Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[N:8][C:4]=2[CH:3]=1.[OH-:23].[NH4+].OO>CO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]([NH2:12])=[O:23])=[N:8][C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Agent: OO
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)n1c(-c2ccccc2C(N)=O)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (1800 mg, 5.08 mmol) in MeOH (40 mL), followed by the addition of ammonium hydroxide (20 mL) and hydrogen peroxide (10 mL) (30% in water). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water then brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-4% MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzamide (1590 mg, 84%) as a light brown solid. LCMS (ESMS): m/z 372.46, 374.35 (M++1)
Reaction SMILES: [F:1][C:2]1[C:3](NC(=O)C)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.N([O-])=O.[Na+].N.[ClH:22]>O>[F:1][C:2]1[C:3]([Cl:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: Cl
Reactant: CC(=O)Nc1c(F)ccc2c1CCC(C)N2
Agent: N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1CCc2c(ccc(F)c2Cl)N1
Reaction time: 1 h

Procedure:
6-Fluoro-5-acetylamino-1,2,3,4-tetrahydroquinaldine (8 g) was dissolved in a mixture of 35 ml of concentrated hydrochloric acid and 20 ml of water. After refluxing the solution for 1 hour 10 ml of an aqueous solution having dissolved therein 5 g of sodium nitrite was added dropwise to the solution under ice-cooling taking care that the reaction temperature should not exceed 5° C. After completion of the addition the reaction mixture was stirred at the same temperature as above for 1 hour and poured into a solution of 12 ml of concentrated hydrochloric acid and 10 g of cuprous hydrochloride. The mixture was allowed to react at 80° C. for 1 hour and ice-cooled. After rendering it alkaline with an aqueous 28% ammonia solution the reaction mixture was extracted with 300 ml chloroform and Celite (diatomaceous earth, produced by Johns Manville Sales Corp.). The chloroform fraction obtained was dried over anhydrous sodium sulfate and concentrated. The residue was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-ethanol (9:1 by volume) to obtain 3.2 g of 6-fluoro-5-chloro-1,2,3,4-tetrahydroquinaldine as light orange oily product. Production of this compound was confirmed by NMR spectral analysis and mass spectral analysis.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CC(C)C[C@@H](Nc1cnc(C(N)=O)c(Nc2cnc3ccccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (70 mg, 0.261 mmol), 3-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 100 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide as a crude residue (131 mg). The crude (R)-2-(5-cyano-6-(quinolin-3-ylamino)pyrazin-2-ylamino)-4-methylpentanamide (131 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (30 mg). MS 394.4 (M+H); UV 201.1, 247.4, 297.8, 352.3 nm; t 0.476 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[Cl:25]C1C=C2N(C3C=CC=CC=3[N+]([O-])=O)CC3(CCN(/C(/C([O-])=O)=C/C([O-])=O)CC3)C2=CC=1.C(O)C.Cl>[Fe].O>[ClH:1].[ClH:25].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=C([O-])/C=C(\C(=O)[O-])N1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1cc(Cl)ccc12
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcohol-ether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine]dihydrochloride.
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=1.[OH-].[Na+].Cl>O.CCO.O.CCO>[CH3:4][C:3]1[C:2]([OH:1])=[CH:13][C:12]2[CH:11]=[N:10][C:9]([S:15][CH3:16])=[N:8][C:7]=2[N:6]=1
Reactant: CC(=O)CO
Reactant: CSc1ncc(C=O)c(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc2cc(O)c(C)nc2n1
Yield: 55.4 %

Procedure:
Add 1-hydroxypropan-2-one (24.3 mL, 355 mmol) and 4-amino-2-(methylthio)pyrimidine-5-carbaldehyde (50 g, 296 mmol) to a solution of sodium hydroxide (23.64 g, 591 mmol) and water (200 mL). Add EtOH (600 mL) to the suspension and stir at RT overnight. Slowly add a solution of concentrated HCl (50 mL) in water (350 mL). Add 1:1 EtOH/H2O (100 mL) and collect the solids by filtration. Wash the solids with 1:1 EtOH/H2O (250 mL), ice cold EtOH (4×25 mL) and hexanes (2×250 mL). Dry in the vacuum oven at 30-35° C. to provide the title compound as a tan solid (34 g, 56% yield). MS (m/z): 208.1 (M+1).
Reaction SMILES: C(=O)(O)[O-].[Na+:5].[C:6]([O:10][C:11](=[O:26])[CH2:12]/[C:13](=[CH:17]\[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[C:14]([OH:16])=[O:15])([CH3:9])([CH3:8])[CH3:7]>CO.O>[Na+:5].[C:6]([O:10][C:11](=[O:26])[CH2:12][C@@H:13]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([O-:16])=[O:15])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)C/C(=C\CCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)[O-]
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 60.8 %

