Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:19])=[O:4].[BH4-].[Na+].O>C(Cl)Cl.CO>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:17][CH3:18])[CH:6]([OH:19])[CH:5]([C:3]([OH:4])=[O:2])[CH2:14][CH2:13]2
Reactant: COC(=O)C1CCc2cc(OC)c(OC)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(cc1OC)C(O)C(C(=O)O)CC2
Temperature: 25 °C

Procedure:
6,7-Dimethoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthoic acid methyl ester [Hashem et al., J. Med. Chem., 19, 229 (1976)] (14 g) is dissolved in a mixture of methylene chloride (200 ml) and methanol (200 ml). Sodium borohydride (1 g) is added to the solution with stirring at room temperature, and the mixture is then stirred for one hour. The resulting mixture is supplemented with sodium borohydride (1 g) and the mixture is stirred for 30 minutes. To the resultant is then further added sodium borohydride (0.5 g) and the mixture is stirred for 30 minutes. After addition of water (500 ml) to the mixture, the methylene chloride layer is separated. The aqueous layer is extracted with methylene chloride (200 ml). The extracts are combined and concentrated under reduced pressure to give the methyl ester of 6,7-dimethoxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthoic acid. This product is dissolved in methanol (10 ml), and an aqueous solution (100 ml) of sodium hydroxide (14 g) is added dropwise to the solution at room temperature with stirring. After finishing the dropwise addition, the mixture is allowed to stand at room temperature for 30 minutes. Water (200 ml) is added to the mixture, and the mixture is extracted with a mixture of ethyl ether (100 ml) and petroleum ether (100 ml). The aqueous layer is made acid with concentrated hydrochloric acid and extracted with methylene chloride (300 ml). The extract is washed with water, dried and concentrated under reduced pressure. To the residue are added dioxane (100 ml) and concentrated hydrochloric acid (10 ml), and the mixture is heated at 80° C. for 5 minutes. The reaction mixture is concentrated under reduced pressure to half of its original volume. To the concentrate is added an aqueous solution (200 ml) of sodium hydroxide (10 g). The mixture is extracted with a mixture of ether (50 ml) and petroleum (50 ml). The aqueous layer is made acid with concentrated hydrochloric acid, and then precipitating colorless prisms are collected by filtration to give 1,2-dihydro-6,7-dimethoxy-3-naphthoic acid (6.2 g), m.p. 191°-194° C.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:12][CH:9]([O:8][C:3]2[C:2]([N:23]3[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: Clc1nccnc1OC1CN(c2ccc3ccccc3n2)C1
Reactant: CC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)C1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 160 °C
Yield: 18 %

Procedure:
To a mixture of 2-(3-((3-chloropyrazin-2-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 312 mg, 1.0 mmol) and 1-(piperidin-4-yl)ethanone (127 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) was added i-PrOH (3 mL) and water (1.0 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (72 mg, 0.18 mmol, 18% yield) as white solid. ESI-MS (M+1): 404 calc. for C23H25N5O2 403.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[NH:10][C:11](=[O:14])[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]([N:23]([CH:32]([CH3:34])[CH3:33])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:22]>>[CH:32]([N:23]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:21](=[O:22])[CH2:20][N:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH2:12][C:11]1=[O:14])([CH3:33])[CH3:34]
Reactant: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Product: COc1ccc(N(C(=O)CN2C(=O)CN=C(c3ccccc3)c3ccccc32)C(C)C)cc1

Procedure:
By employing conditions similar to those described in Intermediate 11, 5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (Bock et. al., J. Org. Chem. 1987, 52, 3232-3239. 3.00 g, 12.71 mmol) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (3.820 g, 13.35 mmol) are converted to the title compound, which is obtained as a wet white solid. The product is dissolved in anhydrous DCM, dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue is triturated with n-hexane, filtered and dried overnight under vacuum to provide the title compound as a white solid (5.380 g, 12.18 mmol). 1H NMR (300 MHz, d6-DMSO) δ=0.91-0.97 (m, 6H); 3.70 (d, J=10.4 Hz, 1H); 3.76 (s, 3H); 4.08 (s, 2H); 4.51 (d, J=10.6 Hz, 1H); 4.67-6.78 (m, 1H); 6.97-7.63 (m, 13H). MS (FAB): [M+H]+ =442.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([O-])=[O:24])=[N:21][CH:22]=1)=O)(C)(C)C.[Li+].CCN(C(C)C)C(C)C>>[CH:1]1([NH:7][C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][NH2:15])=[CH:22][N:21]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])nc1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccc(C(=O)NC2CCCCC2)nc1
Yield: 22 %

