Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[C@@H:5]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])[CH2:6][N+:7]([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[NH2:7][CH2:6][C@H:5]([C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])[C:4]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H](c1ccc(Cl)c(Cl)c1)[C@H]1CCCC[C@H]1O
Reaction time: 15 h

Procedure:
A solution of 28.5 g (0.09 mol) of rac-(2S*)-2-[(R*)-3,4-dichloro-α-(nitromethyl)benzyl]cyclohexanone in 500 ml of dry tetrahydrofuran is added dropwise to a suspension of 8.53 g (0.22 mol) of lithium aluminum hydride in 200 ml of dry tetrahydrofuran under argon so that temperature does not exceed 50°, whereupon the mixture is stirred at 50° for 15 hours. After cooling the reaction mixture is treated with tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The thus-obtained oil is treated with 3N hydrochloric acid, whereupon the mixture is extracted twice with 500 ml of ether each time. The aqueous phase is made alkaline with 3N sodium hydroxide solution and extracted twice with 500 ml of methylene chloride each time. The organic phase is washed twice with 100 ml of water each time, dried over magnesium sulphate and evaporated. There is obtained a viscous oil which crystallizes from isopropyl ether/hexane. There is obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-3,4-dichlorobenzyl]cyclohexanol in the form of colourless crystals of m.p. 117°-118°.
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].CN(C)[CH:42]=[O:43]>C(OC(C)C)(=O)C>[CH2:9]([O:10][C:42](=[O:43])[CH2:3][CH2:2][CH2:34][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])[CH3:8]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 55 °C
Yield: 75 %

Procedure:
To a reactor was charged a solution of 3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione 1e in isopropyl acetate (19.0 kg in 59.6 L solution). Dimethylformamide (18 L) was charged and the mixture was distilled under vacuum to remove the isopropyl acetate. Ethyl-4-bromobutyrate (7.83 kg) was charged to the reactor followed by diisopropylethylamine (5.87 kg). The reactor contents were heated to 55° C. and stirred until completion of reaction. The reactor was cooled to 20° C. and isopropyl acetate (110 L) and water (96 L) were added. The mixture was agitated and the layers allowed to settle. The water layer was removed and the organic layer was washed with water (95 L). The organic layer was treated with a solution of 85% phosphoric acid/H2O (10.4 kg/152 L). The mixture was agitated, allowed to settle, and the layers were separated. The organic layer was treated with a solution of 85% phosphoric acid/H2O (2.7 kg/19 L). The mixture was agitated, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (21 L). After layer separation, dichloromethane (109 L) was added to the aqueous layer, followed by slow addition of a solution of potassium carbonate/water (23.2 kg/29 L) while mixing. The layers were separated and the organic layer was concentrated by vacuum distillation. The solution was passed through a silica gel plug pre-conditioned with CH2Cl2 and the plug eluted using EtOH/CH2Cl2 (5 L/469 L). Appropriate portions were combined and the solution was concentrated by vacuum distillation. Ethanol (80 L) was charged to provide a concentrated stock solution of 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyric acid ethyl ester 4a (82.9 kg total, ˜17.3 kg of 4a, 75% yield) that was used in the next step. LCMS (ESI) m/z 660.2 (MH+)
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[C:9]1([CH2:15][NH:16][CH2:17][C@@H:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@H:19]2[OH:24])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>>[O:5]1[CH2:6][CH2:7][O:8][CH:4]1[CH2:3][CH2:2][N:21]1[CH2:22][CH2:23][C@@H:18]([CH2:17][NH:16][CH2:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:19]([OH:24])[CH2:20]1
Reactant: BrCCC1OCCO1
Reactant: O[C@@H]1CNCC[C@H]1CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O[C@@H]1CN(CCC2OCCO2)CC[C@H]1CNCc1ccccc1
Yield: 46.8 %