Procedure:
A stirred solution of sodium bicarbonate (28.6 g, 0.34 mol), (E)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (100 g, 0.34 mol) and [(S)-2,2′-bis(diphenylphosphino-1,1′-binaphthyl]chloro(p-cymene)ruthenium chloride (0.63 g, 0.68 mmol) in methanol (750 ml) and water (250 ml) was heated to 60° C., under hydrogen (60 p.s.i.), for 24 hours and then allowed to cool to 20-25° C. (enantiomeric excess 87%). The mixture was filtered through a filter aid Celite® and the solvent was stripped and replaced with acetonitrile by distillation at atmospheric pressure, at a constant volume of 500 ml. The resulting suspension was cooled to 20-25° C. and was stirred for 24 hours, then filtered. The residue was washed with acetonitrile (3×25 ml) and then dried in vacuo at 45° C. for 3 hours to leave the title compound as a colourless solid (65 g, 61% yield, enantiomeric excess=94.3%, 95% pure by NMR).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([N:9]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])[CH2:2]2.[CH3:23][C:24]([O:27][C:28]([NH:30][C@@H:31]([C:40](O)=[O:41])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)=[O:29])([CH3:26])[CH3:25].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C@@H:31]([NH:30][C:28](=[O:29])[O:27][C:24]([CH3:26])([CH3:23])[CH3:25])[C:40]([N:8]2[CH:1]3[CH2:7][CH2:6][CH:5]2[CH2:4][CH:3]([N:9]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:10]([N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:11])[CH2:2]3)=[O:41])=[CH:38][CH:37]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
1.8 g of N-8-azabicyclo[3.2.1]oct-3-yl-N-cyclohexyl-N′,N′-diethylurea are dissolved in 70 ml of dichloromethane in the presence of 1.75 g of Boc-D-4-chlorophenylalanine, of 0.79 g of hydroxybenzotriazole, of 1.12 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and of 1.02 ml of diisopropylethylamine. The mixture is stirred at ambient temperature for 16 h. After evaporation to dryness, the residue is hydrolysed and extracted with ethyl acetate until the aqueous phase is completely depleted. The organic phase is washed with H2O and then with a saturated aqueous sodium chloride solution. After drying over MgSO4 and concentration to dryness, the crude is chromatographed on silica gel, elution being carried out with a 99/1 mixture of dichloromethane and methanol, to give 1.42 g of tert-butyl [(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(di-ethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]carbamate.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][CH:9]1[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH2:22])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC1CC(O[Si](C)(C)C(C)(C)C)CC(c2ccncc2N)C1
Reaction time: 15 h
Yield: 90 %

Procedure:
To a solution of 4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)-3-nitropyridine (1.0 equiv.) in methanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 15 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding 4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine (90%). LCMS (m/z): 321.3 (MH+); LC Rt=3.85 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:16]2[O:22][C@H:21]([CH2:23][O:24]C(=O)C)[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:4]2[C:9]([C:10]=1[C:11](=[O:13])[CH3:12])=[CH:8][C:7]([Cl:14])=[C:6]([Cl:15])[CH:5]=2.C[O-].[Na+]>CO>[Cl:1][C:2]1[N:3]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:4]2[C:9]([C:10]=1[C:11](=[O:13])[CH3:12])=[CH:8][C:7]([Cl:14])=[C:6]([Cl:15])[CH:5]=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)c(C(C)=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.3 %

