Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:16]=1[CH2:17][NH2:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:18][CH2:17][C:16]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:15]=3[Cl:14])[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1c(F)cccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3c(F)cccc3Cl)ccc12

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.58 mmol), 2-chloro-6-fluoro-benzylamine (102 mg, 0.64 mmol), Pd2(dba)3 (53 mg, 0.058 mmol), rac-BINAP (108 mg, 0.17 mmol) and NaOt-Bu (140 mg, 1.45 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc (25 mL) and washed with water (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatography on silica (EtOAc/hexanes) yielded the title compound. 4-Chloro-6-(2-chloro-6-fluoro-benzylamino)-2H-phthalazin-1-one: 31 mg (15.8%): m/z (M+H)=338. 1H-NMR (DMSO-d6) δ: 12.38 (s, 1H), 7.94 (d, 1H), 7.42 (m, 3H), 7.30 (m, 1H), 7.21 (dd, 1H) 6.93 (s, 1H), 4.49 (d, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:26]3[C:25]([F:24])=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ncccc1F
Product: C[C@@]1(c2cc(NC(=O)c3ncccc3F)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F (R3=Me) and 3-fluoro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Sn](C)(C)C)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].Br[C:22]1[C:23]2[C:28]([CH:29]=[C:30]3[C:35]=1[CH:34]=[CH:33][CH:32]=[CH:31]3)=[CH:27][CH:26]=[CH:25][CH:24]=2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.N#N>CN(C=O)C.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.C(Cl)Cl>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:22]2[C:35]3[C:30]([CH:29]=[C:28]4[C:23]=2[CH:24]=[CH:25][CH:26]=[CH:27]4)=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc([Sn](C)(C)C)cc1)NC(C)=O
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1)NC(C)=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A solution of 95 (192 mg, 0.50 mmol), 9-bromoanthracene (141 mg, 0.55 mmol), palladium acetate (6 mg, 0.025 mmol), and tri-o-tolylphosphine (15 mg, 0.05 mmol) in DMF (2 mL) was flushed with N2 for 15 min then heated to 70° C. and allowed to stir for 16 h. The reaction was diluted with diethyl ether (20 mL) and washed with water (5×20 mL), dried and evaporated. The crude product was purified by flash column chromatography (15% EtOAc/hexane then 5% MeOH/DCM) to yield the title compound (133 mg, 0.33 mmol, 67%) as an orange oil. [α]D27 +66.9 (c. 0.1, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 8.48 (s, 1H, ArH10″); 8.03 (dd, J=0.9, 8.7 Hz, 2H, ArH3″ and ArH6″); 7.63 (dd, J=0.6, 9.0 Hz, 2H, ArH8″ and ArH1″); 7.45 (m, 2H, ArH4″ and ArH5″); 7.36 (m, 6H, ArH2″ and ArH7″, 4×ArH″); 5.40 (d, J=7.8 Hz, 1H, NH); 5.04 (m, 1H, H2); 3.79 (s, 3H, OCH3); 3.32 (dd, J=5.7, 13.8 Hz, 1H, H3a); 3.25 (dd, J=6.3, 13.8 Hz, 1H, H3b); 2.08 (s, 3H, COCH3). Mass Spectrum (CI, +ve) m/z 398 (100%) [MH+]. HRMS calcd for C26H23NO3 397.1678, found 397.1675.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20](Br)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: CC(C)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)n1ccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
To a solution of (±)-3-benzyl-2-(1-bromo-2-methyl-propyl)-7-chloro-3H-quinazolin-4-one (a compound of Formula 105, 250 mg, 0.616 mmol) in DMF (3 mL) was added triethylamine (0.130 mL, 0.924 mmol) and imidazole (63.0 mg, 0.924 mmol) followed by tetrabutylammonium iodide (228 mg, 0.616 mmol). The resultant solution was heated to 90° C., stirred for 18 h and allowed to cool to room temperature. The reaction mixture was quenched with water (3 mL) and diluted with ether (10 mL). The aqueous layer was extracted with ether (10 mL) ad the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:1 hexanes:ethyl acetate) to provide 38 mg (16%) of the title compound as a yellow solid. MS(ES+) m/e 393.0 [M+H]+.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO.[OH-].[Na+]>O1CCCC1.O>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 30 °C
Reaction time: 6 h
Yield: 63.1 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.35 g.), conc. hydrochloric acid (3.926 g.), methanol (20 ml.), water (10 ml.) and tetrahydrofuran (40 ml.) was stirred at 30° C. for 6 hours. The resultant solution was concentrated in vacuo in order to evaporate the methanol, and the aqueous solution obtained was adjusted to pH 4.2 with 10% aqueous solution of sodium hydroxide. The solution was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]2)=[N:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[NH2:15][C:16]1[CH:17]=[C:18]([C:2]2[S:6][C:5]([N:7]3[CH2:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]3)=[N:4][CH:3]=2)[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1
Reactant: Nc1cc(B(O)O)cc([N+](=O)[O-])c1
Reactant: O=C1CN(c2ncc(Br)s2)CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 24.9 %