Procedure:
A mixture of 2-(2-bromoethyl)-1,3-dioxolane (0.04 mol), intermediate (6) (0.04 mol) and Na2CO3 (10%, 0.08 mol) in MIK (400 ml) was stirred and refluxed for 20 hours and then cooled. The solvent was evaporated. The residue was taken up in DCM and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 96/4). The pure fractions were collected and the solvent was evaporated. Toluene was added and evaporated again, yielding 6 g of (trans)-1-[2-(1,3-dioxolan-2-yl)ethyl]4-[[(phenylmethyl)amino]methyl]-3-piperidinol (intermediate 7).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([C@H:7]2[O:12]C(=O)[C@@H](O)[C@H]2O)[CH2:4][O:3]1.I([O-])(=O)(=O)=O.[Na+].[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:15])[O:6][C@H:5]([CH2:7][OH:12])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H]([C@H]2OC(=O)[C@@H](O)[C@H]2O)O1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Product: CC1(C)OC[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of the product of Example 32, Step B, 5,6-O-isopropylidene-L-gulono-1,4-lactone, in water is added solid sodium periodate in small portions at 3° C. to 5° C. The pH of the mixture is adjusted to 5.5 with 1N aqueous sodium hydroxide. The suspension is stirred for 2 hours at ambient temperature, then saturated with sodium chloride and filtered. To the filtrate, at 3° C. to 5° C., is added sodium borohydride in small portions. The reaction mixture is stirred for 18 hours at ambient temperature. Acetone is added to destroy the excess of sodium borohydride, and the stirring is continued for 30 minutes. The acetone is removed under reduced pressure and the aqueous residue is extracted with dichloromethane and EtOAc. The combined organic layers are dried over magnesium sulfate, filtered, and evaporated to give (R)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[C:8]1[C:13]([CH:14]([OH:18])[CH2:15][CH2:16][OH:17])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)(C)(C)C>[O:17]1[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:13]2[CH:14]([OH:18])[CH2:15][CH2:16]1
Reactant: OCCC(O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: OC1CCOc2ncccc21
Temperature: 25 °C
Yield: 88.7 %

Procedure:
Potassium tert-butoxide (0.88 g) was added to a solution of 1-(2-chloropyridin-3-yl)propane-1,3-diol (0.49 g) in tert-butanol and the solution was heated at reflux for 3 hr, allowed to cool to RT, quenched via the addition al of sat. NH4Cl (2 mL), solvents reduced then silica gel added and remaining solvents removed in vacuo. The material was added to a silica gel column that was eluted with EtOAc and 1% MeOH/EtOAc to yield the titled product (0.35 g) NMR CDCl3 1H δ 8.1 (dd, 1H), 7.7 (dd, 1H), 6.9 (dd, 1H), 4.9 (dd, 1H), 4.5 (m, 2H), 2.1 (m, 2H); MH+=152.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5]1.[H-].[Na+].[CH3:13]I>O1CCCC1>[CH3:13][N:5]1[C:6](=[O:9])[CH2:7][CH2:8][C@H:4]1[C:3]([O:2][CH3:1])=[O:10]
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1CCC(=O)N1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
(L)-pyroglutamic acid methyl ester (1 g, 6.99 mmol) was dissolved/mixed with tetrahydrofuran (10 ml) and cooled to 0° C. using an ice-bath. Sodium hydride (0.201 g of a 60% suspension in oil, 8.38 mmol) was added to the mixture. After bubbling stopped, methyl iodide (0.522 ml, 8.38 mmol) was added and the mixture was allowed to warm to room temperature and then stirred for 1 hr. The solvent was evaporated and water was added (1 ml). The aqueous layer was then extracted with dichloromethane. Evaporation of the dichloromethane gave crude methyl 1-methyl-5-oxo-prolinate (0.308 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[S:30].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[NH:26][C:29](=[S:30])[O:28][N:27]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc2c(Cc3cccc(-c4noc(=S)[nH]4)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 101.2 %

Procedure:
Under an argon atmosphere, to a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamidoxime (174 mg) in acetonitrile (3.7 mL) were added 1,1′-thiocarbonyldiimidazole (125 mg) and 1,8-diazabicyclo[5,4,0]-7-undecene (0.278 mL), and this mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (196 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 4.33 (2H, s), 6.63 (1H, dd, J=2.3, 8.7 Hz), 6.88 (1H, d, J=2.3 Hz), 7.12 (1H, dd, J=2.3, 6.5 Hz), 7.28-7.39 (2H, m), 7.41-7.52 (2H, m), 7.68-7.79 (4H, m), 11.16 (1H, s). ESI-MS (m/z): 415 (M+H)+
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:20]([CH3:29])[CH:19]=1)[CH3:15])=O)(C)(C)C.[O:32]=[C:33]1[O:37][CH:36]([O:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43]C=2)[CH:35]([NH:47][C:48](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:49])[CH2:34]1>>[CH2:39]([O:38][CH:36]1[CH:35]([NH:47][C:48]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:31])[CH:14]([NH:16][C:17](=[O:30])[C:18]2[CH:19]=[C:20]([CH3:29])[C:21]([O:25][CH2:26][CH:27]=[CH2:28])=[C:22]([CH3:24])[CH:23]=2)[CH3:15])=[O:49])[CH2:34][C:33](=[O:32])[O:37]1)[C:40]1[CH:41]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: C=CCOc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)OC(C)(C)C)cc1C
Product: C=CCOc1c(C)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1C
Yield: 46 %