Procedure:
2,5,6-Trichloro-3-acetyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.43, 232 mg, 0.53 mmol) was dissolved in dry MeOH (20 mL) to which was added sodium methoxide (35 mg, 0.65 mmol). The solution was stirred at room temperature for 45 min, and the solvent was then removed under vacuum. The residue was suspended in 10% aqueous NaHCO3 (50 mL) and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid. The solid was recrystallized from boiling EtOAc/hexane to yield 170 mg (81%) of 4.46 as a white crystalline solid: mp 249-250 C; Rf0.4 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.41 (s, 1H), 6.07 (d, 1H), 5.45-5.42 (m, 2H, D2O exch.), 5.30 (d, 1H, D2O exch.), 4.44 (q, 1H), 4.17 (d, 1H), 4.03 (d, 1H), 3.75 (b, 2H), 2.63 (s, 3H). 13C-NMR (125 MHz, DMSO-d6): δ 192.17, 133.10, 132.38, 126.21, 126.00, 125.73, 122.00, 115.44, 112.99, 88.97, 86.39, 71.63, 69.54, 60.97, 30.72. HRMS (ES) m/z calcd. for C15H14C13NO5□Na 415.9835, found 415.9843. Anal calcd for C15H14Cl3NO5: C, 45.65; H, 3.58; N, 3.55. Found: C, 45.75; H, 3.78; N, 3.61.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2)[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[O:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]=1[C:24](Cl)=[O:25]>>[CH2:1]([N:5]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[CH:8]=1)[C:24]([C:23]1[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[O:20][C:19]=1[CH3:18])=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc2cc(O)ccc2c1
Reactant: Cc1oc2ccccc2c1C(=O)Cl
Product: CCCCN(Cc1ccc2cc(O)ccc2c1)C(=O)c1c(C)oc2ccccc12
Yield: 47 %

Procedure:
Prepared in the same manner as described in step 4 of Example 48 and replacing 6-(benzylamino-methyl)-naphthalen-2-ol with 6-butylaminomethyl-naphthalen-2-ol, prepared in step 3 of Example 51, and replacing 2-butyl-benzofuran-3-carbonyl chloride with 2-methy-benzofuran-3-carbonyl chloride, prepared in step 2 of Example 20. Purification of the crude product on 300 g silica gel (230-400 mesh) using 25%-33% ethyl acetate in hexane as the eluent gave 2-methyl-benzofuran-3-carboxylic acid butyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide (1.03 g, 47%) as a tan solid, mp 126-128° C.
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[Cl:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[C:13]([F:20])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]>CO.O>[CH3:3][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([F:20])[C:14]([CH3:19])=[C:15]([N+:16]([O-:18])=[O:17])[C:7]=1[Cl:6]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1c(F)cc(C(=O)O)c(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(F)c(C)c([N+](=O)[O-])c1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of chlorotrimethylsilane (200 mL) in methanol (300 mL) was treated with 2-chloro-5-fluoro-4-methyl-3-nitrobenzoic acid (Preparation 1c, 65.5 g) portionwise under nitrogen. The resulting solution was stirred at 20° C. for 16 h. Further chlorotrimethylsilane (100 mL) was added and the reaction heated at 50° C. for 6 h. The reaction mixture was evaporated to afford crude product which was diluted with water and extracted with ethyl acetate (300 mL). The organic extract was dried (MgSO4), filtered and evaporated to afford the subtitle compound (53.4 g).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:20]1[C:24]([C:25]2[N:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=2)=[CH:23][N:22]=[CH:21]1>>[C:1]([C:5]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]([CH:17]3[CH2:19][CH2:18]3)[C:31]([C:28]3[CH:27]=[N:26][C:25]([C:24]4[O:20][CH:21]=[N:22][CH:23]=4)=[CH:30][N:29]=3)=[O:32])[CH2:14][CH2:15]2)[O:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Reactant: O=C(O)c1cnc(-c2cnco2)cn1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3cnc(-c4cnco4)cn3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine and 5-oxazol-5-yl-pyrazine-2-carboxylic acid following a procedure analogous to that described in Example 1. LC (method 8): tR=1.57 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH:27]=O)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][C:30]1([CH3:46])[CH2:39][C@H:38]([NH2:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=2)[NH:31]1.C(Cl)Cl.COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Si:1]([O:8][C@H:9]([CH2:27][NH:40][C@@H:38]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:36]=2)[NH:31][C:30]([CH3:46])([CH3:29])[CH2:39]1)[C@@H:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cc1ccc2c(c1)[C@@H](N)CC(C)(C)N2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)[C@@H](C=O)O[Si](C)(C)C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCl
Product: CC(C)(C)Cc1ccc2c(c1)[C@@H](NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C)CC(C)(C)N2
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-fluorophenyl)-4-oxobutan-2-ylcarbamate (0.148 g, 0.360 mmol) and (S)-2,2-dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-amine (0.0886 g, 0.360 mmol) in DCM (7.19 ml, 0.360 mmol) was added trimethoxymethane (0.394 ml, 3.60 mmol). The resulting solution was stirred for 1 hour at which time, sodium triacetoxyborohydride (0.229 g, 1.08 mmol) was added. The solution was then stirred for 30 minutes, quenched with saturated Rochelle's salt and stirred for an additional 20 minutes. The mixture was transferred to a sep. funnel containing DCM and H2O. The aqueous layer was washed 4× with DCM. The organic layers were combined, washed 1× with brine, dried with MgSO4, filtered and concentrated to afford the title compound. MS m/z: 642 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:29][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2.[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:37]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12](=[O:28])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:18]=1)=[C:7]([O:29][S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])[CH:6]=[CH:5]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: OCc1ccccc1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(O)ccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OCc3ccccc3)ccc12
Temperature: 0 °C
Yield: 94.7 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (9.00 g, 17.2 mmol) in THF (540 mL). Stir the solution at 0° C. under N2 and add benzyl alcohol (2.78 g, 25.8 mmol), polymer-PPh3 (8.60 g, 25.8 mmol) and DIAD (5.21 g, 25.8 mmol). Continue to stir the reaction mixture at room temperature for 2 hours. Add water (1000 mL), and extract the aqueous layer with CH2Cl2 (3×500 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash chromatography (silica gel, 0-4% MeOH—NH4OH (10/1, v/v)/CH2Cl2) to give 10.0 g (96%) of the title compound: mass spectrum (ion spray) m/z=614.1 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4].[C:22](O)(=[O:24])C>C=O>[CH2:1]([N:5]1[C:9]([CH2:22][OH:24])=[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=[C:6]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCn1cc(-c2ccccc2)nc1-c1ccccc1
Agent: C=O
Product: CCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1CO

