl3) δ 2.00 (t, J=5.6 Hz, 1 H, OH), 3.92 (s, 3 H, CO2CH3), 4.78(d, J=5.3 Hz, 2 H, CH2), 6.84 (td, J=7.6, 1.1 Hz, 1 H, ArH), 7.15 (dd, J=8.6, 0.8 Hz, 1 H, ArH), 7.31-7.39 (m, 2 H, 2×ArH), 7.52 (d, J=7.7 Hz, 1 H, ArH), 7.70 (s, 1 H, H-6'), 8.76 (dd, J=8.0, 1.6 Hz, 1 H, ArH), 9.72 (s, 1 H, NH).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[O:17]CC1C=CC=CC=1)=[O:7]>CO.O1CCCC1>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[OH:17])=[O:7]
Reactant: CN(C)CCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)c1cc2cccc(O)c2[nH]1
Yield: 56 %

Procedure:
Under the conditions of Example 14(C), 9 g of 7-benzyloxyindole-2-carboxylic acid 2-dimethylaminoethyl ester is hydrogenated in a mixture of 50 ml of methanol and 50 ml of tetrahydrofuran and worked up, yielding 3.7 g of 7-hydroxyindole-2-carboxylic acid 2-dimethylaminoethyl ester, mp 149°-152° C.
Reaction SMILES: [CH2:1]([O:15][CH2:16][C@H:17]([OH:20])[CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[S:27]([O:19][CH2:18][C@H:17]([CH2:16][O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:20][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCOC[C@H](O)CO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOC[C@@H](COS(=O)(=O)c1ccc(C)cc1)OS(=O)(=O)c1ccc(C)cc1
Yield: 80.6 %

Procedure:
In 30 ml of pyridine, 5.76 g of 3-tetradecyl-sn-glycerol is allowed to react with 8.39 g of p-toluenesulfonic acid chloride to give 9.6 g (81%) of 1,2-ditosyl-3-tetradecyl-sn-glycerol. This ditosyl compound (9.6 g) is dissolved in 80 ml of ethanol, followed by addition of 7.89 g of fused potassium acetate. After 40 hours of reflux, the reaction mixture is cooled and the resulting precipitates are removed by filtration. The solvent is distilled off and the residue is dissolved in a methanol solution (300 ml) containing 3 g of sodium methoxide. The solution is refluxed for 2 hours and the solvent is removed by distillation. To the residue are added chloroform and water for separation and the chloroform layer is washed with water, dried and subjected to chromatography on silica gel to give 2.82 g of 1-tetradecyl-sn-glycerol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>ClCCl.CO>[BrH:1].[Cl:44][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:17]=2)[CH:34]=[C:29]([Cl:28])[C:30]=1[OH:45]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)cc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Solvent: ClCCl
Solvent: CO
Product: Br
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCCC2)cc1
Yield: 60.9 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(4-(pyrrolidin-1-ylmethyl)phenylamino)quinoline-3-yl)ethanone (4.0 g, 9.42 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.0 g, 14.13 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 40 mL) and HBr gas was bubbled through the suspension until a solution formed. The solution was concentrated to dryness and the resultant solid was triturated with diethyl ether. The mixture was filtered, washed with diethyl ether, and dried to obtain desired product (3.37 g, 52% over two steps) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 12.03 (br s, 1H), 10.59 (br s, 1H), 10.08 (br s, 1H), 9.27 (s, 1H), 8.43-8.27 (m, 2H), 8.112 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.59-7.47 (m, 4H), 4.47 (d, J=5.3 Hz, 2H), 3.40-3.24 (m, 2H), 3.19-3.02 (m, 2H), 2.56 (s, 3H), 2.13-1.81 (m, 4H); APCI MS m/z 506 [C28H25Cl2N3O2+H]+; HPLC>99% (AUC), tR=4.97 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.[SH:11][C:12]1[S:13][C:14]([SH:17])=[N:15][N:16]=1.[CH2:18]([SH:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].OO>C(O)(C)C>[CH:7]12[CH2:6][CH:5]([C:8]1([CH3:10])[CH3:9])[CH2:4][CH2:3][C:2]2([S:11][C:12]1[S:13][C:14]([S:17][S:26][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:15][N:16]=1)[CH3:1]
Reactant: Sc1nnc(S)s1
Reactant: CCCCCCCCS
Reactant: CC1=CCC2CC1C2(C)C
Agent: OO
Solvent: CC(C)O
Product: CCCCCCCCSSc1nnc(SC2(C)CCC3CC2C3(C)C)s1
Temperature: 155 °C
Reaction time: 8 h

