Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:10](=O)/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([F:9])=[C:4]2[C:6]([CH:10]=[CH:11][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5]2)=[CH:7][CH:8]=1
Reactant: O=C/C=C/c1ccccc1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1c(Cl)ccc2ccc(-c3ccccc3)nc12

Procedure:
To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) and trans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6N HCl (100 ml). The resulting suspension was heated at reflux for 40 hours. After cooling, the reaction mixture was poured into 5N NaOH solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organics were washed with brine (2×100 ml), dried (MgSO4), filtered and concentrated. The crude product was dissolved in MeOH and loaded onto an SCX-2 cartridge (50 g/150 ml), and the product eluted with MeOH, giving the title compound as a yellow solid. Additionally, the title compound could be prepared as follows: 4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF (240 mL) were combined in a 3 neck 1 L round bottom flask with a magnetic stir bar under an atmosphere of nitrogen. The reaction was stirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M of n-butyllithium in Hexane (7.34 mL) was then added dropwise over 3 minutes so as not to exceed −90° C. The solution turned light green, and darkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) was added 3 minutes after the n-butyllithium addition was done. The cooling bath was removed, and the reaction was allowed to stir for 20 minutes. To work up, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was transferred to a 1 L separatory funnel with 250 mL of ethyl acetate. The layers were separated, and the organic layer was washed with 2×60 mL of brine. The organic solution was suction filtered through a short pad of silica gel, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was placed under high vacuum overnight to afford the crude product. The crude product was pre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL of Toluene was added, and the slurry was concentrated on the rotovap to afford a finely divided powder. This was applied to a silica column and chromatographed (4:3 hexanes/methylene chloride) affording the title compound as a white solid. The solid was re-chromatographed with, and then placed in the vacuum oven at 45° C. overnight to afford the very pure product as a white solid; 1H NMR (CDCl3, 400 MHz) δ 8.24-8.21 (3H, m), 7.96 (1H, d, J=8.6 Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13 [MH+]; HPLC: tR=3.64 min (MicromassZQ, non-polar—5 min).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1O.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[F:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[O:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4]
Reactant: Oc1cc(F)ccc1F
Reactant: C[C@H](CO)N1C(=O)c2ccccc2C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](COc1cc(F)ccc1F)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-(2-Hydroxy-1-methylethyl)-1H-isoindole 1,3(2H)-dione (Becker, Y. J. J. Org. Chem. 1980, 45, 2145-51) was diluted with 40 mL THF then treated in order with 7.0 g triphenyl phosphine, 4.0 g of 2,5-difluorophenol and finally with 5.0 mL of diethylazocarboxylate. The reaction became warm to the point of reflux and was allowed to cool to room temperature and stirred at room temperature overnight. The solvent was removed in vacuo and the resulting brown oil was taken up in ethyl acetate (EtOAc). The solution was washed sequentially with aqueous sodium bicarbonate, aqueous ammonium chloride, and brine. Removal of the solvent gave an oil which was chromatographed on silica gel, eluting with 10% ethyl acetate-hexane, to afford 5.4 g of the title compound of Step A as a clear colorless oil: 1H NMR (CDCl3) δ1.57 (d, 3H), 4.22 (dd, 1H), 4.57 (t, 1H), 4.82 (m, 1H), 6.55 (m, 1H), 6.70 (m, 1H), 6.95 (m, 1H), 7.72 (m, 2H), 7.82 (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:14]=2[CH:25]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:14]=2[CH:25]=1
Reactant: Cc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1

Procedure:
N-Bromosuccinimide (26 g.) was added to a cold solution of 5-methyl-3-(4-chlorophenyl)-1,2-benzisoxazole (35 g.) in carbon tetrachloride (250 ml.). Benzoyl peroxide (500 mg.) was added and the mixture was heated under reflux for 3 hours in the presence of U.V. light. The solid residue was filtered off, and the filtrate was evaporated to give 5-bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole (m.p. 142°C.).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([C:8]([Cl:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncccc1F
