Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][C:2]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].OC1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])C1>>[N:1]1[C:6]([C:7]([O:9][CH:10]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])[CH2:11]2)=[O:8])=[N:5][C:4]([C:12]([O:14][CH:15]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:34])([CH3:33])[CH2:16]2)=[O:13])=[N:3][C:2]=1[C:17]([O:19][CH:20]1[CH2:30][C:27]([CH3:28])([CH3:29])[N:26]([O:31][CH3:32])[C:25]([CH3:33])([CH3:34])[CH2:21]1)=[O:18]
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Product: CON1C(C)(C)CC(OC(=O)c2nc(C(=O)OC3CC(C)(C)N(OC)C(C)(C)C3)nc(C(=O)OC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of triethyl 1,3,5-triazine-2,4,6-tricarboxylate and 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.O.O.[OH-].[Li+].Cl>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2 g of 4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 10 ml of MeOH:water/3:1. 230 mg of lithium hydroxide monohydrate were added to the solution, and the reaction was stirred at RT for 16 h then at 50° C. for 2 h. The solution was cooled to RT, then acidified with half-concentrated hydrochloric acid. The suspension was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield a white solid. Yield 2.2 g
Reaction SMILES: C1([C:6](O)=[O:7])CCCC=1.COC1C=CC(CS)=CC=1.CO[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][S:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH:30]2[C:34]([OH:36])=[O:35])=[CH:23][CH:22]=1.C1CCCCC1>N1CCCCC1.C(O)(=O)C>[CH3:6][O:7][C:23]1[CH:22]=[CH:21][CH:26]=[CH:25][C:24]=1[CH2:27][S:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH:30]1[C:34]([OH:36])=[O:35]
Reactant: COc1ccc(CSC2CCCC2C(=O)O)cc1
Reactant: O=C(O)C1=CCCC1
Agent: COc1ccc(CS)cc1
Solvent: C1CCNCC1
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: COc1ccccc1CSC1CCCC1C(=O)O
Reaction time: 12 h

Procedure:
A solution of 1-cyclopentene carboxylic acid (1.68 g., 15 mmole) and p-methoxy-α-toluenethiol (2.17 ml., 15.6 mmole) in piperidine (3.9 ml.) is flushed with argon and heated under reflux, protected by a drying tube, for 12 hours. The mixture is then partitioned between ethyl ether (100 ml.) and 1N hydrochloric acid (3×40 ml.). The organic phase is stirred with activated charcoal (about 0.5 g.), dried (MgSO4), filtered through Celite, and concentrated in vacuo to an orange-yellow oil. This oil is recrystallized successively (3 times) from cyclohexane/hexane to yield 1.75 g. of 2-[[(4-methoxyphenyl)methyl]thio]cyclopentanecarboxylic acid as a tan, granular solid; m.p. 63°-66°. TLC (silica gel, cyclohexane:acetic acid, 8:1) Rf =0.23.
