Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH:18]([OH:20])[CH3:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH:18]([O:20][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:19])[S:17][C:13]=2[N:12]2[C:21]([CH3:24])=[N:22][N:23]=[C:11]2[CH2:10][N:9]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nnc2n1-c1sc(C(C)O)cc1C(c1ccccc1Cl)=NC2
Solvent: c1ccncc1
Product: Cc1nnc2n1-c1sc(C(C)OC(=O)C(C)(C)C)cc1C(c1ccccc1Cl)=NC2
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a solution of 3 g of 4-(2-chlorophenyl)-2-(1-hydroxyethyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine dissolved in 30 ml of pyridine is added 1 g of pivaloyl chloride under ice-cooling and then stirred overnight. After completion of the reaction, the mixture is concentrated under reduced pressure and the residue is dissolved in 30 ml of ethyl acetate. The solution is washed with 5% aqueous sodium hydrogencarbonate solution and sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off, the filtrate is concentrated under reduced pressure and the residue is subjected to chromatography on silica gel and eluted with chloroform-methanol (100:1-100:3). The objective fraction is concentrated under reduced pressure followed by crystallization from ligroinethyl acetate to give 1.1 g of 4-(2-chlorophenyl)-9-methyl-2(1-pivaloyloxyethyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine as crystals, melting at 148°-151° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)[CH:4]=1)#[N:2].[N+:23]([CH2:26][CH3:27])([O-])=[O:24].C1(N=C=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:27][C:26]1[N:2]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH:4]=2)[O:24][N:23]=1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C#N)ccn2)CC1
Reactant: CC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1noc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
2,2-Dimethylpropyl 4-(4-cyanopyridin-2-yl)piperazine-1-carboxylate (301 mg) obtained in Example 2 was dissolved in toluene (5 mL), and nitroethane (82.6 mg), triethylamine (one drop) and phenyl isocyanate (0.238 mL) were added thereto, stirred at room temperature for 1 hour, and then heated under reflux for 2 hours. The reaction liquid was filtered, the filtrate was evaporated, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 114 mg of the entitled compound as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:5])=[O:4].O(C)[Na].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>>[CH2:22]([N:2]([CH3:1])[S:3]([C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:12])[F:11])(=[O:5])=[O:4])[CH:24]1[O:26][CH2:25]1
Reactant: CNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: ClCC1CO1
Agent: CO[Na]
Product: CN(CC1CO1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
N-Methylperfluorobutanesulfonamide (MeFBSA, 313 g, 1.0 mol; preparation described in U.S. Pat. No. 6,664,354, Savu et al., Example 1, Part A) was added to a stirred mixture of 220 g NaOCH3 (1.02 mol; 25% NaOMe in MeOH). The solvent was removed under vacuum (pot temperature about 80° C.; 50 mm Hg). The resulting paste was dissolved in 250 mL THF and treated with 473 g (5.11 mol) epichlorohydrin and stirred at reflux for 4 hr. GLC analysis showed complete conversion of MeFBSA. The slurry was cooled, washed with water (300 mL) and the resulting lower layer was taken up in methylene chloride, rewashed with water (300 mL), and dried over MgSO4. The product was stripped and one-plate distilled to a main cut of MeFBSG as a colorless liquid (260.8 g, bp 95-105° C./0.3 mmHg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([SH:27])=[CH:22][C:21]=1[CH3:28])[CH3:15].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CN1C(=O)CCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=2)=[CH:22][C:21]=1[CH3:28])[CH3:15]
Reactant: CC(C)COc1cc(Br)cc(Br)c1
Reactant: CCOC(=O)COc1cc(C)c(S)cc1C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-5-isobutoxy-benzene (1.66 g; 5.4 mmol), (4-Mercapto-2,5-dimethylphenoxy)-acetic acid ethyl ester (1.0 g; 4.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.11 g; 0.12 mmol), and 1,1′-bis-(diphenylphosphino)ferrocene (0.14 g; 0.25 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (2.3 mL) and NMP (10 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane:ethyl acetate (10:1→1:1). Yield: 1.3 g; 67%. HPLC-MS: m/z: 467.0 (M+); Rt: 3.10 min
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:21])[NH:5][C:6](=[O:20])[N:7]([CH:19]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@:10](C(=O)C)([OH:11])[CH2:9]1)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[P:37]([O-])([O-:44])([O:39]CCC#N)=[O:38].N.C(O)(C)C.O>N1C=CC=CC=1>[P:37]([O:14][CH2:13][C@H:12]1[O:15][C@@H:8]([N:7]2[CH:19]=[C:3]([CH2:1][CH3:2])[C:4](=[O:21])[NH:5][C:6]2=[O:20])[CH2:9][C@@H:10]1[OH:11])([OH:44])([OH:39])=[O:38]
Reactant: CCc1cn([C@H]2C[C@@](O)(C(C)=O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Yield: 29.7 %

