Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:21]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.B(Br)(Br)Br.CO>ClCCCl.ClCCl>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:19][C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:21]=3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCCl
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CO)n2Cc1cc(-c2ccc(F)cc2)no1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-(ethoxymethyl)-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine (0.9923 g, 2.377 mmol) in 1,2-dichloroethane (55 mL) was cooled to about 0° C., and boron tribromide (5.9 mL of a 1 M solution in dichloromethane) was added dropwise. After the reaction was stirred cold for 30 minutes, it was heated at 50° C. for six hours. An analysis by HPLC indicated the reaction was incomplete, and the reaction was again cooled to about 0° C., and additional boron tribromide (1.5 mL) was added dropwise. After the reaction was stirred cold for ten minutes, it was heated at 50° C. for 16 hours. Methanol (30 mL) was added, and the reaction mixture was allowed to cool to room temperature. After 16 hours, the precipitate from the reaction was isolated by filtration and washed sequentially with aqueous potassium hydroxide (30 mL of 1 N), methanol (15 mL), and diethyl ether (15 mL). The solid was then triturated with boiling acetonitrile and isolated by hot filtration to provide 0.161 g of (4-amino-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-1H-imidazo[4,5-c]quinolin-2-yl)methanol as a white powder, mp 262.0-263.0° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15]CO)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(#N)C.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:1][Br:5])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCBr
Reaction time: 15 h
Yield: 76.9 %

Procedure:
25 g of carbon tetrabromide in solution in 50 ml of acetonitrile were slowly added at a temperature between 20° and 25° C. to a solution of 9 g of the product of Step A in 120 ml of tetrahydrofuran and 19.7 g of triphenyl phosphine. After stirring for 15 hours, the insoluble part was filtered off and the filtrate was concentrated to dryness under reduced pressure. The 45 g of residue were chromatographed on silica (eluant: hexane-ethyl acetate (8-2)) to obtain 9.4 g of the expected product melting at 40° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13](O)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([Cl:23])=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 268 mg (0.92 mmol) of 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (which can be prepared according to Example 6) in 5 mL of dichloromethane was added 160 μL (1.84 mmol) of oxalyl chloride and two drops of DMF in sequence at room temperature. The mixture was then stirred at the same temperature for about 1 hour. The crude mixture was then concentrated in vacuo. The title material is typically used without additional purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[O:30])=[CH:19][N:20](COCC[Si](C)(C)C)[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:34][CH2:33][C:32]([NH:31][C:29]([C:18]1[C:16]2[C:15](=[N:14][CH:13]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:17]=2)[NH:20][CH:19]=1)=[O:30])([CH3:36])[CH3:35]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccc(Cl)cc21
Reaction time: 3 h
Yield: 16.5 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.04 g, 0.076 mmol), trifluoroacetic acid (0.582 mL, 7.56 mmol) and dichloromethane (3.00 mL) were combined and stirred for 3 h. The reaction mixture was concentrated to dryness and diluted with dichloromethane (3 mL), then ethylenediamine (0.510 mL, 7.56 mmol) was added. After 1 h the mixture was concentrated to dryness and ice water (1 mL) added. The solid formed was collected by filtration then triturated with ethyl acetate to obtain 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (5 mg, 16%). MS (M+H)+=399; 1H NMR (DMSO-d6) δ: 8.94-9.36 (m, 1H), 8.51-8.76 (m, 1H), 8.37 (s, 1H), 7.80-8.08 (m, 2H), 7.29 (t, J=8.8 Hz, 1H), 4.17 (d, J=5.8 Hz, 3H), 3.48-3.80 (m, 2H), 1.45 (d, J=3.3 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34]>C(#N)C>[CH2:9]1[O:8][C:6]2=[CH:7][C:2]3[NH:1][C:33](=[O:34])[N:13]([CH2:14][CH2:15][CH2:16][N:17]([CH3:32])[CH2:18][CH2:19][CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=4)[CH2:12][CH2:11][C:3]=3[CH:4]=[C:5]2[O:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(SCCCN(C)CCCNCCc2cc3c(cc2N)OCO3)cc1OC
Solvent: CC#N
Product: COc1ccc(SCCCN(C)CCCN2CCc3cc4c(cc3NC2=O)OCO4)cc1OC