Procedure:
Use the General Procedure 6-2, using cyclohexylamine (1 mL), lithium 5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylate (1 g, 3.96 mmol) and DIEA (5 mL) as cosolvent, to give the title compound as a white solid (200 mg, 22%). MS (ES+) m/z: 234 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][OH:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CCOC(C)=O>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:18]=[O:19])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCc1ccc(Br)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](C=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of [(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-propyl]-carbamic acid tert-butyl ester (11.5 g) and triethylamine (27.9 ml) in DMSO (70 ml) was added dropwise sulfur trioxide-pyridine complex (16.0 g) while the reaction mixture was cooled in a ice bath. The mixture was then stirred at room temperature for 30 min to afford a yellow solution. The reaction mixture was poured into EtOAc and extracted sequentially with water and with saturated brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc 3/1) to afford [(S)-3-(4-bromo-phenyl)-1-formyl-propyl]-carbamic acid tert-butyl ester as a yellow oil (7.3 g, 64%). MS (EI): 343 ([{81Br}M]+), 341 ([{79Br}M]+), 287 ([{81Br}M−C4H8]+), 285 ([{79Br}M−C4H8]+), 214 ([{81Br}M−C4H8—CO2]+), 212 ([{79Br}M−C4H8—CO2]+), 171, 169, 103, 57 ([C4H9]+).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[CH2:11][O:10]2)=[CH:4][C:3]=1[F:24].[CH3:25][N:26]1C(=O)CCC1>>[C:25]([C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[O:14][CH2:13][C@H:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]3)[CH2:11][O:10]2)=[CH:4][C:3]=1[F:24])#[N:26]
Reactant: CCCC1CCC(C2COC(c3cc(F)c(Br)c(F)c3)OC2)CC1
Reactant: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3cc(F)c(C#N)c(F)c3)OC2)CC1
Temperature: 25 °C

Procedure:
7.3 g (0.018 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-(4'-propylcyclohexyl)-1,3-dioxane, 2.5 g (0.027 mol) of CuCN2 and 54 cm3 of NMP were refluxed for 2 hours with a mantle heater. After cooling the reactant to room temperature, 40 cm3 of EDA was added, it was poured into 50 cm3 of ice water, extracted with chloroform and washed with an aqueous EDA solution and water. The chloroform was removed, and the residue was dissolved in hexane and washed with water to remove the NMP. The hexane was removed, and the residue was treated in a silica gel column with chloroform as the solvent. The chloroform was removed, and the residue was repeatedly recrystallized in a solvent mixture of acetone and methanol until there were no cis forms to obtain 1.4 g (0.004 mol) of trans-2-(4'-cyano-3',5'-difluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition temperature of this compound was measured with DSC as follows. ##STR17## (here, C shows crystals, N shows the nematic phase and I shows isotropic liquid.)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].S(Cl)([Cl:25])(=O)=O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:20][CH3:21])[Cl:25]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC1Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following the method of Example 12, Step B, 4-(1-oxo-2ethyl-6,7-dichloro-5-indanyloxy)butyric acid (13.24 g., 0.04 mole) is treated with sulfuryl chloride (3.6 ml., 0.044 mole) in acetic acid (100 ml.) to obtain 9.33 g. of 4-(1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)butyric acid, m.p. 123°-124° C. after recrystallization from ethanol.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[Si:9]([O:26][CH2:27][CH:28]([OH:35])[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1>C(#N)C>[Si:9]([O:26][CH2:27][CH:28]1[O:35][C:2](=[O:3])[C:31]2=[N:32][CH:33]=[CH:34][N:30]2[CH2:29]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](OCC(O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)[Si](OCC1Cn2ccnc2C(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
Slowly add trichloromethyl chloroformate (8.74 mL; 2.0 equiv; 72.84 mmoles) over 10 minutes to a 0° C. solution of 1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (13.86 g; 1.0 equiv; 36.42 mmoles) and pyridine (23.56 mL; 8 equiv; 291.36 mmoles) in acetonitrile (500 mL). Stir for 1 hour and then allow the solution to warm to ambient temperature over 1 hour. Add water (50 mL) and concentrate the reaction mixture to 75 mL volume. Add dichloromethane (100 mL), and slowly pour the resulting solution into 50% saturated sodium bicarbonate (200 mL). Separate the layers and further extract the aqueous layer with dichloromethane (3×150 mL). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate. Purification by column chromatography (10% to 100% ethyl acetate in hexanes) affords the desired 6-[[tert-butyl(diphenyl)silyl]oxymethyl]-5,6-dihydroimidazo[2,1-c][1,4]oxazin-8-one (9.48 g; 64%) as a light pink gum: MS (m/z): 407(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1]
Reactant: Cc1cccc(Br)c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cccc1Br