Reaction SMILES: [Cl:1][C:2]([C:12]([Cl:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].[OH-].[K+].Br[CH2:19][C:20]1[C:21]([Cl:33])=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[Cl:26].N12CCN(CC1)CC2>CCCCCCC.C(#N)C>[Cl:1][C:2]([C:12]([Cl:15])([F:13])[F:14])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH2:19][C:20]2[C:21]([Cl:33])=[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: Clc1ccc(-c2ccccc2)c(Cl)c1CBr
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)Cl)[C@@H]1C(=O)O
Agent: C1CN2CCN1CC2
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCCCCCC
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)Cl)[C@@H]1C(=O)OCc1c(Cl)ccc(-c2ccccc2)c1Cl

Procedure:
This compound was prepared in the manner of Examples 8, 9, and 10 using 2.3 g (0.009 mole) of cis, trans-3-(2,3-dichloro-3,3-difluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid (compound 4.4, Table III), 0.6 g (0.009 mole) of potassium hydroxide, 2.8 g (0.009 mole) of 3-bromomethyl-2,4-dichloro[1,1'-biphenyl] and 0.1 g of 1,4-diazabicyclo[2.2.2]octane in 50 ml of heptane and 50 ml of acetonitrile. The crude product was purified by removing the volatiles by distillation using a Kugelrohr bulb to bulb distilling system at 130°-140° C./0.3-0.5 mm. The pot residue was subjected to column chromatography on silica gel, eluting with hexane, then 25:1-hexane:ethyl acetate. Appropriate fractions were combined and subjected to liquid chromatography using 66.6:1-hexane:ethyl acetate as the eluant. The appropriate fractions were combined to give 0.29 g of (2,4-dichloro[1,1'-biphenyl]-3-yl)methyl cis-3-(2,3-dichloro-3,3-difluoro- 1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([CH2:5][CH3:6])([F:4])[F:3].[Br-].[Mg+2].[Br-].[Br:10][C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=1)[C:14](N(OC)C)=[O:15]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([C:14](=[O:15])[CH2:6][CH2:5][C:2]([F:4])([F:3])[F:1])[CH:20]=[CH:21][CH:22]=1
Reactant: CON(C)C(=O)c1cccc(Br)c1
Reactant: CCC(F)(F)F
Agent: [Br-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)F)c1cccc(Br)c1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A prepared solution of trifluoromethyl ethane-magnesium bromide (made by refluxing Mg with 1-bromo, 2-trifluoromethyl ethane in THF for 2 hours; 4.6 g=25.82 mmol) in THF was added slowly to a cold (0° C.) solution of 3-bromo-N-methoxy-N-methylbenzamide (3.5 g, 14.3 mmol) in THF. The stirring continued at room temperature for 1 hour, quenched with cold saturated aqueous NH4Cl, acidified with 1 N HCl and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo. The crude product was purified on silica gel (ISCO) using hexanes/EtOAc (10/1) as the eluting solvent to give 1-(3-Bromo-phenyl)-4,4,4-trifluoro-butan-1-one as a colorless oil (3.1 g, 77% yield). m/e (M−H)-279, 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.5-2.6 (m, 2H), 3.3-3.4 (m, 2H), 7.5 (t, J=7.9 Hz, 1H), 7.8-7.8 (m, 1H), 7.9-8.0 (m, 1H), 8.1 (t, J=1.7 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=[O:7].Cl.[CH3:10]O>>[CH3:10][O:7][C:6]([CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:8]
Reactant: CO
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: COC(=O)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tetrahydrofuran-2-carboxylic acid (37.7 g, 325 mmol) in methanol containing hydrogen chloride (200 mL) was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was taken up in dichloromethane (150 mL). The solution was washed with sodium hydrogen carbonate solution and water (in each case 2×100 mL), dried over sodium sulphate, filtered and concentrated to dryness.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][OH:18]>>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][O:18][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1cccs1
Product: O=[N+]([O-])c1ccc(OCc2cccs2)c(Cl)c1