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncccc1F
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A suspension of 3-fluoropicolinic acid (4.23 g, 30 mmol) and thionyl chloride (35.7 g, 21.9 ml, 300 mmol) was heated to reflux for 15 h at which time it became a dark brown solution. Then, the heating was stopped and the reaction mixture was allowed to cool to room temperature and it was diluted with toluene. Then, the solvent and excess thionyl chloride were removed under vacuum. The residue was azeotrophed one more time with toluene and the resulting brown residue was dried under high vacuum to obtain 3-fluoropicolinoyl chloride (30) (4.70 g, 98.2% yield) as a brown paste which was used directly in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2([F:22])[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[N:2].[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>ClCCl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[F:22][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(C#N)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C2(F)CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a stirred solution of tert-butyl 4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate (compound 26.3, 1 g, 3.11 mmol, 1.00 equiv, 95%) in dichloromethane (20 mL) was added dropwise TFA (3.75 g, 32.89 mmol, 10.57 equiv). After stirring for 1 h at 25° C., the mixture was concentrated under reduced pressure to yield 0.5 g of the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]2)[CH:7]=1
Reactant: N=C(N)NN
Reactant: Cc1ccc(F)cc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(F)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 94.7 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g) and aminoguanidine hydrochloride (0.54 g) in ethanol (30 ml) were added concentrated hydrochloric acid (1.0 ml) and water (1.0 ml), and the mixture was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The mixture was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make it alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the mixture was added 1N hydrochloric acid (10 ml). The mixture was concentrated, and precipitated crystals were recrystallized from ethanol to give 7-(5-fluoro-2-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 165) (1.4 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:37][CH2:36]3)[CH2:27][CH2:26]2)=[O:24])[C:13]([Cl:38])=[CH:12][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9](O)=[O:10])=[O:5].[NH2:39]CCC(N)=O>>[C:9]([CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:12]=[C:13]([Cl:38])[C:14]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH:35]3[CH2:36][CH2:37]3)[CH2:27][CH2:26]2)=[O:24])=[CH:15][C:2]=1[Cl:1])(=[O:10])[NH2:39]
Reactant: O=C(O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: NCCC(N)=O
Product: NC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 52, from 3-{2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoylamino}-propionic acid (Example 34) and 3-amino-propionamide (commercially available, CAS RN 4726-85-6). Light brown foam (74%). MS (ESI): m/z=554.136 [M+H]+.
Reaction SMILES: O[NH:2][C:3](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]=1)[C:4]([CH3:7])([CH3:6])[CH3:5].N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:4]([C:3]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]2[N:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C(=Nc1ccc(I)cn1)NO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)c1nc2ccc(I)cn2n1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 75.7 %

Procedure:
N-Hydroxy-N′-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamidine (example 39, step 3) (2.8 g, 8.77 mmol) was suspended in 15 ml of toluene and pyridine (2.8 ml, 35.1 mmol, 4 equiv.). The mixture was cooled to 0-5° C. and p-toluenesulfonyl chloride (6.7 g, 35.1 mmol, 4 equiv.) was added. The reaction mixture was stirred for 1 hour at 0-5° C. and 4 hours at room temperature. The reaction mixture was extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0->0:100. The desired 2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (2 g, 76% yield) was obtained as a light yellow oil, MS: m/e=302.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(C)C=CC=CC=1.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]#[CH:37])[CH:33]=[CH:34][CH:35]=1.Cl>C(#N)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 37.5 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