Procedure:
Alpha-pinene (38 g, 0.28 mol) and 2,5-dimercapto-1,3,4-thiadiazole (40 g, 0.27 mol) were charged to the reaction flask and cautiously heated to 155° C. since the reaction was exothermic. The reaction was maintained at 155° C. for 15 min. and then cooled. Isopropanol (32 g) and n-octylmercaptan (43.7 g, 0.30 mol) were charged. Hydrogen peroxide, 35% (60 g, 0.62 mol) was added slowly while maintaining the temperature at 40°-50° C. The reaction was then allowed to stand overnight. The product was extracted with 150 ml of n-hexane and washed with 150 ml of 1M sodium carbonate. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed by rotary evaporation.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH2:18][CH:19]=[CH2:20])[O:13][CH2:14][CH:15]=[CH2:16])[P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].C(Cl)Cl.C[N:28](C=O)C>C1COCC1>[NH2:28][CH:1]([P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6])[P:12](=[O:21])([O:13][CH2:14][CH:15]=[CH2:16])[O:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCOP(=O)(CP(=O)(OCC=C)OCC=C)OCC=C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)C(N)P(=O)(OCC=C)OCC=C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of bisphosphonate 23 (2.0 g, 5.95 mmol) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 254 mg, 6.35 mmol) portionwise. The solution was stirred for 45 min at room temperature and added to a solution of O-(diphenylphophinyl)hydroxylamine (1.35 g, 5.77 mmol) in THF (40 mL), cooled in a dry ice/acetone bath. The resulting mixture was stirred for 10 min at the same temperature then 18 h at room temperature. CH2Cl2 (40 mL) was added, the solids were removed by filtration and washed with several portions of CH2Cl2. The combined filtrates were concentrated in vacuo and purified by flash chromatography on silica gel using a gradient of 0-5% MeOH/EtOAc to provide aminobisphosphonate 24 as a clear yellow oil (1.24 g, 3.53 mmol, 59%). 1H NMR (400 MHz, CDCl3) δ 1.69 (bs, 2H), 3.52 (t, J=20.8 Hz, 1H), 4.64-4.67 (m, 8H), 5.24-5.27 (m, 4H), 5.36-5.42 (m, 4H), 5.92-6.02 (m, 4H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:32]>>[CH3:29][O:28][C:26](=[O:27])[CH2:25][CH:8]1[C:7]2[S:6][C:5]([C:3](=[O:2])[NH2:32])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:22])[CH3:23])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: N
Reactant: COC(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(=O)OC)sc21
Solvent: CO
Product: COC(=O)CC1COc2ccc(C#CC(C)(C)O)cc2-c2nc(C(N)=O)sc21