Yield: 40 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 8 which is concerned with the preparation of starting materials, 3-chloro-4-fluoronitrobenzene was reacted with 2-thienylmethanol to give 2-chloro-4-nitrophenyl 2-thienylmethyl ether in 40% yield.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.BrC1C=C(O)C=CC=1.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23](=[O:44])[C:24](=[O:43])[N:25]2[CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]([OH:44])([C:8]1[C:9]([OH:11])=[CH:10][C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=1)[C:24](=[O:43])[N:25]2[CH:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C1(O)c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydro-1,4-benzodioxin-6-ol to replace 3-bromophenol, and 4-bromo-1-benzhydrylindoline-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 4-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (99%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ9.06 (s, 1H), 7.44-7.28 (m, 10H), 6.98-6.82 (m, 2H), 6.68 (s, 1H), 6.33 (d, J=7.4 Hz, 1H), 6.16 (s, 1H), 4.23-4.08 (m, 4H); MS (ES+) m/z 566.1 (M+23), 568.1 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][Cl:19])=[N:16][C:15]([C:20]([O:22]CC)=[O:21])=[N:14]1)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][Cl:19])=[N:16][C:15]([C:20]([OH:22])=[O:21])=[N:14]1)=[O:5]
Reactant: CCOC(=O)c1nc(CCl)n(-c2sc(CC)cc2C(=O)c2ccccc2Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2nc(C(=O)O)nc2CCl)s1

Procedure:
Hydrolysis of 0.438 g. of ethyl 1-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate is hydrolyzed with sodium hydroxide in the same manner as in a) gives 1-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid as an oily substance. Infra red absorption spectrum (neat): 1735cm-1 (COOH), 1665cm-1 (C=O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][C:9]=2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:43][C:44]1[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]2[CH:52]=[C:53]3[C:58](=[CH:59][CH:60]=2)[N:57]=[CH:56][N:55]([CH3:61])[C:54]3=[O:62])[CH:49]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C:13]([F:14])([F:15])[F:16])=[N:10][C:9]=2[C:17]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([CH3:63])=[C:48]([NH:50][C:51]3[CH:52]=[C:53]4[C:58](=[CH:59][CH:60]=3)[N:57]=[CH:56][N:55]([CH3:61])[C:54]4=[O:62])[CH:49]=2)=[O:19])=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: O=C(O)c1nc(C(F)(F)F)oc1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2nc(C(F)(F)F)oc2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Yield: 27 %

Procedure:
To a flask containing DCM (3 mL) at 0° C. was added 5-(4-fluorophenyl)-2-(trifluoromethyl)oxazole-4-carboxylic acid (S-68) (17 mg, 0.06 mmol), EDC (10.6 mg, 0.07 mmol), HOAt (10.9 mg, 0.08 mmol), and DIPEA (0.043 mL, 0.25 mmol). The resulting solution was allowed to react at 0° C. for 1 hr, at which point 6-((5-amino-2-methylphenyl)amino)-3-methylquinazolin-4(3H)-one (HGM-7) (17.3 mg, 0.06 mmol) was added. The reaction was allowed to react for 18 hours at ambient temperature at which point saturated sodium bicarbonate (5 mL) was added and extracted with DCM (2×10 mL) then EtOAc (2×10 mL). The organic extracts were washed with brine, combined, dried over Na2SO4, and concentrated. The crude material was fractionated by SiO2 chromatography (stepwise gradient of DCM to 10% MeOH, the desired product elutes in 6% MeOH) (9 mg, 27% yield). 1HNMR (400 MHz, CDCl3/MeOD): d 8.29 (m, 2H), 7.98 (s, 1H), 7.62 (d, 1H, J=2.4 Hz), 7.57 (m, 2H), 7.51 (s, 1H), 7.42 (dd, 1H, J=2.8, 9.2 Hz), 7.39 (dd, 1H, J=2.4, 8.4 Hz), 7.24 (d, 1H, J=8.0 Hz), 7.19 (t, 2H, J=8.4 Hz), 3.58 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:39][C:40]([F:48])([F:47])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([N:44]5[CH2:45][CH2:46][CH:41]([C:40]([F:48])([F:47])[F:39])[CH2:42][CH2:43]5)=[O:34])=[CH:31][CH:32]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: FC(F)(F)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Yield: 81.4 %

Procedure:
Stir a solution of 4-[(R)-3-(4′-Carboxy-3,5-dichloro-biphenyl-4-ylmethyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 25) (0.1 g, 0.18 mmol), 4-(Trifluoromethyl)piperidine Hydrochloride (42 mg, 0.22 mmol), N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol), 1-Hydroxybenzotriazole (73 mg, 0.22 mmol) and 4-Methylmorpholine (0.08 mL, 0.73 mmol) in CH2Cl2 (3 mL) at room temperature for 6 hr. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.10 g (80%) of desired product. MS (m/e): 582 (M−BOC+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C@H:24]3[C:33]4[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=4)[O:27][CH2:26][CH2:25]3)[C:20]([N+:35]([O-])=O)=[CH:19][N:18]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C1COCC1.O.CO>[NH2:35][C:20]1[C:21]([NH:23][C@H:24]2[C:33]3[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=3)[O:27][CH2:26][CH2:25]2)=[N:22][C:17]([NH:16][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCOc3c(F)cccc32)n1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc(N)c(N[C@@H]2CCOc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 4-fluoro-2-(4-(8-fluorochroman-4-ylamino)-5-nitropyrimidin-2-ylamino)phenylcarbamate (141 mg) in THF (20 mL) was added a premixed solution of sodium hydrosulfite (0.6 g) and sodium bicarbonate (0.3 g) in water (50 mL). MeOH (5 mL) was also added to aid solution of the mixture, which was stirred at room temperature for 30 min, when sodium chloride was added to saturate the solution. The resultant mixture was extracted with EtOAc (2×), the combined organics were dried, filtered and evaporated to yield (R)-tert-butyl 2-(5-amino-4-(8-fluorochroman-4-ylamino)pyrimidin-2-ylamino)-4-fluorophenylcarbamate that was used as such for the next step, MH+=485.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Br)=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1.C([O-])(O)=[O:17].[Na+]>CC(C)=O.O>[Br:1][C:2]1[C:11]([CH2:12][OH:17])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2ccc(Br)c(CBr)c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2ccc(Br)c(CO)c2n1
Yield: 56 %

Procedure:
A suspension of 7-bromo-8-bromomethyl-2-methoxyquinoline (35.2 g; prepared according to WO 2007/081597) and NaHCO3 (14.63 g) in acetone (430 mL) and water (430 mL) was refluxed for 6 h. The org. solvent was removed under reduced pressure and the aq. layer was extracted twice with EA. The combined org. layers were sequentially washed with water and brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was crystallized from TBDME, affording an off-white solid (16.01 g; 56% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:10]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH2:30][C:31](=O)[CH:32]([CH3:34])[CH3:33])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>C(OCC)C>[CH:32]([C:31]1[C:30]([S:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][S:10]([C:13]3[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=3)(=[O:12])=[O:11])=[CH:22][CH:23]=2)(=[O:28])=[O:29])=[CH:4][C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)([CH3:34])[CH3:33]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)CC(=O)C(C)C)cc2)cc1
Reactant: Nc1ccccc1C=O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Oc2ccc(S(=O)(=O)c3cc4ccccc4nc3C(C)C)cc2)cc1
Temperature: 185 °C

Procedure:
In a sealed tube a mixture of 0.02 mol of 2-aminobenzaldehyde and 0.02 mol of 1-(4-tosyloxybenzenesulphonyl)-3-methyl-butan-2-one was heated at 185° C. for 2 hours. The mixture was then taken up in dry ethyl ether and filtered. M.P. of the hydrochloride: about 90° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][C@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].N[C@H](CO[C@H](C1C=CC(F)=CC=1)C)CO.[C:31](O)(=[O:40])[C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[OH:33]>C(O)(C)C>[OH:33][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31]([O:4][CH2:3][C@H:2]([NH2:1])[CH2:5][O:6][C@H:7]([C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH3:8])=[O:40]
Reactant: C[C@H](OC[C@H](N)CO)c1ccc(F)cc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: C[C@H](OC[C@@H](N)CO)c1ccc(F)cc1
Solvent: CC(C)O