Procedure:
Prepared from 1-[2-(4-allyloxy-3,5-dimethyl-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and 40 according to the procedure used to prepare 98a to afford 264 mg (yield 46%) of the title compound. 1H-NMR (500 MHz, CDCl3): δ 1.09-1.43 (m, 3H), 1.90-2.20 (m, 3H), 2.20-2.38 (m, 7H), 2.38-2.52 (m, H), 2.80-2.95 (m, H), 3.52-3.67 (m, H), 3.70-3.80 (m, H), 4.10-4.40 (m, 2H), 4.40-4.95 (m, 5H), 5.26-5.55 (m, 3H), 6.00-6.14 (m, H), 6.87 (d, H), 7.10-7.70 (m, 8H); retention time on analytical HPLC: 18.56 and 18.92 min1; LC-MS: m/z=564 (M+H+).
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([N:28]4[CH2:33][CH2:32][S:31][CH2:30][CH2:29]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:42])C=1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:19][CH:20]=4)[CH2:12][N:11]([C:26]([N:28]4[CH2:33][CH2:32][S:31](=[O:42])[CH2:30][CH2:29]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(N1CCSCC1)N1CC(c2ccc(CC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Product: O=C(N1CCS(=O)CC1)N1CC(c2ccc(CC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
78.0 mg (0.162 mmol) of the compound from Example 46A were reacted according to General Method 1 with 50.4 mg (0.146 mmol) of meta-chloroperbenzoic acid. Yield: 76.2 mg (88% of theory)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: NCCc1cccs1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1cccs1
Yield: 90 %

Procedure:
In close analogy to the procedure described above, 2-Thiophen-2-yl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.S(=O)(=O)(O)O.[CH3:41]O>O>[OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:41])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@]3(O)CC[C@@H](C(=O)O)C(C)(C)C3)s2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@@H]1CC[C@@](O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reaction time: 16 h
Yield: 83 %

Procedure:
(1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (100 mg, 0.197 mmol) was dissolved in methanol (3 ml) and concentrated sulfuric acid (10.52 μl, 0.197 mmol) added. The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (3×) and washed with saturated aqueous sodium bicarbonate. Solvent evaporation gave the title compound (85 mg, 0.163 mmol, 83% yield). MS ESI: [M+H]+ m/z 521.1. 1H NMR (500 MHz, DMSO-d6) 1H NMR δ 10.25 (s, 1H), 8.83 (d, J=4.9, 1H), 7.93 (s, 2H), 7.46 (s, 1H), 7.28 (d, J=4.9, 1H), 7.14 (s, 1H), 5.92 (s, 1H), 3.59 (s, 3H), 2.31 (s, 4H), 1.84 (s, 3H), 1.65 (m, 3H), 1.08 (s, 3H), 0.96 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[CH:13]=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClCCl.[OH-].[NH4+:24].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:24][C:8]1[C:7]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[N:9]=1
Reactant: CC(C)(O)Cn1cnc2cnc3cc(Br)ccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(O)Cn1cnc2c(N)nc3cc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1-liter round bottom flask was charged with 1-(7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (25.0 g, 78.0 mmol), dichloromethane (400 mL) and chloroform (100 mL). To this solution was slowly added in small portions 3-chloroperoxybenxzoic acid (34.0 g of 60% purity, 117 mmol, 1.5 eq). The reaction was maintained at room temperature for 2 hours and then concentrated ammonium hydroxide solution (200 mL) was added. The mixture was vigorously stirred as p-toluenesulfonyl chloride (22.4 g, 117 mmol) was slowly added in small portions. The reaction was complete within 1 hour but was left to stir at room temperature overnight. The reaction mixture was filtered to collect a pale yellow solid. The product was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-30% CMA in chloroform). The resulting pale yellow solid was slurried in cold acetonitrile, isolated by filtration, and air-dried on the vacuum filter to provide 17.2 g of 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with chloroform (3×100 mL). The chloroform fractions were combined, washed with brine (100 mL), dried over magnesium sulfate and concentrated to dryness to provide an additional 0.8 g of 1-(4-amino-7-bromo-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol, mp>250° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>C(N(CC)CC)C>[Cl:13][C:14]([Cl:19])([Cl:18])[C:15]([NH:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[N:4]2)=[O:16]
Reactant: Cc1cc2c(N)cccc2nn1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(NC(=O)C(Cl)(Cl)Cl)cccc2nn1

