Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)=[N:8][C:7]=2[CH:20]=1
Reactant: COc1cc(OC)c2sc(-c3ccc([N+](=O)[O-])cc3)nc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c2sc(-c3ccc(N)cc3)nc2c1

Procedure:
To a stirred solution of 3,5-dimethoxybenzenamine (16c, 4g, 26.1 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.3 g, 28.7 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filtered, washed with dil HCl and dried to afford compound N-(3,5-dimethoxyphenyl)-4-nitrobenzamide (18c). To a stirred solution of amide (18c, 5g, 16.5 mmol) taken in toluene to this lawessons reagent (4.6 g, 11.5 mmol) is added and refluxed at 110° C. for 8h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound N-(3,5-dimethoxyphenyl)-4-nitrobenzothioamide (19c). Treating the thioamide product (19c, 3g, 9.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,7-dimethoxy-2-(4-nitrophenyl)benzo[d]thiazole (20c) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20c. Reduction of the nitro compound (20c, 500 mg, 1.5 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21c). The compound 4-(5,7-dimethoxybenzo[d]thiazol-2-yl)benzenamine (21c, 200 mg, 0.698 mmol) on reaction with 3,5-dimethoxybenzaldehyde (22d, 116 mg, 0.698 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction by using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 6d as a brown solid (63%).
Reaction SMILES: C(OC([N:8]([O:30]C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:28][CH3:29])=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:26][C:24]1[C:23]([Cl:27])=[CH:22][C:21]2[N:17]([C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][OH:30])=[CH:16][CH:15]=3)[C:18]([CH2:28][CH3:29])=[N:19][C:20]=2[CH:25]=1
Reactant: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc2cc(Cl)c(Cl)cc2n1-c1ccc(CCNO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-[4-(2-{(tert-butoxycarbonyl)[(tert-butoxycarbonyl)oxy]amino}ethyl)phenyl]-5,6-dichloro-2-ethyl-1H-benzimidazole (step 1, 174 mg, 0.3 mmol) and 2N hydrochloric acid (3 mL) in ethyl acetate (20 mL) was stirred at room temperature for 1 day. The reaction mixture was poured into water (100 mL), neutralized with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 162 mg (quant.) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 10.35 (2H, br.s), 7.89 (1H, s), 7.46-7.50 (2H, m), 7.29 (2H, d, J=6.8 Hz), 7.17 (1H, s), 3.37 (2H, t, J=6.9 Hz), 3.12 (2H, t, J=6.9 Hz), 2.80 (2H, q, J=6.9 Hz), 1.34 (3H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>C1COCC1>[OH:16][CH2:15][C:14]([NH:13][C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[S:12])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=S)Nc1ccc([N+](=O)[O-])cc1
Yield: 66.2 %

Procedure:
A solution of 4-nitro-phenyl-isothiocyanate (4 g, 22.2 mmol) and 2-amino-2-methyl-propan-1-ol (1.9 g, 21.3 mmol) in THF was stirred overnight at r.t. The solvent was evaporated to give a residue which was triturated with ether to give 1-(2-hydroxy-1,1-dimethyl-ethyl)-3-(4-nitro-phenyl)-thiourea (3.8 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:9]=1)C#N.[OH-:17].[Na+].[CH2:19]([OH:21])[CH3:20]>Cl>[Cl:1][C:2]1[CH:3]=[C:20]([CH:7]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:9]=1)[C:19]([OH:17])=[O:21]
Reactant: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: CN1CCN(c2cc(Cl)cc(C(=O)O)c2)CC1

Procedure:
To 3-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile (1.4 g, 5.9 mmol) dissolved in ethanol (10 ml) was added 2M NaOH (20 ml) and reaction mixture was heated at reflux for 20 hours. The mixture was reduced in vacuo and the crude product was acidified in 1N HCl to pH 6 and partitioned between EtOAc and H2O. The organic layer was evaporated to dryness in vacuo to give 0.7 g of the title compound as a white solid (LC/MS: Rt 1.67, [M+H]+ 256, acidic method).
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[F:8][C:9]1[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([O:18]C)=[N:11][CH:10]=1.O>C(#N)C.C(Cl)(Cl)Cl>[F:8][C:9]1[N:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([OH:18])=[N:11][CH:10]=1
Reactant: COc1ncc(F)nc1C(N)=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: O
Product: NC(=O)c1nc(F)cnc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.2 %