Product: C[C@H](OC[C@@H](N)COC(=O)[C@H](O)c1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a stirred solution of the 80:20 mixture of (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol & (S)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (2.94 g) in isopropanol (3 ml) was added a solution of D-(−)-mandelic acid (2.10 g) in isopropanol (2 ml). The solvent was evaporated and replaced with ethyl acetate to afford white crystals which were collected by filtration. The crystals were dissolved in hot EtOAc (65 ml) at 80° C. and the mixture was allowed to cool slowly. Crystals appeared on reaching a temperature of 70° C. and the suspension was then stirred at room temperature for 16 h. The crystals were collected by filtration and redissolved in hot EtOAc (80 ml) at 80° C. and the mixture was allowed to cool slowly until cyrstallisation started and then the resulting suspension was stirred at room temperature for 16 h. The crystals were collected by filtration to afford pure (R)-2-amino-3-[(S)-1-(4-fluoro-phenyl)-ethoxy]-propan-1-ol (R)-hydroxy-phenyl-acetate (3.08 g, 61%) as a white solid. 1H NMR (300 MHz, DMSO, δ ppm): 1.34 (d, J=6.3 Hz, 3H), 3.13 (m, 1H), 3.23 (m, 1H), 3.37 (m, 4H), 3.83 (m, 1H), 4.46 (q, J=6.3 Hz, 1H), 4.54 (s, 1H), 7.20 (m, 5H), 7.35 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[C:5](=[O:15])[C:4]([CH3:16])=[CH:3]1.CN1C2C(=CC=C([N+]([O-])=O)C=2)C(=O)C(C)=C1.[H][H]>CO.[Pd]>[NH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5](=[O:15])[C:4]([CH3:16])=[CH:3][N:2]2[CH3:1]
Reactant: Cc1cn(C)c2cccc([N+](=O)[O-])c2c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1cn(C)c2cc([N+](=O)[O-])ccc2c1=O
Solvent: CO
Product: Cc1cn(C)c2cccc(N)c2c1=O
Yield: 28 %

Procedure:
A mixture of 1,3-dimethyl-5-nitroquinolin-4(1H)-one and 1,3-dimethyl-7-nitroquinolin-4(1H)-one Compound 299B, 2.2 g, 10 mmol) in MeOH (150 mL) was hydrogenated over 5% Pd/C (0.8 g) at 40° C. under 40 psi hydrogen pressure overnight. The catalyst was filtered off and the filtrate was concentrated and purified by HPLC to give the title compound (540 mg, 28%) as a pure regioisomer. 1H NMR (DMSO-d6, 400 MHz): δ=1.92 (s, 3 H), 3.69 (s, 3 H), 6.63 (d, J=8.0 Hz, 1 H), 6.80 (d, J=8.4 Hz, 1 H), 7.40 (t, J=8.0 Hz, 1 H), 7.91 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:32])([F:33])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCCO2)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2ccc(CO)cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 15, 129 mg, 0.25 mmol) in ethyl ether (6 mL) cooled to 0° C. was treated with a 1.0M solution of lithium aluminum hydride solution in diethyl ether (0.30 mL, 0.30 mmol). The orange-colored reaction mixture was stirred at 0° C. for 1 h. The reaction was then quenched by the dropwise addition of water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S Silica, 8/2 hexanes/ethyl acetate) afforded N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionamide (44 mg, 36%) as a cream foam: EI-HRMS m/e calcd for C22H25F3N2O5S (M+H)+ 487.1509. found 487.1514.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([NH:20][C@H:21]([C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH3:22])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:83])[CH3:82])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43]C(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CC1C=CC(O)=CC=1)NC(OC(C)(C)C)=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:84])[C@H:39]([CH2:80][CH:81]([CH3:82])[CH3:83])[NH:40][C:41](=[O:79])[C@H:42]([CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[NH:43][C:27](=[O:28])[CH2:26][NH:25][C:23](=[O:24])[C@H:21]([CH3:22])[NH:20][C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When an equivalent quantity of N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycine is substituted for the N-t-butoxycarbonyl-L-tyrosylglycyl-L-alanine of Example 12 and the procedure detailed therein substantially repeated, there is obtained N-t-butoxycarbonyl-L-tyrosyl-L-alanylglycyl-L-phenylalanyl-L-leucine benzyl ester.