Procedure:
The title compound is prepared from N-[3-(2-(2-amino-4,5-methylenedioxy-phenyl)-ethylamino)-propyl]-N-[3-(3,4-dimethoxyphenylthio)-propyl]-methylamine and carbonyldiimidazole in acetonitrile analogously to Example 56.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]#[N:9])[NH:5][CH:6]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]#[N:9])[NH:5][C:6]=1[C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: N#CCc1cc(Br)c[nH]1
Solvent: ClCCl
Product: N#CCc1cc(Br)c(C(=O)c2ccc(Cl)cc2)[nH]1

Procedure:
A solution of 0.90 g (0.005 mole) of 4-bromopyrrole-2-acetonitrile and 0.87 g of p-chlorobenzoyl chloride (0.0005 mole) in 10 ml of methylene chloride is chilled in a dry-ice acetone bath to -30° C and is stirred while treated with 0.58 mg of anhydrous stannic chloride (0.005 mole). An orange solid precipitates. The reaction mixture is allowed to warm slowly over 1 hour to 5° C and is poured and scraped into ice-water. The whole is extracted with chloroform and the combined organic layers are washed successively with aqueous N,N-dimethylamino-1,3-propanediamine, 3N hydrochloric acid, aqueous sodium bicarbonate solution, and brine, and are dried over sodium sulfate. The viscous oil which results from evaporation of the solvent is vacuo is chromatographed on silica gel (Mallinkrodt CC-7) packed with benzene and eluated with a benzene-ether gradient. The desired material is eluted with 15% ether in benzene and recrystallized from methanol to give 4-bromo-5-(p-chlorobenzoyl)pyrrole-2-acetonitrile as a beige solid; m.p. 185°-186° C.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](OCC)(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]>C(O)C>[C:15]([O:14][CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18]
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCO
Product: CC(=O)CC(=O)OC(c1ccccc1)c1ccccc1
Yield: 39.1 %

Procedure:
Benzhydrol (20 g, 0.1087 mole) and ethyl acetoacetate (13 g, 0.1 mole) were heated together to 170° and the ethanol so formed removed by distillation. Fractional distillation at 1.0 mm Hg yielded 10.5 g, 39% of benzhydryl acetoacetate as a colourless liquid which later solidified, melting point 44°-54°.
Reaction SMILES: [N+](C1C=CC([N:10]([C:14]2[C:19]([F:20])=[C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:17]=[C:16]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:15]=2)[C:11](=O)[O-:12])=CC=1)([O-])=O.[CH3:33][NH:34][C:35]1[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=1.C(O)(=O)C>C1COCC1>[F:20][C:19]1[C:14]([NH:10][C:11](=[O:12])[N:34]([CH3:33])[C:35]2[CH:40]=[CH:39][C:38]([Br:41])=[CH:37][CH:36]=2)=[N:15][C:16]([O:27][CH2:28][C:29]([F:30])([F:32])[F:31])=[CH:17][C:18]=1[O:21][CH2:22][C:23]([F:25])([F:24])[F:26]
Reactant: CNc1ccc(Br)cc1
Reactant: O=C([O-])N(c1ccc([N+](=O)[O-])cc1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)c1F
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)c1F)c1ccc(Br)cc1
Reaction time: 288 h
Yield: 48.1 %