Procedure:
In an atmosphere of nitrogen gas, 1.51 g of sodium iodide was dissolved in 22 mL of acetonitrile. After adding 1.10 g of trimethylsilyl chloride, the mixture thus obtained was stirred at room temperature for 20 minutes. Then, 0.43 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was added, and the mixture thus obtained was stirred at the same temperature as above for 18 hours. The reaction mixture was added to a mixture of 10 mL of water and 200 mL of chloroform, and the mixture thus formed was separated into layers. The organic layer was washed successively with 5% aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: hexane:ethyl acetate=2:1] to obtain 0.06 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white-colored solid product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[Br:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24]C=2)[CH:20]=[C:19](Br)[N:18]=1.C[N:29]1CCCC1=O>O>[Br:16][C:17]1[CH:26]=[C:21]2[C:20](=[C:19]([O:1][C@H:2]3[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]3)[N:18]=1)[N:29]=[CH:24][CH:23]=[CH:22]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CN1CCCC1=O
Reactant: Brc1cc2ccccc2c(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Br)cc3cccnc23)C1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (890 mg, 4.75 mmol) in N-methyl-2-pyrrolidinone (16 mL) at 0° C. was added NaH (60%) (158.4 mg, 3.96 mmol). The mixture was stirred for 5 minutes. Next, 1,3-dibromoisoquinoline (1139 mg, 3.96 mmol) was added and the reaction mixture was stirred at RT for 5 minutes and then heated in a microwave reactor at 135° C. for 30 minutes and at 160° C. at for another 30 minutes. The mixture was subsequently diluted with water and extracted with EtOAc (2×). The organic phase was separated, dried over Na2SO4, and concentrated. The crude product was purified by silica column chromatography eluting with a gradient of 0-75% EtOAc in hexane over a 45 minute period to give the title compound (1.3 g, 70% from two batches).
Reaction SMILES: [OH-].[K+].N1C=CC=CC=1C1C=CC=CN=1.[CH:15](=[CH:22][C:23](=[O:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H]>CC(O)C>[C:16]1([CH2:15][CH2:22][C:23](=[O:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:16]1([CH2:15][CH2:22][CH:23]([OH:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: CC(=O)C=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CC(C)O
Product: CC(=O)CCc1ccccc1
Product: CC(O)CCc1ccccc1
Reaction time: 3 h
Yield: 19.8 %
Yield: 80.2 %