Procedure:
The title compound was prepared using 3-methylcinnolin-5-amine (commercially available, Maybridge), triethylamine, trichloroacetyl chloride and the procedure described in Example 1A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:10])=[O:9])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc(Br)c2)CC1
Reaction time: 16 h

Procedure:
3-Bromo-benzenesulfonyl chloride (2.2 g, 8.7 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2 g, 10 mmol) were combined and diluted with DCM (50 mL) and TEA (3.6 mL, 26 mmol). After 16 h, reaction was poured into separatory funnel and washed with water. Organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil which solidified upon standing (3.6 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:21]4[CH2:22][CH2:23][CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][C:20]4=[N:19][C:14]=3[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:46][C:15]1[C:14]2[N:19]=[C:20]3[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][CH2:23][CH2:22][N:21]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[N:16]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1

Procedure:
The methods described in Part I of Example 368 were used to treat tert-butyl 3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (5.52 g, 12.4 mmol, Example 369 Parts A through D) with mCPBA (4.17 g of 77% purity, 18.6 mmol) followed by ammonium hydroxide (25 mL) and p-toluenesulfonyl chloride (2.6 g, 13.7 mmol) and purify the final compound to provide 2.07 g of tert-butyl 6-amino-3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1CC(=O)[C@H](CC1C=CC=CC=1)NC(=O)[C@H](C)NC(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)(C)C>[C:1]([O:5][C:6](=[O:39])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)CN1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1

Procedure:
0.45 g (0.84 mmol) of N-[[N-[N-(benzyloxycarbonyl)-L-alanyl]-L-phenylalanyl]methyl]-L-proline tert.butyl ester, prepared as described in Example 5, was reduced in 15 ml of isopropanol in the presence of 80 mg of sodium borohydride as described in Example 7. After working-up the two isomers were separated by chromatography on silica gel using System A for the elution. There were obtained 70 mg of isomer 1 of N-[3(S)-[[N-(benzyloxycarbonyl)-L-alanyl]amino]-2(R or S)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester in the form of a gum; Rf (System A): 0.38; MS: m/e 540 [M+H]+, and 50 mg of isomer 2 in the form of a gum; Rf (System A) 0.21; MS: m/e 540 [M+H]+.
Reaction SMILES: O[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:3]=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(O)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Product: Cn1c(Cl)nc(-c2ccncc2)c(-c2ccc3ccccc3c2)c1=O
Temperature: 105 °C

Procedure:
A suspension of 2-hydroxy-3-methyl-5-naphthalen-2-yl-6-pyridin-4-yl-3H-pyrimidin-4-one (10.0 g, 30.4 mmol) and phosphorous oxychloride (250 mL, 3 mol) was heated to 105° C. for 6 h to form a solution. Monitoring reaction by HPLC showed ˜90% conversion. The reaction solution was cooled and the solvent removed under reduced pressure. Foam residue was dissolved in 500 mL 5% ethanol/chloroform. The organic layer was washed with 100 mL water three times and once with 100 mL 5% NaHCO3. Organic dried over magnesium sulfate, then dried onto 30 g of silica. Final product purified on 400 g silica eluting with 0 to 2.5% methanol/dichloromethane to give a yellow solid. M+1=348.
Reaction SMILES: [Na].Cl.Cl[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH3:11][O:12][CH2:13][CH2:14][OH:15]>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: COCCO
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na]
Product: COCCOCc1ccncc1

Procedure:
To a solution of sodium (7.57 g) in 2-methoxyethanol (135 ml) was added dropwise a solution of 4-chloromethylpyridine hydrochloride (22.5 g) in 2-methoxyethanol (150 ml) under cooling in an ice-salt bath and stirring. The mixture was stirred for 45 minutes at 65° C. and evaporated under reduced pressure. The residue was dissolved in water (500 ml) and the solution was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residual oil was distilled to give 4-(2-methoxyethoxymethyl)pyridine (21.56 g), bp 98° to 101° C. at 3 to 3.5 mmHg.