Procedure:
4-Nitrophenyl-3-fluoro-4,6-bis(2,2,2-trifluoroethoxy)pyridin-2-ylcarbamate (520 mg, 1.1 mmol) was dissolved in anhydrous THF (3 mL). To this solution was added N-methyl-4-bromoaniline (200 mg, 1.1 mmol). The reaction was allowed to stir for 12 d. The THF was evaporated and the crude material purified by reverse phase chromatography (HPLC grade CH3CN and H2O, both with 0.1% acetic acid) to afford the product as a tan solid (275 mg, 48% yield): mp 89-90° C.; 1H NMR (CDCl3) δ 8.78 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 6.79 (d, J=4.7 Hz, 1H), 5.04-4.95 (q, J=8.8 Hz, 2H), 4.94-4.85 (q, J=9.1 Hz, 2H), 3.27 (s, 3H); ESI/MS 520, 522 (M+H), 518, 520 (M−H).
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH:3]([CH3:39])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[OH:1][C:2]([CH3:40])([CH3:41])[CH:3]([CH3:39])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:48][N:47]=[N:46][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 88 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.33 g), trimethylsilylazide (1.9 g), dibutyltinoxide (0.14 g) and toluene (15 mL) was stirred at 110° C. for 88 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (2.3 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at 70° C. for 1 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate-diisopropyl ether) to give the title compound as a colorless solid (0.10 g, 30%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:32])[CH2:4][NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30].N1C=CC=CC=1.[S:39](Cl)(Cl)=[O:40].Cl>ClCCl>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2([C:18]([F:20])([F:21])[F:19])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:4][CH:3]4[O:32][S:39](=[O:40])[NH:1][CH2:2]4)=[O:31])=[C:8]([CH3:30])[CH:9]=3)[CH2:17]2)[CH:23]=[C:24]([Cl:29])[CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(O)CN
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC1CNS(=O)O1
Reaction time: 4 h

Procedure:
A solution of N-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated with pyridine (0.32 ml) and thionyl chloride (0.06 ml), and stirred for 4 hours. The mixture was diluted with dichloromethane (50 ml), neutralized with 2N hydrochloric acid, and washed with water (50 ml). The organic layer was separated, dried over sodium sulfate and concentrated. Purification by chromatography on silica gel (eluent hexane/ethyl acetate 40:60) gave the title compound (20 mg). LCMS (Method G) 3.88 min, (M−H)− 534. 1HNMR (CDCl3, 400 MHz): 7.45-7.52 (m, 6H), 6.50 (m, 1H), 4.05 (d, 1H), 3.98 (m, 1H), 3.72 (d, 1H), 3.62 (m, 1H), 3.51 (m, 3H), 2.46 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Brc1ccc(/C=C\C(SC(/C=C\c2ccc(Br)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl benzylsulfide. The title compound was obtained in 80% yield following oxidation. 1HNMR (CDC13) δ 4.52 (2H, s), 6.80 (1H, d, JH,H=11.98), 7.18-7.59 (9H aromatic+1H ethylenic).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([P:16](=[O:19])([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:24][O:25][C:26](=[O:53])[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[N:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1)O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:24][O:25][C:26](=[O:53])[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[N:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1)[O:19][P:16]([C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])([OH:18])=[O:17]
Reactant: COC(=O)C(O)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)P(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(OP(=O)(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 55.4 %

Procedure:
A solution of (1R)-(+)-(1-benzyloxycarbonylamino-2-methylpropyl)phosphonic acid (4.27 g, 14.9 mmol) in 50 mL of DMF was cooled to −20° C. using a dry ice/methanol bath. To this was added thionyl chloride (1.20 mL, 16.5 mmol) and the reaction mixture was stirred at −5° C. for 40 minutes. 2-(3-(N′,N″-Di(t-butoxycarbonyl)guanidino)phenyl)-2-hydroxyethanoic acid methyl ester (5.60 g, 13.2 mmol) was added to the reaction mixture as a solution in 15 mL of DMF and the reaction was allowed to warm to ambient temperature. After stirring for 3 days, 20 mL of saturated NaHCO3 was added. The solution was washed with ether (2×), combined and concentrated in vacuo to give a mixture of product and starting material. The product was purified by flash column chromatography (10%-100% ethyl acetate/methylene chloride), followed by methanol to give 5.07 g (55%) of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([O-])([OH:20])=[O:19].O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:16]([N+:18]([O-:20])=[O:19])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])c(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-benzyloxy-2-hydroxybenzaldehyde (0.5 g, 2.2 mmol) in 4.4 mL of acetic acid, at 0° C., is added nitric acid (0.28 mL, 4.4 mmol) dropwise. The mixture is stirred at ambient temperature for 18 h. The mixture is poured into water and extracted with EtOAc. The organic layer is washed with water, sat. NaCl and dried over sodium sulfate. The solvent is removed under reduced pressure and the crude material is purified by flash chromatography using hexane/EtOAc (6:1) to afford 4-benzyloxy-2-hydroxy-5-nitrobenzaldehyde as a yellow solid: 1H NMR (acetone-d6) δ 11.84 (s, 1H), 10.08 (s, 1H), 8.59 (s, 1H), 7.64-7.45 (m, 5H), 6.99 (s, 1H), 5.54 (s, 2H); (M−H)−=272.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[S:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:9]1[CH:13]=[CH:12][C:11]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:10]1
Reactant: OB(O)c1ccsc1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCO
Product: Nc1cnc(-c2ccsc2)cn1
Yield: 69 %

