Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][C:3](=[O:34])[CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[O:11])[CH2:5][C:6]([OH:8])=O.C(Cl)CCl.[CH2:39]([NH2:41])[CH3:40]>C(Cl)Cl.C1COCC1>[CH2:39]([NH:41][C:6](=[O:8])[CH2:5][CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:27][C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])=[O:11])[C:3](=[O:34])[CH2:2][F:1])[CH3:40]
Reactant: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Reactant: CCN
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
To a stirred mixture of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid (196 mg, 0.4 mmol), prepared as in Example 1, in anhydrous DCM (8 ml), was added Polymer bound EDC (400 mg, 0.8 mmol) and a solution of the ethylamine in THF (0.6 ml of a 2M solution, 12 mmol). The mixture was stirred at room temperature for 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (2.5% methanol in dichloromethane) to afford the title compound as a white solid (22.7 mg, 11%): 1H NMR (400 MHz, CDCl3) δ 1.09-1.39 (3H, m), 1.44-1.66 (6H, m), 2.04-3.66 (7H, m), 4.18-4.76 (6H, m) and 7.10-7.79 (8H, m). 19F NMR (376 MHz, CDC3) δ −223.32, −223.73, −225.92 and −226.76.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1>CC(O)C.CS(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:29]3[C:28]([N:30]4[CH2:35][CH2:34][CH:33]([NH:36][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]5[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=5)[CH2:32][CH2:31]4)=[N:27][CH:26]=[N:25][C:24]=3[S:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccc(F)cc4)c23)CC1
Reactant: OCc1cccc(OCC2CO2)c1
Solvent: CC(C)O
Solvent: CS(C)=O
Product: OCc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccc(F)cc5)c34)CC2)c1
Yield: 35 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 1:1, 14 h), using 150 μmol (3-(oxiran-2-ylmethoxy)phenyl)methanol and 1-(5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give the title compound with 35% yield upon purification by prep. HPLC (reversed phase).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH2:12]O)=[CH:10][CH:11]=1)=[O:5])[CH3:2].P(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([SH:34])[CH2:32][CH3:33]>ClCCl.CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH2:12][S:34][CH2:31][CH2:32][CH3:33])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCS
Reactant: CCOC(=O)c1ccc(CO)n(-c2ccccc2)c1=O
Agent: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCSCc1ccc(C(=O)OCC)c(=O)n1-c1ccccc1
Yield: 25.2 %

Procedure:
1,2-dihydro-6-hydroxymethyl-2-oxo-1-phenylpyridine-3-carboxylic acid ethyl ester (5.0 g, 18 mmol) was dissolved in dichloromethane (100 mL), and phosphorus tribromide (1.95 g, 7.2 mol) was added to this solution at −20° C. under a nitrogen atmosphere. The mixture was allowed to react for 4 hours. The reaction mixture was poured into water and a liquid separation was subjected. The organic layer was washed with an aqueous sodium bicarbonate solution and water, dried, and concentrated to obtain 3.30 g of a crude desired product. This crude product was dissolved in N,N′-dimethylformamide (30 mL), and potassium carbonate (2.0 g, 14 mmol) and propyl mercaptan (1.1 g, 14 mmol) were added thereto. The mixture was allowed to react for 2 hours at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of citric acid and water, dried, and concentrated. Thus obtained oily product was purified by column chromatography (elution solvent: hexane/ethyl acetate=3/2) to obtain 1.17 g of a desired product (yield: 20%, two stages).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[C:24]([F:25])=[C:23]([C:26](Cl)=[O:27])[C:22]([F:29])=[C:21]([F:30])[C:17]=1[C:18](Cl)=[O:19].C(Cl)(=O)[C:32]1[CH:40]=[CH:39][C:35](C(Cl)=O)=[CH:34][CH:33]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl.CN(C=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:12][C:18](=[O:19])[C:17]2[C:16]([F:15])=[C:24]([F:25])[C:23]([C:26]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([O:1][C:32]4[CH:33]=[CH:34][CH:35]=[CH:39][CH:40]=4)=[CH:9][CH:10]=3)=[O:27])=[C:22]([F:29])[C:21]=2[F:30])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1c(F)c(F)c(C(=O)Cl)c(F)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1c(F)c(F)c(C(=O)Nc2ccc(Oc3ccccc3)cc2)c(F)c1F