Procedure:
A mixture of 0.3 g (0,001 mole) of 5-ethyl-3'-acetyl-2'-desoxyuridine, 1.2 g of dicyclohexylcarbodiimide and 2 ml of a pyridine solution of 0.002 mole of β-cyanoethyl phosphate were reacted to obtain 200 mg (62% yield) of 5-ethyl-2'-desoxyuridine-5'-monophosphate with an Rf=0.17 [1-7-2 ammonia-isopropanol-water mixture].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[S:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccc(Cl)cc2C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=S)Nc2ccc(Cl)cc2C1
Yield: 157.1 %

Procedure:
A mixture of 7-chloro-2-oxo-1,2,3,5-tetrahydro-benzo[1,4]diazepine-4-carboxylic acid tert-butyl ester (41.1 g, 0.139 mol) and 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (31.5 g, 0.0763 mol) in tetrahydrofuran (1100 ml) was heated at reflux for 3 h. The solvent was evaporated and the residue was triturated in tert-butyl methyl ether. The precipitate was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized from hot ethanol to give the title compound (37.5 g, 86.4%) as light yellow solid. MS m/e: 311 (M−H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:15][CH2:23][CH3:24]
Reactant: CCI
Reactant: Oc1cc(Oc2ccccc2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(Oc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-bromo-5-phenoxyphenol (120 mg, 0.45 mmol) in acetone (7 mL) was added potassium carbonate (0.375 g, 2.72 mol) followed by iodoethane (0.0724 mL, 0.905 mol) at rt. The mixture was stirred at rt overnight. Reaction mixture was concentrated down in vacuo and washed with brine extracting with EtOAc. The organics were combined, dried over Na2SO4 and concentrated to afford the title compound which was used for next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.37 (t, J=6.95 Hz, 3H), 3.95 (q, J=7.07 Hz, 2H), 6.37 (dd, J=8.59, 2.78 Hz, 1H), 6.52 (d, J=2.53 Hz, 1H), 6.90-6.97 (m, 2H), 7.00-7.08 (m, 1H), 7.22-7.30 (m, 2H), 7.36 (d, J=8.59 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[C:22]2[CH:23]([NH2:26])[CH2:24][O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:15][O:16][C:17]1[C:22]2[CH:23]([NH:26][C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=4)[N:3]=3)[CH2:24][O:25][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: COc1cccc2c1C(N)CO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cccc2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CO2
Temperature: 140 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A mixture of 2-chloro-6-nitro-quinoline (3.8 g, 18.2 mmol) in 1-methyl-2-pyrrolidone (5 mL) with the above described rac-4-methoxy-2,3-dihydro-benzofuran-3-ylamine (3.61 g, 21.9 mmol) and N-ethyldiisopropylamine (4.68 mL, 27.3 mmol) was stirred at 140° C. for 2 h. Cooled to 23° C., poured onto water and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally to give a crude product which was purified by silica gel column chromatography with heptane/dichloromethane followed by trituration with diethyl ether to give the title compound as a yellow solid (4.0 g, 65%); MS: m/e=336.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:6])[CH3:2].CO[CH2:19][N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:21][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:5]1([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:19][N:20]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:21]1)=[O:16])[CH3:2]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(C(=O)OCC)C(C)(C)O[SiH2]C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a cold solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-acrylic acid ethyl ester (463 mg, 1.89 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (540 μl, 2.11 mmol) in dichloromethane (3 ml) was added at 0° C. trifluoroacetic acid (26 μl, 0.34 mmol). The resulting solution was warmed to room temperature in two hours. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:10, 1:5) to give the title compound (490 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=2)=[CH:6][CH:7]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(N)cc2)on1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(NC(=O)c3ccccc3)cc2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
5-(4-Aminophenyl)-3-(2-(N-tert-butoxycarbonylamino)ethoxy)isoxazole (0.1 g) was dissolved in tetrahydrofuran (I ml), and triethylamine (0.05 ml) and benzoyl chloride (0.04 ml) were successively added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.08 g, 62%) as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH2:4][CH:3]1[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:33].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:35]1([CH3:40])[C:34]([C:32]([CH2:31][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:4][CH:3]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:2]2=[O:1])=[O:33])=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-cyclohexylcarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) was suspended in toluene (28 ml), 2-bromo-2′-methylacetophenone (1.28 g), 1N aqueous sodium hydroxide (14 ml) and tetra n-butylammonium bromide (20 mg) were added, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl was added to the residue for trituration, collected by filtration, to thereby obtain 2.15 g of the titled compound (Yield: 80.7%).
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.[CH2:13](Cl)[CH:14]=[CH2:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:15]([N:6]1[C:2](=[O:12])[C:3]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:4]2[C:5]1=[O:7])[CH:14]=[CH2:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 42 %

Procedure:
To a stirred mixture of phthalimide potassium salt (20 g, 108 mmol) and tetrabutylammonium bromide (1.04 g, 3.24 mmol, 0.03 equiv) in anhydrous DMF (75 mL) was added allyl chloride (8.84 mL, 108 mmol) at room temperature, and the mixture was stirred at room temperature for 22 h, resulting in a light-yellow suspension. The reaction was quenched by adding cold H2O (150 mL), and the mixture was stirred for 10 min (an ice bath was applied during this time to aid the precipitation). The resulting white suspension was filtered off, washed with H2O (3×50 mL), and air-dried to give N-allylphthalimide (8.5 g, 42% yield) as white solid.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:43]([CH3:45])[CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[N:15]=1)=[O:13])(C(C)(C)C)(C)C.OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH:43]([CH3:45])[CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2Cl)nc(O)c1OCc1ccccc1
Yield: 54 %