Procedure:
A mixture of 2-amino-5-bromopyrazine (500 mg, 2.874 mmol), dichlorobis(triphenylphosphine)palladium(II) (290 mg, 0.413 mmol), 3-thiopheneboronic acid (500 mg, 3.908 mmol), and a saturated aqueous sodium carbonate solution (4 mL) in ethylene glycol dimethyl ether (8 mL) and ethanol (8 mL) was heated under reflux for 45 min. The reaction mixture was then cooled, diluted with ethyl acetate, and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) afforded 5-thiophen-3-yl-pyrazin-2-ylamine (351.3 mg, 69%) as a light purple solid: EI-HRMS m/e calcd for C8H7N3S (M+) 177.0361, found 177.0358.
Reaction SMILES: [C:1]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH2:22]1[CH2:26]OC[CH2:23]1.C([Li])(C)C.[NH4+].[Cl-]>O.CCOC(C)=O>[C:1]([S@:5]([NH:7][C@@H:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:20][CH:21]=1)[CH:22]([CH3:26])[CH3:23])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=N/[S@](=O)C(C)(C)C)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]C(C)C
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](N[S@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To an oven-dried 50-mL round-bottom flask was added tert-butyl 4-[(E)-{[(R)-tert-butylsulfinyl]imino}methyl]benzoate (3.00 g, 9.70 mmol) and THF (48 mL). The solution was cooled to −78° C. then isopropyllithium (55.4 mL, 38.8 mmol, 0.70 M of in pentane) was slowly added via a syringe pump over 15 min. The resulting reaction mixture was stirred at −78° C. After 1 h, EtOAc (100 mL), sat. NH4Cl solution (20 mL), and water (10 mL) were added to the flask at this temperature. After separation, the aqueous layer was extracted with EtOAc (2×60 mL). Combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. Purification via flash chromatography (20% EtOAc-hexanes to 50% EtOAc-hexanes) afforded major diastereomer tert-butyl 4-[(1R)-1-{[(R)-tert-butylsulfinyl]amino}-2-methylpropyl]benzoate (1.59 g, 46%) as a white solid. [c]D20=−18.9 (c=1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.96 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.1 Hz, 2H), 4.18 (d, J=6.0 Hz, 1H), 3.45 (d, J=6.0 Hz, 1H), 2.22 (m, 1H), 1.58 (s, 9 μl), 1.24 (s, 9H), 0.94 (d, J=6.8 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.[ClH:45]>C1COCC1>[ClH:43].[ClH:45].[Cl:43][C:37]1[CH:36]=[C:35]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH:40]=[C:39]([F:41])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCNCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl 4-((trans-4-((3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)methyl)piperazine-1-carboxylate (66 mg, 0.10 mmol) in THF (5 mL) was added water (5 mL) and aqueous 6 N HCl (1.0 mL). The reaction mixture was heated at 65° C. for 2 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (5 mL) and HCl (6 M in water, 0.5 mL, 3 mmol) was added. The resultant solution was concentrated to give the desired product (24.2 mg, 41%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.48 (s, 1H), 8.27 (dd, J=8.7, 1.7 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=11.3 Hz, 1H), 4.57-4.53 (br s, 1H), 3.67 (br s, 4H), 3.50 (br s, 2H), 3.17 (br s, 2H), 2.74 (s, 3H), 2.46 (d, J=11.9 Hz, 2H), 2.18 (d, J=12.5 Hz, 2H), 2.10 (br s, 1H), 1.83-1.77 (m, 2H), 1.41-1.34 (m, 2H). ESI MS m/z 511 [C28H32ClFN4O2+H]+; HPLC 98.3% (AUC), tR=9.38 min.