Procedure:
RuClCp* (cod) (3.8 mg, 0.01 mmol), KOH (0.04 mmol), 2,2′-bipyridyl (3.1 mg, 0.02 mmol) and benzalacetone (730.95 mg, 5.0 mmol) were dissolved into 10 ml of 2-propanol, and deaerated by argon substitution, after which the total amount of the resulting mixture was transferred into a 100-milliliter metallic autoclave. Hydrogen was then charged to a predetermined pressure (50 atm), and the reaction was started at room temperature (28° C.). After the reaction solution was stirred for 3 hours, the reaction pressure was brought back to atmospheric pressure, and the reaction products, 4-phenyl-2-butanone (yield 19.8%) and 4-phenyl-2-butanol (yield 80.2%), were identified and determined by TLC monitor (silica gel: n-hexane/ethyl acetate=4/1) and gas chromatography of the reaction solution.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[CH2:22]([O:29][CH2:30][C:31](Cl)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([O:29][CH2:30][C:31]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: C1CCOC1
Product: Cc1nc2cccc(NC(=O)COCc3ccccc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 80 °C
Yield: 46 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.42 g, 1.4 mmol) in tetrahydrofuran (10 mL), was added benzyloxyacetyl chloride (0.75 mL, 4.8 mmol) and heated at 80° C. for three hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-benzyloxy-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]acetamide as a white solid (280 mg, 47% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.46 min (99.2%); mp, 272-274° C.; 1HNMR (DMSO-d6) δ 2.17-2.22 (m, 1H, CHH), 2.65-2.93 (m, 6H, CHCH2, CH3), 4.13-4.30 (dd, J=15, 36 Hz, 2H, CH2), 4.64 (s, 2H, CH2), 5.33 (dd, J=5, 11 Hz, 1H, CH), 7.25-8.68 (m, 8H, Ar), 11.10 (s, 1H, NH), 12.48 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.62, 23.38, 30.83, 56.93, 70.17, 72.80, 107.95, 115.38, 120.97, 127.47, 127.53, 128.13, 135.52, 137.33, 138.95, 147.90, 154.90, 162.73, 168.94, 169.28, 172.51, 172.62. LCMS MH=435; Anal Calcd For C23H22N4O5+0.6H2O: C, 62.04; H, 5.25; N, 12.58. Found: C, 61.82; H, 4.90; N, 12.49.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:42][CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:42][CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCNC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: O=C(O)C1CCCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with nipecotic acid. A yellow solid 128 was obtained (0.034 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([S:13]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]2=3)(=[O:15])=[O:14])=[CH:4][C:3]=1[C:27]1[C:28]([CH3:35])=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=1.C(#N)C.[OH2:39].CO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]2[CH:32]=[N:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=2[CH3:35])=[CH:4][C:5]([S:13]([N:16]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]2=3)(=[O:15])=[O:14])=[C:6]([CH:7]=1)[O:8][CH2:9][CH2:10][C:11]([OH:39])=[O:12]
Reactant: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(OCCCO)cc1Cl
Reactant: O
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(OCCC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 5-[2-chloro-4-(3-hydroxy-propoxy)-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile 8-1 (31 mg, 0.06 mmol) in a mixture of DCM (0.3 mL), acetonitrile (0.3 mL) and water (0.4 mL) was added NaIO4 (38 mg, 0.18 mmol) and RuCl3 (2.5 mg, 0.012 mmol). The mixture was stirred at rt for 40 minutes, then 1 mL of methanol was added. The mixture was filtered and purified by prep. LCMS to afford 3-[5-chloro-4-(6-cyano-4-methyl-pyridin-3-yl)-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenoxy]-propionic acid 10-1. MS: 526.0 (M+H)+; tR=4.65 min (method 4). NMR (CDCl3), δ, 8.378 (1H, s), 7.649 (1H, s), 7.621 (1H, s), 7.259 (1H, s), 7.136-7.203 (2H, m), 6.981-7.038 (1H, m), 6.746 (1H, d, J=7.8 Hz), 4.423 (2H, t), 3.728 (2H, m), 2.803-2.842 (4H, m), 2.162 (3H, s), 1.894-1.929 (2H, m), 1.658 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[C:13]1([Li])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.C1CCCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: [Li]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 20 g (0.123 mol) of 6-methoxy-l-indanone in 500 mL of ether cooled to -20° C. was added 72 mL (0.129 mol) of 1.8M phenyllithium in cyclohexane/ether and the mixture was stirred at room temperature for 1 h. An additional (10 mL) phenyllithium solution was added and stirred at room temperature for 1 h. To the reaction mixture was added saturated ammonium chloride solution and the resulting mixture was extracted with ethyl acetate (3×250 mL), and the organic layer was dried over sodium sulfate and concentrated in vacuo to afford 32.3 g of crude (contains solvent) 6-methoxy-1-phenyl-indan-1-ol.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>>[CH3:11][O:12][C:13](=[O:28])[C@H:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:15][C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:8](=[O:10])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC1CCCCC1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CC1CCCCC1

Procedure:
Following General Procedure U and using cyclohexylacetic acid (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared by coupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl ester hydrochloride (Bachem) using General Procedure U, followed by removal of the BOC-group using General Procedure Y), the title compound was prepared as a solid (mp=156-158° C.). The reaction was monitored by tlc (Rf=0.25 in 1:1 EtOAc/hexanes).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(OCC)(=O)C>C(Cl)Cl>[CH2:10]([O:9][C:7]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-methylethanolamine (149 mmol) in methylene chloride (100 ml) at 0° C. was added benzyl chloroformate (70 mmol). The mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2M HCl, saturated NaHCO3 solution, and brine, then dried over Na2SO4 and evaporated to provide the desired compound. 1H NMR (CDCl3TMS) δ 736 (m,5H), 5.14 (s,2H), 3.78 (m,2H), 3.47 (m,2H), 3.01 (s,3H).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)O[C:8](=[O:13])C(F)(F)F)=O.B(F)(F)F.CCOCC.[CH3:31][CH2:32][O:33][C:34]([C:36]([CH2:38][C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])=O)=O)=[O:35].[CH3:45][NH:46][NH2:47]>CO>[CH2:32]([O:33][C:34]([C:36]1[N:46]([CH3:45])[N:47]=[C:39]([C:41]([CH3:42])([CH3:43])[CH3:44])[C:38]=1[O:13][CH3:8])=[O:35])[CH3:31]
Reactant: CNN
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)c1c(OC)c(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (430 mg, 1.00 mmol) was dissolved in anhydrous MeOH (4 mL), the resulting solution was stirred at room temperature for 3 min. BF3.OEt2 (0.123 mL, 1.00 mmol) was then added via syringe. Ethyl trimethylacetopyruvate (200 mg, 1.00 mmol) was added dropwise via syringe and the resulting mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure and the resulting residue was dissolved in dry EtOH (2 mL). CH3NHNH2 (52.6 μL, 1.00 mmol) was added via syringe and the resulting mixture was stirred at 80° C. for 8 h. The solvent was removed under reduced pressure and the resulting residue was chromatographed on a 24-g SiO2 pre-packed column eluting with 0:1-3:7 EtOAc/hexanes to yield 5-tert-butyl-4-methoxy-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDCl3) δ: 4.39 (q, J=7.1 Hz, 2H), 4.03 (s, 3H), 3.83 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.34 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[CH:4]=1.N1C=CC=CC=1.Cl>[OH-].[Na+]>[CH2:13]([O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:20]=[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[NH:9][C:7]2=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(NC(=O)c2cccc([N+](=O)[O-])c2)c(C(N)=O)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OCc1ccccc1
Temperature: 25 °C
Yield: 47 %