Procedure:
A solution of 9-(3-Hydroxy-3-methyl-but-1-ynyl)-4-methoxycarbonylmethyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (70 mg, 0.117 mmol) in methanol-ammonia (40 mL) was stirred at room temperature for 2 h. Then the mixture was concentrated to afford crude compound which was purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford [2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid methyl ester as light yellow oil. LC-MS (ESI & APCI): 401.4 (M+1).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][NH2:27]>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][NH:27][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: NNc1ccccc1Br
Product: COc1ccc2c(c1)CCn1c-2cc(NNc2ccccc2Br)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and (2-bromo-phenyl)-hydrazine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO at 60° C.) δ 9.19 (br, 1H), 7.66 (brd, 1H), 7.46 (d, 1H), 7.44 (br, 1H), 7.20 (t, 1H), 6.98-6.75 (3H), 6.71 (t, 1H), 6.23 (s, 1H), 3.94 (t, 2H), 3.82 (s, 3H) and 2.93 (t, 2H); MS (ESI) (M+H)+ 413, 415.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[S:6][CH:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:4](=O)[CH2:3]1.[CH2:14]([C:19]1[CH:20]=C(O)C=[C:23]([CH:25]=1)[OH:24])[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][C:2]1([CH3:13])[S:6][C:5]2[C:7](=[O:8])[O:9][C:10]3[CH:20]=[C:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]=[C:23]([OH:24])[C:11]=3[C:4]=2[CH2:3]1
Reactant: CCCCCc1cc(O)cc(O)c1
Reactant: CCOC(=O)C1SC(C)(C)CC1=O
Product: CCCCCc1cc(O)c2c3c(c(=O)oc2c1)SC(C)(C)C3
Yield: 72.5 %

Procedure:
Ethyl 5,5-dimethyl-3-oxo-tetrahydrothiophene-2-carboxylate was reacted with 5-n-pentyl resorcinol following a procedure similar to that of Example 3-C to produce 1,2-dihydro-2,2-dimethyl-9-hydroxy-7-n-pentyl-4-oxo-4H-thieno-[2,3-c][1] benzopyran in a 72.5% yield, m.p. 203°-206°C.
Reaction SMILES: [Na].[O-][CH2:3]CCC.COC1C=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:19])[CH2:16]2)=[CH:11][CH:10]=1.CI.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>CCOC(C)=O.O>[CH3:24][O:25][C:26]1[CH:22]=[C:23]2[C:12]([CH2:17][CH2:16][C:15](=[O:19])[C:14]2([CH3:13])[CH3:3])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CCCC[O-]
Reactant: C1CCOC1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Temperature: 25 °C

Procedure:
A slurry of sodium tent butoxide (21.1 g, 220 mmol) in THF (100 mL) was cooled to 0° C. A solution of 7-methoxy-3,4-dihydro-1H-napthalen-2-one (17.6 g, 100 mmol) and methyl iodide (30.1 g, 220 mmol) in THF (100 mL) was added dropwise over 40 min, and the reaction mixture was warmed to room temperature after 10 min. Water (200 mL) and EtOAc (600 mL) was added. The layers were separated, the organic layer was washed with water (5×100 mL) and saturated NaCl (100 mL), filtered and dried with Na2SO4 to provide the title compound (20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: CCCCCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cn1
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(Cl)c1
Yield: 64.5 %

Procedure:
Using a method similar to Example 405, using 5-(2-chloro-4-formylphenoxy)pyridine-2-carboxamide (0.0388 g, 0.140 mmol) and amylamine (0.012 g, 0.140 mmol) gives the title compound (0.0314 g, 64.3%): TOF MS ES+ 348.1 (M+H)+, HRMS calcd for C18H23N3O2Cl 348.1479 (M+H)+, found 348.1456, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.6 min, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH:12]([N:15]=[C:16]=[O:17])([CH3:14])[CH3:13]>>[CH:12]([NH:15][C:16]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:17])([CH3:14])[CH3:13]
Reactant: CC(C)N=C=O
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Product: CC(C)NC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6v (98% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and iso-propyl isocyanate as a white solid. IR(CHCl3) 3294, 1712, 1533 cm−1; 1H-NMR (CDCl3) δ1.29 (d, J=6.8 Hz, 6H), 4.12 (hep, J=6.8 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.92 (d, J=8.2 Hz, 1H), 8.65 (br s, 1H); ESIMS m/e 271 and 273 (M++1, 35Cl and 37Cl).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9](=[O:17])[C:8]2=[O:18])=[CH:4][CH:3]=1.[N+:21]([CH3:24])([O-:23])=[O:22]>O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=3)[C:9]([OH:17])([CH2:24][N+:21]([O-:23])=[O:22])[C:8]2=[O:18])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(Cl)cc21
Solvent: O
Product: O=C1N(Cc2ccc(Br)cc2)c2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
1-(4-bromobenzyl)-5-chloroindoline-2,3-dione (0.175 g) and nitromethane (0.15 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[F:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:23][CH2:22][CH2:21][CH2:20][F:19])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NCCCF
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NCCCF