1.98 Kg of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 30 litres of acetonitrile and 10 litres of toluene and 1.0 Kg of 3-aminophenyl acetylene was charged at 25-30° C. and hydrochloric acid was added. The reaction mass was heated and stirred at 35-40° C. for 6 hours. The solid obtained was filtered and washed with a mixture of acetonitrile and toluene. The product was dried at 38-40° C. to obtain 2.5 Kg of erlotinib hydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:23][N:22]4[CH2:32][CH2:33][CH2:34][C:21]=34)=[CH:15][CH:16]=2)[N:11]=1>CN(C=O)C.ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][C:14]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:23][N:22]4[CH2:32][CH2:33][CH2:34][C:21]=34)=[CH:15][CH:16]=2)[N:11]=1
Reactant: CN(C)CCO
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(Cl)nc4c2)CCC3)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(OCCN(C)C)nc4c2)CCC3)n1
Reaction time: 0.17 h

Procedure:
Combine of 2-dimethylaminoethanol (180 mg, 2 mmol) with of sodium hydride (48 mg, 2 mmol) in dry DMF (5 mL) at 0-5° C. Stir for 10 min, add 2-chloro-7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline (Example 83; 60 mg, 0.17 mmol) in DMF (5 mL). Stir the reaction mixture for an additional 1 h. Dilute the mixture with dichloromethane. Wash the organic solution with brine, dry over sodium sulfate, filter and evaporate. Purify the crude product by column chromatography on silica gel to give target compound 35 mg (51%) as white solid. MS (electrospray, m/z) 414.2 (M+1). 1H NMR (CD2Cl2) δ 8.4 (s, 1H), 7.85 (d, 8.8 Hz, 1H), 7.81 (d, 1.6 Hz, 1H), 7.56 (t, 8.0 Hz, 1H), 7.51 (dd, 8.8 Hz, 1.6 Hz, 1H), 7.43 (d, 8.0 Hz, 1H), 7.09 (d, 8.0 Hz, 1H), 4.59 (t, 6 Hz, 2H), 4.27 (t, 7.2 Hz, 2H), 3.13 (t, 7.2 Hz, 2H), 2.80 (t, 6 Hz, 2H), 2.73 (m, 2H), 2.42 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[N:9][C:10]([CH3:11])=[C:4]2[CH:3]=1.[B:12]1(B2OC(C)(C)C(C)(C)O2)[O:16]C(C)(C)C(C)(C)[O:13]1.CC([O-])=O.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH3:11][C:10]1[N:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([B:12]([OH:16])[OH:13])=[CH:3][C:4]=12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1nnn2ccc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nnn2ccc(B(O)O)cc12
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added 5-bromo-3-methyl-[1,2,3]triazolo[1,5-a]pyridine (424 mg, 2 mmol), PdCl2(dppf)-DCM (327 mg, 0.4 mmol), bis(pinacolato)diboron (660 mg, 2.6 mmol), and KOAc (589 mg, 6 mmol). Anhydrous dioxane (10 mL) was added, and the mixture was heated to 100° C. for 3 hours. After cooling to room temperature, the mixture was filtered over a plug of Celite, and concentrated to provide the crude product, which was used directly without further purification. LCMS-ESI+: calc'd for C7H9BN3O2: 178.1 (M+H+); Found: 178.04 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][C:18](=[O:22])[C:19](=[O:21])[CH3:20]>CCCCCC>[OH:21][C:19]([C:2]([CH3:1])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:20])[C:18](=[O:22])[CH3:17]
Reactant: CCCCCCCCCC(C)C(=O)OCC
Reactant: CC(=O)C(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCC(C)(C(=O)OCC)C(C)(O)C(C)=O
Yield: 58.5 %

Procedure:
The reaction of ethyl 2-methylundecanoate (11.4 g, 0.05 mole) with 2,3-butanedione (4.73 g, 0.055 mole) is conducted in the manner described in Example I, and 16.6 g of a crude oil is obtained. The crude oil product is subjected to high pressure liquid chromatography on silica gel using 5% ethyl acetate in hexane as the eluant, yielding a pure product (9.2 g, 59%), b.p. 100° C. (Kugelrohr air bath temperature) at 0.01 mm Hg.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[C:56](Cl)(=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[CH3:58][C:57]([CH3:60])([CH3:59])[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:41]2([C:38]3[CH:37]=[CH:36][C:35]([O:34][CH2:33][C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=[C:23]([CH3:22])[CH:32]=4)=[CH:40][CH:39]=3)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]2=[O:49])[CH2:51][CH2:52]1)=[O:61]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(C(=O)C(C)(C)C)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 38.9 %

Procedure:
Using a procedure analogous to Example 26, the product from Example 14 (120 mg, 0.150 mmol) was treated with pivaloyl chloride (21.7 mg, 1.2 eq) to provide the title barbituric acid (45.0 mg, 40%). MS found: (M+H)+=544.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH2:22][CH:23]=[CH2:24])[C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([NH:11][CH:12]([CH3:14])[CH3:13])[CH3:10])[CH:5]=[CH:6][CH:7]=1.B.C1C[O:29]CC1.[OH-].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([C@@:9]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([NH:11][CH:12]([CH3:14])[CH3:13])[CH3:10])[CH2:22][CH2:23][CH2:24][OH:29])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CC[C@H](c1cccc(Cl)c1)[C@](C)(NC(C)C)c1ccc(Cl)cc1