Procedure:
2-Bromo-6-methyl-benzoic acid (4.95 g) and K2CO3 (16.26 g) were suspended in acetone (150 mL). MeI (7.5 mL) was added and the mixture was heated at reflux for 3.5 h. The solid was removed by filtration and the filtrate was concentrated. The residue was taken into EtOAc and washed with saturated NH4Cl, H2O and saturated NaCl. The organic phase was dried over MgSO4, filtered, and concentrated to yield 2-bromo-6-methyl-benzoic acid methyl ester as an orange oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:23](C1C(NC2C3C(=CC=CC=3)CCC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:23][CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1cnc(CC)c(NC2CCCc3ccccc32)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(NC2CCCc3ccccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.34, 7.21, 5.40, 4.54, 2.55, 2.09, 1.95, 1.28; 13C NMR (100 MHz, CDCl3) δ 152.49, 150.66, 141.49, 138.29, 138.21, 129.63, 129.27, 127.64, 126.65, 124.90, 60.81, 49.31, 29.89, 28.87, 29.39, 21.46, 20.32, 14.61, 11.26. (MS/CI) calcd for C18H22BrN3+H 360.3, found 360.3.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C[Si]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(C)C.[Si]([O:30][C@H:31]1[C:36](=[CH2:37])[C@H:35]([O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:34][C:33](=O)[CH2:32]1)(C(C)(C)C)(C)C>O1CCCC1>[Si:39]([O:38][C@H:35]1[C:36](=[CH2:37])[C@H:31]([OH:30])[CH2:32]/[C:33](=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19])/[CH2:34]1)([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C1[C@H](O)C/C(=C\C(=O)OCC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of diisopropylamine (1.2 mL, 9.4 mmol) in 10 mL of tetrahydrofuran was cooled to −78° C.; n-butyllithium (2.5 M in hexanes, 3.6 mL) was added, followed after 5 minutes by ethyl trimethlysilylacetate (1.7 mL). The resultant solution was stirred at −78° C. for 30 minutes, and then a solution of the compound of Example 13E (2.0 g, 4 mmol) in 10 mL of tetrahydrofuran was added over 5 minutes. Stirring was continued for 4 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl; the mixture was warmed to ambient temperature, the partitioned between ethyl acetate and water. The organic phase was washed with 1 N aqueous HCl and brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix IntelliFlash 280™, eluting with a gradient of 5% to 10% ethyl acetate in hexanes. The product (1.9 g) was dissolved in 17 mL of ethanol; 1.3 mL of concentrated HCl was added, and the resultant solution was stirred overnight at ambient temperature. The solvents were removed in vacuo, the residue was taken up in saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was concentrated in vacuo and purified by chromatography on an Analogix Intelliflash 280™, eluting with a gradient of 2% to 3% dichloromethane in acetonitrile. The title compound was isolated as the slower-eluting material (0.62 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=1)[CH3:2].O.[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cccc(Oc2ccc(N)cc2)c1
Yield: 82 %