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 3-fluoro-propylamine following general procedure B to afford 4-(3-fluoro-propylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (262 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (196 mg) following general procedure E. The above ethylamide (0.64 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-1-(3-fluoro-propyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (138 mg). LCMS: m/z 332 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[CH2:9]1[O:11][CH:10]1[CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C.O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:12][CH:10]2[CH2:9][O:11]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: OCC1CO1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnn(CC2CO2)c1
Yield: 47.7 %

Procedure:
To a stirred, cooled (0° C.) solution of 4-nitro-1H-pyrazole (1.0 g, 8.8 mmol), glycidol (0.58 mL, 8.8 mmol) and triphenylphosphine (2.14 g, 10.6 mmol) in THF (40 mL) was added DIAD (2.25 mL, 11.4 mmol). After 24 h the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed (brine), dried (anhydrous MgSO4) and concentrated. Flash chromatography (Isolera, silica, 50 g, 0-90% ethyl acetate in petroleum ether) afforded 4-nitro-1-(oxiran-2-ylmethyl)-1H-pyrazole as an off-white solid (0.71 g, 48% yield). LCMS (UPLC, low pH), RT=0.74 min.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[CH3:12][C:13]1([CH3:27])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[O:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:27])[O:14][B:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]3[O:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[CH:7]=3)=[CH:22][CH:21]=2)[O:16]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: BrCc1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(OCc3cc4ccccc4o3)cc2)OC1(C)C
Temperature: 70 °C
Yield: 63 %

Procedure:
To 2-Bromomethyl-benzofuran (1.5 g, 7.1 mmol, 1 eq.), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (1.56 g, 7.1 mmol, 1 eq.), potassium carbonate (1.96 g, 14.2 mmol, 2 eq.) was dissolved in acetonitrile (50 m]L) under argon and heated at 70° C. for 16 hours. After work-up and flash column chromatography, 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-benzofuran is obtained. Yield: 63%. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.3 (s, 12 H) 5.3 (s, 2 H) 7.1 (m, 3 H) 7.3 (m, 1 H) 7.3 (m, 1 H) 7.6 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](=[O:17])(O)[O-:15].[Na+].[C:19](O)(=[S:22])CO.[Na]>CCOCCO>[C:14]([CH2:19][S:22][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([OH:15])=[O:17]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: OCC(O)=S
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CCOCCO
Product: O=C(O)CSc1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 86.3 %

Procedure:
In a 5 liter flask equipped with an impervious agitator, a reflux refrigerant and a thermometer, there are introduced 146 g (0.72 mole) of 2-chloro-5-nitro-benzoic acid and 2200 ml of cellosolve. There is obtained a solution to which is added 181 g of sodium bicarbonate and 66 g of thio-glycolic acid. The mixture is refluxed. There is very rapid precipitation of the sodium salt of the carboxymethylthio acid formed. After 3 1/2 hours of reflux, the heating is stopped, and the sodium salt is cooled, drained and washed on a filter with 200 ml of cellosolve. This salt is then redissolved in water and the acid is precipitated with 145 ml of concentrated hydrochloric acid. It is drained, washed with water until the chloride ions are eliminated and dried at 50° C. There are obtained 159 g (yield: 86%) of 2-carboxymethylthio-5-nitro-benzoic acid (m.p.: 216°-217° C).