Procedure:
1-Butyl-2,4-diphenylimidazole (3 g)is dissolved in 50 ml of acetic acid with 50 ml of 37% aqueous formalin solution. The mixture is heated at reflux for 48 h, cooled and the solvents evaporated. The residue is triturated with ether and filtered. The filtrate is concentrated and partitioned between ethyl acetate (100 mL) and 5% aqueous acetic acid (100 mL). The aqueous layer is extracted with ethyl acetate (100 mL). The combined organic extracts are washed with 1N NaOH solution, brine, dried over Na2SO4, and concentrated. The crude product is triturated with ethyl acetate to give the product as a white solid, 1H NMR (CDCl3) 7.73 (d, J=5 Hz, 2H), 7.62 (d, J=4 Hz, 2H), 7.3-7.5 (m, 6H), 4.82 (s, 2H), 4.10 (t, J=7 Hz, 2H), 1.7 (m, 2H), 1.25 (m, 2H), 0.8 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][CH:15]=3)[NH:1][C:22]2=[O:24])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c12
Yield: 104.2 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-3-methoxybenzamide (302 mg, 0.901 mmol) and triphosgene (321 mg, 1.081 mmol) in THF (20 mL) was stirred at room temperature for 2 h. The mixture was treated carefully with saturated aqueous NaHCO3 and stirred until gas evolution ceased. The mixture was extracted twice with DCM, and the combined organic phases were washed with water, dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-8-methoxyquinazoline-2,4(1H,3H)-dione (339 mg) which was used without further purification. Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([Cl:19])=[N:10][C:4]=2[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: ClC1=Nc2cc(Cl)ccc2Oc2ccccc21
Yield: 89.8 %

Procedure:
To a stirred solution of 8-chloro-10, 11-dihydrodibenz[b,f][1,4]oxazepin-11-one (0.53 g, 2.15 mmol) in toluene (20 mL) was added phosphorus pentachloride (0.54 g, 2.58 mmol) at room temperature under argon. The resulting mixture was heated at reflux for 4 h and the solvent was removed in vacuo. The residue was redissolved in toluene and reconcentrated. The light yellow solid (0.51 g, quantitative yield) was used directly for the next reaction without further purification.