Procedure:
A solution of 1-(ethyloxy)-3-[(4-nitrophenyl)oxy]benzene (Intermediate 3, 4 g) and tin chloride monohydrate (28.8 g, 139 mmol) in ethyl acetate (200 mL) was heated at reflux overnight (15 hours). The reaction mixture was cooled down. It was then diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 (100 mL), brine (100 mL) and dried over sodium sulphate. After evaporation of the volatiles, the residue was purified by an SCX (wash of the column with methanol, adsorption of the compound, wash with methanol (3CV), desorption with 2N methanolic ammonia (3CV)). Evaporation afforded the title compound (2.9 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O:23]=[C:24]1[C@H:30]([NH:31][C:32]([N:34]2[CH2:39][CH2:38][CH:37]([NH:40][C:41]([NH:43][C@H:44]([C:47]([O:49][CH3:50])=[O:48])[CH2:45]O)=[O:42])[CH2:36][CH2:35]2)=[O:33])[N:29]=[C:28]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:27]2[CH:57]=[CH:58][CH:59]=[CH:60][C:26]=2[N:25]1[CH2:61][C:62]([F:65])([F:64])[F:63]>ClCCl>[O:42]=[C:41]1[NH:43][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][N:40]1[CH:37]1[CH2:38][CH2:39][N:34]([C:32]([NH:31][C@@H:30]2[N:29]=[C:28]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:27]3[CH:57]=[CH:58][CH:59]=[CH:60][C:26]=3[N:25]([CH2:61][C:62]([F:65])([F:64])[F:63])[C:24]2=[O:23])=[O:33])[CH2:35][CH2:36]1
Reactant: COC(=O)[C@H](CO)NC(=O)NC1CCN(C(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(F)(F)F)C2=O)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cn(C2CCN(C(=O)N[C@@H]3N=C(c4ccccc4)c4ccccc4N(CC(F)(F)F)C3=O)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
Dess-Martin periodinane (126 mg, 0.298 mmol) was added to a solution of methyl N-({[1-({[(3R)-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]amino}carbonyl)piperidin-4-yl]amino}carbonyl)serinate (75 mg, 0.124 mmol) in dichloromethane (15 mL) at 0° C. The reaction warmed to ambient temperature, stirred for 4 h, and was quenched with a 1:1 mixture of saturated sodium thiosulfate and sodium bicarbonate solution. The mixture was extracted with dichloromethane (2×) and the combined organic extracts were dried over sodium sulfate, filtered, concentrated. Purification by silica gel chromatography (100% dichloromethane→8% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (55 mg). MS 585.4 (M+1)
Reaction SMILES: [SH:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][O:14][C:15](=[O:22])[N:16]=[C:17](SC)SC>C(O)C>[CH3:13][O:14][C:15](=[O:22])[NH:16][C:17]1[S:1][C:2]2[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][C:3]=2[N:4]=1
Reactant: COC(=O)N=C(SC)SC
Reactant: CCCOc1ccc(N)c(S)c1
Solvent: CCO
Product: CCCOc1ccc2nc(NC(=O)OC)sc2c1
Reaction time: 12 h

Procedure:
In a round bottom 1 liter flask equipped with a reflux condenser, a magnetic stirrer and a heating mantle is placed 45.75 g. of 2-mercapto-4-propoxyaniline; 48.25 g. of methyl-N-[di(methylthio)-methylene]carbamate, and 250 ml absolute ethanol. This mixture is heated to boiling under an inert atmosphere of nitrogen for 12 hrs. It is then chilled and the white crystalline solid which is formed is isolated by filtration, washed with cold ethanol and dried. m.p. 178°-180° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[OH-].[K+].[I:14]I>CN(C=O)C>[I:14][C:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: O=c1cc[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1c(I)c[nH]c2ccccc12

Procedure:
1H-Quinolin-4-one (2.90 g, 20 mmol, 1 equiv) in 5 mL of DMF was treated with 1.12 g of KOH (2 equiv) and 5.30 g of iodine (1.05 equiv) for 2 hours. The reaction was quenched by slow addition of saturated aqueous solution of Na2S2O3. Filtration gave 3-iodo-1H-quinolin-4-one as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 108.8 %

Procedure:
A mixture of 4-bromobenzotrifluoride (10.0 g), 4-formylphenylboronic acid (7.33 g), tetrakis(triphenylphosphine)palladium(0) (308 mg), potassium carbonate (30.7 g), tetrahydrofuran (300 mL) and water (100 mL) was stirred at 85° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added to it, which was then extracted with ethyl acetate twice and the combined organic layers were washed with saturated brine. After adding anhydrous magnesium sulfate to the organic layers, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in n-hexane (60 mL) with heating and thereafter cooled to 0° C. The resulting precipitate was recovered by filtration to give the titled compound as a gray solid (12.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:12][CH2:11][CH2:10][CH2:9]1>O>[C:2]1([N:1]2[CH2:8][CH2:9][CH2:10][C:11]2=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCO1
Reactant: Nc1ccccc1
Solvent: O
Product: O=C1CCCN1c1ccccc1
Yield: 39.1 %

Procedure:
9.3 g (0.1M) aniline and 9.5 g (0.11M) γ-butyrolactone were mixed and heated to 200° for 48 hours. The mixture was then placed under high vacuum whereupon unreacted γ-butyrolactone, analine and water were removed. Distillation of the residue at 138°-140°/300 μ gave 6.3 g (39%) of the product. [84% yield, based on reclaimed starting materials.]