Procedure:
N,N'-Bis-(4-phenoxyphenyl)-2,3,5,6-tetrafluoroterephthalamide was prepared from p-phenoxyaniline and 2,3,5,6-tetrafluoroterephthaloyl chloride. This amide (6.0108 g, 0.0105 moles) was polymerized with terephthaloyl chloride (2.1316 g, 0.0105 moles) by the procedure of Example 27. The amounts of aluminum chloride, DMF and DCE used were 12.55 g (0.094 moles), 3.3 mL (0.042 moles) and 60 mL, respectively. The white fibrous polymer which was obtained had the repeat unit ##STR45##
Reaction SMILES: [C:1]([C:5]1[C:10](=[O:11])[CH:9]=[CH:8][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:6]=1)(=O)[CH2:2][CH3:3].[CH3:22][O-].[Na+].[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>C(OC)=O.O.Cl>[CH3:3][C:2]1[CH:22]=[N:32][N:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:1]=1[C:5]1[C:10](=[O:11])[CH:9]=[CH:8][N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:6]=1
Reactant: CCC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: Cc1cnn(-c2ccccc2)c1-c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 31.2 %

Procedure:
To a suspension of 3-propanoyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (384 mg, 1.30 mmol) in methyl formate (3.8 mL) was added NaOMe (28% in MeOH, 326 mg, 1.69 mmol) at room temperature. The mixture was stirred at room temperature for 3.5 h. The mixture was diluted with water and 1 M HCl aqueous solution, extracted with AcOEt, washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and crystallized with AcOEt/hexane. To the solid were added phenylhydrazine (0.405 mL, 4.12 mmol) and MeOH (6.7 mL). The mixture was heated to reflux for 15 h. The mixture was diluted with 1 M HCl aqueous solution, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/AcOEt=50/50 to 0/100) and crystallized with AcOEt/heptane to yield the title compound (161 mg, 39% yield) as a pale yellow solid: mp 208-211° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.09 (3H, s), 6.62 (1H, d, J=8.0 Hz), 7.26-7.35 (3H, m), 7.35-7.44 (2H, m), 7.64-7.85 (5H, m), 8.95 (1H, d, J=8.2 Hz). Anal. Calcd for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.46; H, 3.92; N, 13.98.
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH2:20]>[OH-].[Na+].CN(C)C=O>[Br:1][C:2]1[C:10]([CH2:9][OH:8])=[C:6]([CH:5]=[CH:4][CH:3]=1)[C:7]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:20]
Reactant: O=C1OCc2c(Br)cccc21
Reactant: BrCc1ccccc1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(Br)c1CO
Temperature: 25 °C
Reaction time: 336 h

Procedure:
A solution of 4-bromo-2-benzofuran-1(3H)-one (4.02 g, 18.9 mmol) in aqueous sodium hydroxide solution (1M, 18.9 ml) was heated at 100° C. for 1 h. The solution was concentrated in vacuo and the residue was dissolved in toluene and re-concentrated. To a solution of the residue in N,N-dimethylformamide (20 ml) was added benzyl bromide (2.26 ml, 18.90 mmol) and the reaction mixture was stirred at room temperature for 14 days. The mixture was poured into water and the resulting precipitate was collected by filtration, washed with water and pentane and dried to give the title compound (4.77 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)=O>O.C1(C)C=CC=CC=1>[C:16]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]1[C:7]([OH:9])=[O:8])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 96 %

