Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1Br.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: COc1cc(OC)c(Br)c(OC)c1
Reactant: O=C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c(C2=CCCCC2)c(OC)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
2,4,6-Trimethoxybromobenzene (1 eqvt.) was taken in a flame dried 3-necked flask under nitrogen. Dry tetrahydrofuran (THF) (983 ml) was added and the reaction mixture was cooled to -30° C. n-BuLi (1.3 eqvt.) in hexane (commercial) was added dropwise and after the addition the reaction mixture was stirred for 30 min. Thin layer chromatographic examination at this stage indicated completion of metallation reaction. Cyclohexanone (1.1 eqvt.) diluted with equal volume of dry THF was added to the reaction mixture at -30° C. and the reaction mixture was stirred for another one hour at -30° C. and later allowed to come to room temperature. Water (150 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was taken in dichloromethane and stirred for 30 min. with catalytic amount of p-toluenesulphonic acid (9 g). The dichloromethane layer was washed with sodium bicarbonate solution followed by water and dried. The residue was crystallized from Diisopropylether to give the title compound; m.p. 127° C., Yield: 64.7%.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:3]1=[O:18].S(Cl)([Cl:22])(=O)=O.N>C(Cl)Cl>[CH3:1][N:2]1[C:7]2[S:8][C:9]([Cl:22])=[CH:10][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:4][C:3]1=[O:18]
Reactant: Cn1c(=O)nc(-c2ccccc2F)c2ccsc21
Reactant: O=S(=O)(Cl)Cl
Agent: N
Solvent: ClCCl
Product: Cn1c(=O)nc(-c2ccccc2F)c2cc(Cl)sc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 0.5 g of 1-methyl-4-(o-fluorophenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-2-one in 20 ml of methylene chloride is added dropwise 1.21 g of sulfuryl chloride. After stirring the reaction mixture for 72 hours at room temperature, the reaction mixture is neutralized with aqueous ammonia, then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried and evaporated under reduced pressure to a residue, to give crystals which are recrystallized from ethanol to give 1-methyl-4-(o-fluorophenyl)-6-chloro-1,2-dihydrothieno[2,3-d]pyrimidin-2-one as crystals having a melting point of 192.5° - 194°C.
Reaction SMILES: C(OC([NH:11][C:12]1[C:13]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[N:34]2[CH2:39][CH2:38][CH2:37][C@H:36]([NH:40]C(=O)OCC3C=CC=CC=3)[CH2:35]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17]([CH:23]=[CH2:24])[CH:16]=2)=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C:12]1[C:13]([C:25]([NH:27][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:33]=2[N:34]2[CH2:39][CH2:38][CH2:37][C@H:36]([NH2:40])[CH2:35]2)=[O:26])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([F:22])=[C:17]([CH2:23][CH3:24])[CH:16]=2
Reactant: C=Cc1cc2nc(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OCc4ccccc4)C3)c(NC(=O)OCc3ccccc3)cc2cc1F
Agent: [Pd]
Solvent: CO
Product: CCc1cc2nc(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)c(N)cc2cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
To a solution of benzyl [(3S)-1-(3-{[(3-{[(benzyloxy)carbonyl]amino}-6-fluoro-7-vinylquinolin-2-yl)carbonyl]amino}pyridin-4-yl)piperidin-3-yl]carbamate (242.7 mg, 0.3597 mmol) in MeOH (7.00 mL), 10 wt % Pd on carbon (66.7 mg, 0.0627 mmol) was added. The mixture was then stirred at room temperature under hydrogen (1 atm.) for 15 h. The reaction mixture was filtered through a pad of diatomaceous earth (eluted with MeOH) and was then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to give the title compound as a yellow solid (20.2 mg, 14%). LCMS calc. for C22H26FN6O (M+H)+: m/z=409.2. found 409.2. 1H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.28 (d, J=5.2 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.53-7.44 (m, 2H), 7.17 (d, J=5.2 Hz, 1H), 6.95 (s, 2H), 3.56-3.13 (m, 2H), 3.13-3.01 (m, 1H), 2.82-2.67 (m, 3H), 2.55 (m, J=9.6 Hz, 1H), 2.03-1.94 (m, 1H), 1.94-1.79 (m, 2H), 1.37-1.32 (m, 1H), 1.29 (t, J=7.5 Hz, 3H) ppm.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[C:13]1(OP(OC2C=CC=CC=2)OC2C=CC=CC=2)C=CC=CC=1>[Rh].C1CCC=CCCC=1>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CC(=O)OCC=CCOC(C)=O
Agent: [Rh]
Solvent: C1=CCCC=CCC1
Product: C=C(C=O)CCOC(C)=O
Yield: 50545.7 %

Procedure:
A solution of 1,4-diacetoxy-2-butene (170 g.), (1,5-cyclooctadiene) rhodium (acetylacetonate) (0.17 g.) and triphenylphosphite (0.51 g.) was heated to 75° C. in a 1 liter stainless steel autoclave under a pressure of 2,000 psig of synthesis gas. After a few hours, the reaction was complete. After cooling and venting, the resulting solution was distilled to remove benzene. P-toluenesulphonic acid (0.5 g.) was added and the mixture was distilled (115°-120° C./5 mmHg). The resulting distillate was fractionated to give 2-formyl-4-acetoxybutene (118.1 g., 89% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]=[C:10]=[S:11])=[CH:4][C:3]=1[F:12].[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>ClC(Cl)Cl>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([NH:9][C:10]([NH:17][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13])=[S:11])=[CH:6][C:7]=1[F:8]
Reactant: COC(CN)OC
Reactant: Nc1c(F)cc(N=C=S)cc1F
Solvent: ClC(Cl)Cl
Product: COC(CNC(=S)Nc1cc(F)c(N)c(F)c1)OC

Procedure:
A solution of 4-amino-3,5-difluorophenyl isothiocyanate in trichloromethane is treated with an equimolar amount of aminoacetaldehyde dimethyl acetal. The solvent is evaporated, and the residue is recrystallized from ethanol to yield N-(4-amino-3,5-difluorophenyl)-N'-(β,β-dimethoxyethyl)thiourea. A suspension of this thiourea in concentrated sulfuric acid and water (1:4) was refluxed for three hours. The mixture then is cooled and the solid that forms is filtered, washed with water, and dried. Recrystallization from ethanol yields 1-(4'-amino-3',5'-difluorophenyl)imidazole-2-thiol.
Reaction SMILES: C([C:3]1[C:11]([N+:12]([O-])=O)=[C:10]([CH:15]=[CH:16][C:17]([O:19]C)=O)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[C:21](O)(=O)[CH3:22]>[Pd]>[O:19]=[C:17]1[CH2:16][CH2:15][C:10]2[C:11](=[CH:3][C:4]([C:5]([O:7][CH2:21][CH3:22])=[O:6])=[CH:8][CH:9]=2)[NH:12]1
Reactant: CC(=O)O
Reactant: CCc1c(C(=O)O)ccc(C=CC(=O)OC)c1[N+](=O)[O-]
Agent: [Pd]
Product: CCOC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The solution of 2.80 g of ethyl 4-(2-methoxycarbonylvinyl)-3-nitrobenzoic acid in 20 ml of glacial acetic acid is hydrogenated in the presence of 0.288 g of 10% Pd/C at room temperature over 16 hours. The reaction mixture is stirred at 70° C. over 1 hour and subsequently concentrated by evaporation to dryness. The residue is admixed with 250 ml of 1M sodium hydrogencarbonate and extracted with ethyl acetate (2×250 ml). The organic phases are washed with water (250 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of crystallization (ethyl acetate-hexane). Rf=024 (1:1 EtOAc-heptane).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1.[CH3:15]O>>[Br:6][C:7]1[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)s1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)s1
Temperature: 25 °C

Procedure:
Concentrated H2SO4 (3 mL) was added to a solution of 5-bromothiophene-2-carboxylic acid (5.0 g, 2.42 mmol) in methanol (100 mL). The reaction mixture was heated to reflux for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (60 mL), washed with saturated sodium carbonate (60 mL), and saturated sodium chloride (40 mL) and dried over anhydrous sodium sulfate. The solution was concentrated to give the compound 1021 (4.8 g). 1H NMR (CDCl3, 300 MHz) δ 3.90 (s, 3H), 7.09-7.10 (d, 1H), 7.57-7.58 (d, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH2:8][C@H:9]([C@@H:11]1[CH:15]=[CH:14][CH2:13][O:12]1)[OH:10].[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>O.O1CCCC1>[O:12]1[CH2:13][CH:14]=[CH:15][C@H:11]1[C@H:9]([OH:10])[CH2:8][NH:7][C:24](=[O:25])[O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@@H](O)[C@@H]1C=CCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
A solution of sodium carbonate (12.26 g, 115.7 mmol) in water (80 mL) was added whilst stirring to a solution of (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol (assumed to be 55 mmol) in tetrahydrofuran (100 mL). The mixture was cooled to 0° C. then benzylchloroformate (9.69 mL, 68.87 mmol) was added. The mixture was stirred at 0° C. for 45 minutes, then dichloromethane (400 mL) and water (400 mL) added. The organic phase was separated and the aqueous reextracted with dichloromethane (2×400 mL). The organic layer was washed with brine (400 mL), then dried (Na2SO4), filtered and reduced in vacuo to leave a residue. Flash chromatography over silica, eluting with ethyl acetate:heptane mixtures 0:100 to 65:35 gave alcohol (18) (11.58 g, 80%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.Br[C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CSc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Temperature: 25 °C
Yield: 15.1 %

Procedure:
Heat a solution of 6-methoxytetralone (9.6 g, 54 mmol), 4-bromothioanisole (25 mL, 123 mmol), sodium tert-butoxide (20.9 g, 217 mmol), palladium (II) acetate (610 mg, 2.72 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.8 g, 2.72 mmol) and toluene (150 mL) at reflux for 18 hours, then cool to ambient temperature and evaporate to dryness under reduced pressure. Dissolve the residue in dichloromethane and wash with aqueous hydrochloric acid (1N), filter through celite and chromatograph twice on silica gel with hexane/ethyl acetate mixtures to give 2.41 g of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (15%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>O1CCOCC1>[C:17]1([C:5]2[N:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]3[C:3]([N:4]=2)=[C:2]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:10]=[CH:9][N:8]=3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCO
Reactant: Clc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Solvent: C1COCCO1
Product: OCCCNc1ncnc2c1nc(-c1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
To the solution of 6-chloro-8,9-diphenyl-9H-purine obtained in step 4 of Example 8 (0.67 g, 2.18 mmol) in dioxane was added 3-aminopropan-1-ol (1.66 mL, 21.8 mmol) at room temperature and stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2, and washed with water. The organic layer thus separated was dried over anhydrous MgSO4 and evaporated in vacuo to provide title compound (0.77 g, 98%) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[N:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[CH3:20][C:15]1[N:14]=[C:13]([NH:12][C:4]2[CH:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=2)[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: Nc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Cc1cc(N)nc(C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N)c([N+](=O)[O-])cn2)nc(C)n1
Temperature: 110 °C
Yield: 23.2 %

Procedure:
To a 200 ml flask was added 4-amino-2-chloro-5-nitropyridine (1.00 g, 5.76 mmol), 4-amino-2,6-dimethylpyrimidine (1.42 g, 11.5 mmol), Pd2(dba)3 (0.528 g, 0.576 mmol), XantPhos (0.400 g, 0.691 mmol), Cs2CO3 (4.13 g, 12.7 mmol) and dioxane (45 mL). The mixture was degassed with N2 for 2 min and then heated at 110° C. for 16 hrs. After cooling to room temperature the reaction was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-10% methanol/dichloromethane) to give N-(2,6-dimethylpyrimidin-4-yl)-5-nitropyridine-2,4-diamine (0.348 g, yield: 23%). LCMS (ESI) m/z: 261.2 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccccc3)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc3c(c2)CNCCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A mixture of tert-butyl 7-phenyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (160 mg, 0.471 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (112 mg, 91.1%) as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23](OC)=[O:24])[CH2:14]1>>[CH:11]12[CH:20]3[CH2:21][CH:17]([CH:18]=[CH:19]3)[CH:16]1[CH:15]1[CH2:22][CH:12]2[CH:13]([C:23]([O:1][CH2:2][CH2:3][CH2:4][C:5]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:24])[CH2:14]1
Reactant: COC(=O)C1CC2CC1C1C3C=CC(C3)C21
Reactant: OCCCC1(O)CCCC1
Product: O=C(OCCCC1(O)CCCC1)C1CC2CC1C1C3C=CC(C3)C21
Yield: 88 %

Procedure:
By following the procedure of Synthesis Example 2 except that 1-(3-hydroxypropyl)cyclopentanol was used instead of 4-methyl-1,4-pentanediol and methyl 8-tetracyclo-[4.4.0.12,5.17,10]dodecene-3-carboxylate used instead of methyl 5-norbornene-2-carboxylate, there was obtained 3-(1-hydroxycyclopentyl)propyl 8-tetracyclo[4.4.0.12,5.17,10]-dodecene-3-carboxylate. Yield 88%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[C:28](Cl)(=[O:30])[CH3:29].CO.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.C(=O)([O-])O.[Na+].O1CCCC1>[C:28]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1)(=[O:30])[CH3:29]
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4ncccc4C)c3)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (130 mg, 0.362 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (26.0 μL, 0.366 mmol), and the mixture was stirred at room temperature for 3 hr. Methanol, tetrahydrofuran and aqueous sodium carbonate solution were added to the reaction mixture, and the mixture was stirred at 60° C. for 68 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (71.7 mg, 49%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([C:21](=[O:31])[C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)C.C(O)(=O)C.[Fe]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:10]([C:8](=[O:9])[C:7]3[CH:32]=[CH:33][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12][CH2:13]2)=[O:31])=[CH:27][CH:26]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCCN(C(=O)c3ccc(N)cc3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