Agent: B
Agent: OO
Agent: [Na+]
Product: CC(C)N[C@](C)(c1ccc(Cl)cc1)[C@H](CCCO)c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-N-isopropylhex-5-en-2-amine (Example 418, Step E, 160 mg, 0.442 mmol) in THF (4 mL) cooled by an ice-water bath was added borane-tetrahydrofuran complex, (1.0M in THF, 2.21 mL, 2.21 mmol). After 90 minutes, an additional 5 equivalents of borane-THF were added and the cold bath removed. After 30 minutes the reaction was cooled in an ice-water bath and quenched by addition of 0.5 mL water followed by 4N aqueous sodium hydroxide (1.1 mL, 4.42 mmol) and aqueous hydrogen peroxide solution, (30% (w/w), 0.45 mL, 4.42 mmol). The biphasic mixture was stirred rapidly at 0-5° C. for 15 minutes then partitioned between water and ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine then dried with anhydrous magnesium sulfate and concentrated to afford a colorless oil. The product was isolated by chromatography on silica (24 g RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) eluting with 50 to 100% ethyl acetate gradient in hexane to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH:10]C(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([O-:22])=[O:21].[K+].[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[S:6][C@@H:5]2[C@H:7]([NH2:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:20]([OH:22])=[O:21]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
To a slurry of 12 g of the wet treated immobilized cell preparation of Example 10 in 100 ml of water at pH 8.0 and 37°C is added 1 g of potassium penicillin G. The pH of the reaction is maintained at 8.0 by the monitored addition of 1N NaOH and the reaction is complete after about 3 hours. The immobilized cell material is filtered, washed with water and stored as a wet cake until further use. The filtrate is adjusted to pH 2 with 2N HCl and extracted with ethyl acetate. The resulting aqueous layer is adjusted to pH 4.3 with 2N NaOH, concentrated and cooled to give crystalline 6-APA.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:19])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4.ClC1C=C(C=CC=1)C(OO)=[O:25].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[C:7]2=[N:8][C:9]3[CH:10]=[N+:11]([O-:25])[C:12]4[C:17]([C:18]=3[N:6]2[C@@H:5]([CH3:19])[CH2:4][O:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1OC[C@H](C)n2c1nc1cnc3ccccc3c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1OC[C@H](C)n2c1nc1c[n+]([O-])c3ccccc3c12
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A solution of (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (80 mg, 0.316 mmol) and 5 mL of CHCl3 was treated with MCPBA (meta-chloroperoxybenzoic acid) (93 mg, 77% max). After 18 hours, the reaction was treated with ˜10 mL of CHCl3 and 5 mL of 2% Na2CO3 solution and the layers were separated. The aqueous layer was extracted with CHCl3 (5×10 mL). The organic layers were combined then washed with brine, dried over Na2SO4, filtered, and concentrated to give (11S)-8,11-dimethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (85 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[O:13]CC(O)CO)=[CH:8][CH:7]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[O:33]1CCO[CH2:35][CH2:34]1>O>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[O:13][C:34](=[O:33])[CH3:35])=[CH:8][CH:7]=1)=[O:5])[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCC(O)CO)cc1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-[2-(4-Diethylcarbamoylbenzyl)phenoxy]-2,3-dihydroxypropane (263 mg) was dissolved in a mixed solution of dioxane (2.6 ml) and water (2.6 ml), added with sodium periodate (362 mg) and stirred at room temperature for 1 hour. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 239 mg of the title compound. Yield: 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:36][CH2:35][CH2:33][OH:34])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:23])=[O:24])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Reactant: NCCO
Product: CS(=O)(=O)CCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.33 (t, J=4.9 Hz, 1 H), 8.56 (s, 1 H), 7.67 (s, 1 H), 7.22 (dd, J=8.4, 5.4 Hz, 2 H), 7.01 (t, J=8.6 Hz, 2 H), 4.37 (t, J=7.8 Hz, 2 H), 4.12 (s, 2 H), 3.86 (t, J=5.2 Hz, 2 H), 3.63 (m, 2 H), 3.14 (t, J=6.8 Hz, 2 H), 2.95 (s, 3 H), 2.18 (m, 2 H); HRMS C22H24FN3O6S (M+H)+ calcd 478.1370, found 478.1440.