Procedure:
A suspension of 4-methoxy-5-benzyloxy-2-(3-nitrobenzoylamino)benzamide (8.00 g, possesses some pyridine.HCl) in 4N NaOH (200 mL) was heated at 100±5° C. for 10 h. The reaction mixture was allowed to cool to room temperature and pH was adjusted to 7-7.5 with 6 N HCl. A solid separated out, which was collected by filtration, washed with water (100 mL) and dried under vacuum to give 6-(benzyloxy)-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (3.22 g, 7.99 mmol, 47% over two steps). MS 404 (M+1) HPLC retention time 8.026 min.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH2:8][CH2:7][NH:6][C:5]2=[O:10].[Br:11][CH2:12][CH2:13][F:14]>C(#N)C>[Br-:11].[F:14][CH2:13][CH2:12][N+:2]1[CH:1]=[C:9]2[N:4]([C:5](=[O:10])[NH:6][CH2:7][CH2:8]2)[CH:3]=1
Reactant: O=C1NCCc2cncn21
Reactant: FCCBr
Solvent: CC#N
Product: O=C1NCCc2c[n+](CCF)cn21
Product: [Br-]
Temperature: 160 °C

Procedure:
7,8-Dihydro-6H-imidazo[1,5-c]pyrimidin-5-one (0.45 g, 3.28 mmol) was suspended in acetonitrile (4 ml) and 1-bromo-2-fluoroethane (0.326 ml, 4.38 mmol) added. The reaction mixture was heated in a microwave reactor at 160° C. for 1 hour, then the solvent evaporated and the crude reaction mixture purified by silica chromatography eluting with dichloromethane:methanol 9:1 to afford the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]([C:18](=O)[CH3:19])[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.N.C([BH3-])#[N:25].[Na+]>CO.C(O)(=O)C>[NH2:25][CH:18]([CH3:19])[CH:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(N)C(Cc1ccc(Cl)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Benzyl 2-(4-chlorobenzyl)-3-ketobutyrate (317 mg, 1 mmole, obtained from Step A) was added to a cooled mixture of 7M ammonia in MeOH (2.42 mL) and glacial acetic acid (1.6 mL). To this solution, at ˜10° C., was added sodium cyanoborohydride (101 mg, 1.75 mmol) in small portions. This mixture was stirred at room temperature for 40 h. The excess sodium cyanoborohydride was destroyed by the addition of 6M HCl (to pH 1). The residue obtained after removal of volatiles was taken up in a minimal amount of water and extracted with ether. The aqueous layer was basified to pH 10 using solid KOH. This layer was then saturated with sodium chloride and then extracted with EtOAc. Further analyses of the ether and the EtOAc layers suggest that the desired product resides the EtOAc layer. This material was used in the ensuing coupling reactions without further purification. Proton NMR spectrum show that the two pairs of diastereomers are obtained in ˜1:1 ratio, homogeneous by TLC, Rf=0.4 in 95:5 CH2Cl2:MeOH. LC/MS m/e=318 (M+1). 400 MHz 1H NMR (CDCl3) δ 1.27, 1.29 (2 d, J=7 Hz, 3H), 2.85 (m, 1H), 3.03 (m, 1H), 3.15 (m, 1H), 3.55 (m, 1H), 4.85 (br, 2H), 5.00-5.18 (m, 2H), 7.0-7.2 (m, 9H).