A mixture of 1,5-bis(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (737 mg) and iron powder (738 mg) in a mixture of ethanol (10 ml) and acetic acid (1 ml) was refluxed for 2 hours and the solution was cooled to ambient temperature. The mixture was filtered through a bed of celite and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform and the solution was basified with saturated aqueous sodium bicarbonate solution. The solution was filtered through a bed of celite, and then the filtrate was washed with brine. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (eluent: 2% methanol in chloroform) to give 1,5-bis(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine as a slightly yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].Cl[C:13]([C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][CH:16]=1)=O.N1C=CC=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[O:1][C:2]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)=[CH:33][CH:32]=1)[CH3:31])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CN(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-hydroxyanthranilic acid (0.300 g, 1.96 mmol) in toluene (10 mL) is added benzyl 4-(chlorocarbonyl)benzyl(methyl)carbamate (1.811 g, 5.7 mmol) followed by pyridine (0.545 g, 6.92 mmol) at room temperature. The resulting mixture is stirred at room temperature for 30 minutes then heated to 80° C. for 1 hr. After this time the reaction is cooled and poured into a mixture of ethyl acetate (50 mL) and 5% aqueous hydrochloric acid (50 mL). Subsequent separation of the layers, drying the organic over MgSO4 and filtration afford a solution. After removal of the solvent, the residue is dissolved in xylenes (20 mL) and the solution treated with p-TsOH (0.800 g, 4.20 mmol). The reaction mixture is then heated to reflux for 6 hrs. After this time the reaction is cooled and poured into water (50 mL), the organic layer is separated and then washed with water (3×50 mL). The organic is dried over MgSO4, filtered and concentrated to a solid. Flash column chromatography on silica gel using ethyl acetate and hexanes as the eluents gives a solid product, 2-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)phenyl)benzo[d]oxazole-4-carboxylic acid. MS (ESI) m/e 417 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[CH:15]=[CH2:16].C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH2:14]([S:17][C:18]([CH3:22])([CH3:21])[CH2:19][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH:15]=[CH2:16]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: C=CCSC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (3.5 g, 1.78×10-2 mol) and 2-(allylthio)-2-methylpropanal (3.85 g, 2.67×10-2 mol, 150 M%) were dissolved in 200 ml methanol. Glacial acetic acid (2.05 ml, 3.56×10-2, 200 M%) and sodium cyanoborohydride (3.36 g, 5.35×10-2 mol, 300 M%) were then added. The reaction was stirred at room temperature for 18 hr, then 100 ml 0.5 M HCl was added and the mixture was extracted with 2×100 ml diethyl ether. The combined organic extracts were washed with 100 ml saturated NaHCO3, then with 100 ml saturated NaCl. The ether layer was dried over anhydrous Na2SO4, and the solvent was removed on the rotary evaporator. The crude product (6.7 g) was purified by filtration through a 600 ml sintered glass funnel filled silica bed, using 95% hexane/diethyl ether as the eluting solvent to give 4 g (70% yield) of 1-(2-allylthio-2-methylpropylamino)-2-(2-mercapto-2-methylpropylamino]benzene as a yellow oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([N+:26]([O-:28])=[O:27])([CH3:25])[CH2:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O>C(N(CC)CC)C>[CH2:1]([NH:8][CH2:13][CH2:12][CH2:11][C:10]([CH3:25])([N+:26]([O-:28])=[O:27])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCC(C)(C)[N+](=O)[O-])cc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(CCCNCc1ccccc1)[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a stirred mixture of benzylamine (9 ml) and triethylamine (5.5 ml) was added 4-methyl-4-nitro-1-tosyloxypentane (11.9 gm). The mixture was then heated to 70° C. for 2 hrs. The mixture was cooled and partitioned between ethyl acetate and water, the ethyl acetate solution was washed twice with water, then with brine and dried over magnesium sulphate. The solution was evaporated and the product isolated by column chromatography of the residue using gradient elution (Kieselgel; 1:1 60/80 petroleum ether:ethyl acetate going to ethyl acetate). Yield 6.89 gm.