Procedure:
Cis-4-hydroxy-D-proline 8 (10.0 g, 76.3 mmol) was dissolved in H2O (165 mL) containing NaHCO3 (16.0 g, 190 mmol). Benzyl chloroformate (12.5 mL, 15.0 g, 87.7 mmol) in toluene (40 mL) was added to this stirring solution at room temperature over 30 minutes using a dropping funnel. The reaction was stirred for 16 h. By this time, CO2 evolution had ceased, and the two phases were separated. Excess benzyl chloroformate was removed from the aqueous layer by washing with ether (3×50 mL). The aqueous phase was cooled in an ice bath and acidified to pH2 with concentrated HCl, causing precipitation of the oily product. This oil was extracted from the aqueous layer by repeated washings with ethyl acetate (5×50 mL). Further acidification of the aqueous layer produced no more precipitate, indicating the extraction was complete. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to a colorless viscous oil, which crystallized upon standing at room temperature to provide 19.42 g (96%) of N-CBZ-cis-4-hydroxy-D-proline: mp 110°-111° C. (lit. 19 mp 110.5°-111.5° C.); [α]25d +24.4° (c 1.0, CHCl3) ]lit. 19 [α25D +26.3° (c 1.0, CHCl3)].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([F:13])[CH2:10][CH:9]1[CH2:14][O:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=1[O:27][CH3:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:14][O:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10]1
Reactant: CCOC(=O)c1ccc(OCC2CC(F)CN2C(=O)OC(C)(C)C)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(OCC2CC(F)CN2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a stirred solution of ethyl 4-[1-(tert-butoxycarbonyl)4-fluoro-2-pyrrolidinyl]methoxy-3-methoxybenzoate (482.2 mg, 1.213 mmol) in CH2Cl2 (10.0 mL) was added TFA (1.9 mL) at 0° C., and the mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure and the residue was made basic by the addition of 1N NaOH and extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 348.7 mg (97%) ethyl 4-(4-fluoro-2-pyrrolidinyl)methoxy-3-methoxybenzoate as a brownish oil. 1H-NMR (400 MHz, CDCl3) δ1.39 (t, J=6.8 Hz, 3H), 1.97 (ddt, J=1.5, 5.4, 14.7 Hz, 1H), 2.27 (dddd, J=5.9, 8.8, 14.7, 32.7 Hz, 1H), 3.02 (ddd, J=3.9, 13.1, 35.2 Hz, 1H), 3.36 (dd, J=12.7, 21.5 Hz, 1H), 3.65 (m, 1H), 3.90 (s, 3H), 4.09 (m, 1H), 4.35 (q, J=6.8 Hz, 2H), 5.17, 5.31 (br m each, 1H), 6.90 (d, J=8.3 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.65 (dd, J=2.0, 8.3 Hz, 1H); MS (FAB) m/z 298 (M++1).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[N:25]=[C:24]([N:26]2[CH:30]=[C:29]([C:31](O)=[O:32])[N:28]=[CH:27]2)[CH:23]=[CH:22][CH:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[N:28]=[CH:27][N:26]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([CH3:19])[N:25]=4)[CH:30]=3)=[O:32])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1cccc(-n2cnc(C(=O)O)c2)n1
Product: Cc1cccc(-n2cnc(C(=O)N[C@@H](C)Cn3ccc(-c4ccc(C#N)c(Cl)c4)n3)c2)n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (220 mg, 0.844 mmol) and 1-(6-methylpyridin-2-yl)-1H-imidazole-4-carboxylic acid (223 mg, 1.097 mmol). The product was triturated with acetonitrile. Yield 153 mg (40%). 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 1.45 (s, 3H), 2.59 (s, 1H), 4.28-4.45 (m, 2H), 4.55-4.64 (m, 1H), 6.62 (d, 1H), 7.16 (d, 1H), 7.19 (d, 1H), 7.52 (d, 1H), 7.67 (d, 1H), 7.75 (t, 1H), 7.80 (m, 1H), 7.89 (d, 1H), 8.12 (d, 1H), 8.21 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[N:13]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Yield: 13.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-92, 0.300 g, 0.852 mmol), pivaloyl chloride (0.108 g, 0.852 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.40 (d, J=7.8 Hz, 1H), 7.52-7.59 (m, 3H), 7.91-8.18 (m, 3H), 12.65 (s, 1H); MS (m/z): 437.23 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:36][CH3:37])=[CH:4][C:5]([C:10]2[CH:11]=[N:12][C:13]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[N:6][C:7]=1[C:8]#[N:9].[N:38]([O-])=O.[Na+]>O.O1CCOCC1>[C:8]([C:7]1[C:2]2[N:1]=[N:38][N:36]([CH3:37])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[C:13]([O:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:25][CH2:24]3)=[N:12][CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2cnc(OCCC3CCN(C(=O)OC(C)(C)C)CC3)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3cnc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a suspension of tert-butyl 4-(2-(5-amino-6-cyano-4-(methylamino)-5′-(trifluoromethyl)-2,3′-bipyridin-6′-yloxy)ethyl)piperidine-1-carboxylate (5.20 g) in water (40 ml) and 1,4-dioxane (40 ml) was added 2N hydrichloric acid (6.89 ml) at 0° C. To above suspension was then added dropwise sodium nitrite (0.92 g) in water (10 ml). The mixture was then stirred at 0° C. for 10 min and at 20° C. for 16 h. The solid product was collected by filtration and washed with water, dried in vacuum oven to give 4.61 g tert-butyl 4-(2-(5-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(trifluoro-methyl)pyridin-2-yloxy)ethyl)piperidine-1-carboxylate (94%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[O:16][CH3:17].[Li]CCCC.CN(C)[CH:25]=[O:26]>C1COCC1.O>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH:25]=[O:26]
Reactant: COCOCCc1cc(OC)c(Br)cc1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOCCc1cc(OC)c(C=O)cc1OC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
In a round bottom flask, 1-bromo-2,5-dimethoxy-4-(2-methoxymethoxy-ethyl)-benzene (0.55 g, 18.02 mmol) was dissolved in 30 mL of dry THF. The reaction mixture was cooled to −78° C. using a dry ice-acetone bath and stirred for 10 min. A solution of n-BuLi (0.86 mL of 2.5 M solution in hexane) was added and the reaction mixture was stirred for an additional 30 min. Dimethyl formamide (0.26 g, 36.06 mmol) was added and then the temperature was allowed warm up slowly to room temperature and stirred for 30 min. The reaction mixture was diluted with water and the organic material was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated in vacuo. The crude material was purified by flash column chromatography using a hexane and ethyl acetate gradient to give colorless oil in 56% yield. MS (m/z) 255 (M+1)+. 1HNMR(CDCl3): δ ppm 2.96 (m, 2H), 3.32 (m, 3H), 3.75 (m, 2H), 3.79 (s, 3H), 4.13 (s, 3H), 4.63 (s, 2H), 6.98 (s, 1H), 7.26 (s, 1H), 10.40 (s, 1H).
Reaction SMILES: [C:1]([OH:6])(=O)C(O)=O.[NH2:7][C@@H:8]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]([CH2:25][CH3:26])[C:9]1=[O:27].C(N(CC)CC)C.Cl.[NH:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44][C:43]2=[O:52])[CH2:38][CH2:37]1>O1CCCC1.CS(C)=O>[O:52]=[C:43]1[N:42]([CH:39]2[CH2:40][CH2:41][N:36]([C:1]([NH:7][C@@H:8]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=4[N:10]([CH2:25][CH3:26])[C:9]3=[O:27])=[O:6])[CH2:37][CH2:38]2)[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44]1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Reactant: O=C(O)C(=O)O
Reactant: CCN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCN1C(=O)[C@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)N=C(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.9 %