Procedure:
5-Benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (10-04) (1.2 g, 53.97%) was synthesized as a yellow liquid from 5-benzyloxy-2-(2′-chloro-biphenyl-2-ylmethyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (9-04) (2.7 g, 4.18 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-01).
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C:7](I)=[N:6][CH:5]=1.CN(C)C=O.[C:25](=O)([O-:27])[O-:26].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:3][C:4]1[C:5]([C:25]([OH:27])=[O:26])=[N:6][C:7]2[C:14]3[S:15][CH:16]=[CH:17][C:13]=3[CH2:12][CH2:11][O:10][C:8]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cnc(I)c(OCCc2ccsc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2c(nc1C(=O)O)-c1sccc1CCO2
Temperature: 90 °C
Yield: 52.8 %

Procedure:
To a solution of 6-Iodo-5-(2-thiophen-3-yl-ethoxy)-nicotinic acid methyl ester (4.40 g, 11.3 mmol) in N,N-Dimethylformamide (176 mL, 2270 mmol) was added potassium carbonate (9.37 g, 67.8 mmol), triphenylphosphine (1.19 g, 4.52 mmol) and palladium acetate (508 mg, 2.26 mmol). The reaction mixture was stirred at 90° C. 8 h. The reaction mixture was diluted with MeOH then filtered through celite. The filtrate was concentrated. The crude product was purified by flash chromatography EtOAc/Hex (0-100%) (product eluted at 30%) to give 3-methylcarboxy-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (52.8%). MS: (ESI+) 262.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([NH:24][CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'carbonyldiimidazole (2.69 g, 0.0166 mole), and dry tetrahydrofuran (100 ml) was stirred at room temperature for 1.75 hours with a stream of nitrogen bubbling through it. A solution of methylene in tetrahydrofuran (33 ml of a 3.03M solution, 0.996 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol, charcoaled, and filtered while hot. Water was added to the cloud point, and upon cooling, solid precipitated. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 3.21 g (62%) of title compound, mp 217°-218° C.
Reaction SMILES: COC1C=C(C)C(S(N2CCCC2COCC(O)=O)(=O)=O)=C(C)C=1.N1(CC2C=C(C=CC=2)C#N)CCNCC1.C(=O)([O-])O.[Na+].[CH3:45][O:46][C:47]1[CH:52]=[C:51]([CH3:53])[C:50]([S:54]([N:57]2[CH2:61][CH2:60][CH2:59][CH:58]2[CH2:62][O:63][CH2:64][C:65]([N:67]2[CH2:72][CH2:71][N:70]([CH2:73][C:74]3[CH:75]=[C:76]([CH:79]=[CH:80][CH:81]=3)[C:77]#[N:78])[CH2:69][CH2:68]2)=[O:66])(=[O:56])=[O:55])=[C:49]([CH3:82])[CH:48]=1.[Cl:83][Si](C)(C)C>ClCCl.CC(C)=O.C(OCC)C.C(OCC)C>[ClH:83].[CH3:45][O:46][C:47]1[CH:48]=[C:49]([CH3:82])[C:50]([S:54]([N:57]2[CH2:61][CH2:60][CH2:59][CH:58]2[CH2:62][O:63][CH2:64][C:65]([N:67]2[CH2:72][CH2:71][N:70]([CH2:73][C:74]3[CH:75]=[C:76]([CH:79]=[CH:80][CH:81]=3)[C:77]#[N:78])[CH2:69][CH2:68]2)=[O:66])(=[O:55])=[O:56])=[C:51]([CH3:53])[CH:52]=1
Reactant: C[Si](C)(C)Cl
Agent: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)N2CCN(Cc3cccc(C#N)c3)CC2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)O)c(C)c1
Agent: N#Cc1cccc(CN2CCNCC2)c1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (150 mg, 0.420 mmol) in dichloromethane (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 3-(piperazin-1-ylmethyl)benzonitrile (84 mg, 0.420 mmol) in dichloromethane (3 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/hexane/ammonia solution (25% aq.) (100:10:1). 3-((4-(2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetyl)piperazin-1-yl)methyl)benzonitrile (190 mg, 0.351 mmol) was dissolved in acetone/diethyl ether (1:1; 8 ml), and chlorotrimethylsilane (89 μl, 0.702 mmol) was added slowly. Diethyl ether (10 ml) was then added, and the mixture was stirred for 1 h at 0° C. The resulting precipitate was filtered off, dried with the exclusion of air and washed with diethyl ether.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:31])[CH3:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC(O)CN
Solvent: c1ccncc1
Product: CC(O)CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) and 1-amino-2-propanol (150 mg) were added to pyridine (500 mg), and the mixture was stirred at 45° C. for 16 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (150 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (157 mg) as a pale brown powder.