Procedure:
A solution of (3R)-3-amino-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine oxalic acid salt (27.6 mg, 0.0747 mmol) and p-nitrophenylchloroformate (15.1 mg, 0.0747 mmol) was dissolved in tetrahydrofuran (0.5 mL), and cooled to 0° C. under argon. Triethylamine (10.4 uL, 0.0747 mmol) was added and the reaction stirred for 1 h. Additional triethylamine (26.0 uL, 0.186 mmol) was added, along with 3-(4-piperidinyl)-3,4 dihydroquinazolin-2(1H)-one hydrochloride (20.0 mg, 0.0747 mmol) in dimethylsulfoxide (0.5 mL). The reaction was allowed to warm to room temperature and stirred overnight. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution), isolating 4-(2-oxo-1,4-dihydroquinazolin-3(2H)-yl)-N-[(3R)-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]piperidine-1-carboxamide (10.0 mg) MS 537 (M+1) and 4-(2-oxo-1,4-dihydro-4-hydroxyquinazolin-3(2H)-yl)-N-[(3R)-1-ethyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]piperidine-1-carboxamide (5 mg) MS 535 (M−17).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1([S:13]([CH2:16][CH2:17][SH:18])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:20]1[C:29]([C:30]([NH:32][CH2:33][C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:31])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.CCCCCC>CN(C=O)C>[C:7]1([S:13]([CH2:16][CH2:17][S:18][C:20]2[C:29]([C:30]([NH:32][CH2:33][C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:31])=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1Cl
Reactant: O=S(=O)(CCS)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(NCc1cccs1)c1cc2ccccc2nc1SCCS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
112 mg (1.0 mmol) potassium tert-butylate were added to a solution of 202 mg (1.0 mmol) 2-(phenylsulfonyl)ethanethiol in DMF (6 ml) at 0° C. and the mixture was stirred for 10 min at 0° C. Then 303 mg (1.0 mmol) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV01) were added at 0° C. and the reaction solution was heated slowly to 50° C. and stirred for 16 h at this temperature. After cooling to RT it was diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 326 mg (0.7 mmol, 70%) 2-[2-(phenylsulfonyl)ethylthio]-N-(2-thienyl-methyl)-3-quinoline carboxamide. MS: m/z 469.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=S)[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O>O1CCCC1>[O:17]1[CH2:18][CH2:19][N:14]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=3[N:9]=2)[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc2oc(N3CCOCC3)nc2c1
Yield: 92.3 %

Procedure:
5-nitrobenzo[d]oxazole-2(3H)-thione (98.1 mg, 0.5 mmol) and morpholine (66 μL, 0.75 mmol) in tetrahydrofuran (3 mL) were heated at 150° C. for 15 min in the microwave. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4 and absorbed on silica. Purification by column chromatography, eluting with ethyl acetate/hexanes 25:75 v/v affords 115 mg (92%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:28])=[O:15])=[C:4]([CH:26]=[O:27])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN(CCCCCC(=O)O)c2ccc(Br)cc2C=O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN(Cc1ccc(OC)cc1)c1ccc(Br)cc1C=O
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of 6-((4-bromo-2-formylphenyl) (4-methoxybenzyl)amino)hexanoic acid (32.0 g) and potassium carbonate (12.2 g) in DMF (300 ml) was added dropwise a solution of iodomethane (14.6 g) in DMF (100 ml) under nitrogen atmosphere at 0° C. After returning to room temperature, the reaction mixture was stirred for 2 hours, then water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water five times and with saturated brine once, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure to give methyl 6-((4-bromo-2-formylphenyl)(4-methoxybenzyl)amino)hexanoate (30.5 g) as a brown oily material.