Procedure:
4-(5-Bromo-1,3-thiazol-2-yl)-1,4-diazepan-2-one (Step 5 of Intermediate XX, 1.96 g, 7.10 mmol), (3-amino-5-nitrophenyl)boronic acid (1.291 g, 7.10 mmol), tetrakis-(triphenylphosphine)palladium(0) (0.410 g, 0.355 mmol), 1,2-dimethoxyethane (42 mL) and 2M aqueous sodium carbonate (10.65 mL, 21.29 mmol) were successively introduced in a high pressure reaction vessel. The headspace was flushed with nitrogen, the vessel capped and the mixture was stirred at 100° C. for 18 h. The reaction was then cooled to room temperature and 25% aqueous ammonium acetate was added. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification via CombiFlash (ethanol/ethyl acetate) afforded 590 mg (1.77 mmol, 25% yield) of 4-[5-(3-amino-5-nitrophenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one as a yellow solid. MS APCI: [M+H]+ m/z 334.1.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[C:30]([CH2:32][CH3:33])[CH:29]=[CH:28][C:27]=1O.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[CH2:32]([C:30]1[CH:29]=[CH:28][C:27]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:25][C:26]=2[CH:31]=1)[CH3:33]
Reactant: CCc1ccc(O)c(N)c1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCc1ccc2oc(-c3ccc4c(c3)nc(C)n4C3CCOCC3)nc2c1
Yield: 18.1 %

Procedure:
To 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (182 mg, 0.612 mmol) was added thionyl chloride (2 mL), and this was stirred at reflux for 3 hours. After the reaction was complete, concentration at reduced pressure gave a residue that was added to 2-amino-4-ethylphenol (106 mg, 0.612 mmol), triethylamine (309 mg, 3.06 mmol) and tetrahydrofuran (5 mL), and this was stirred at room temperature for 14 hours. After the reaction was complete, this was concentrated, and to a dioxane (5 mL) solution of the residue obtained was added methanesulfonic acid (353 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (40 mg, 18% yield) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1.[CH3:28]C1N=C(CO)C=CC=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Reactant: Cc1cccc(CO)n1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4cccc(C)n4)nn23)on1

Procedure:
The title-compound was prepared from the product of Example 120, step a, and 6-methyl-2-pyridylcarbinol using the procedure given for Example 1, 1H NMR (360 MHz, CDCl3) δ 2.48 (3H, s, CH3), 2.64 (3H, s, CH3), 5.74 (2H, s, CH2), 7.07 (1H, s, Ar—H), 7.18 (1H, d, J=7.7 Hz, Ar—H), 7.44 (1H, d, J=7.6 Hz, Ar—H), 7.69 (1H, t, J=7.7 Hz, Ar—H), 7.85 (1H, m, Ar—H), 7.99 (1H, m, Ar—H), 8.35 (1H, d, J=8.6 Hz, Ar—H), 8.71 (1H, d, Ar—H); MS (ES30) m/e 373 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:9]=[C:10](Br)[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:22]([O:29][CH:30]1[CH:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:32][C:31]1=[O:61])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1>[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:32][C:31]1([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:9]=1)[OH:61])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(Cc2cccc(Br)c2)cc1
Reactant: O=C1CC(COCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cccc(C3(O)C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Reaction time: 0.42 h
Yield: 29.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-1-bromobenzene (155 mg, 0.559 mmol) in THF (0.80 mL), an n-butyllithium 2.44 M hexane solution (0.23 mL, 0.559 mmol) was added dropwise at −78° C. and the mixture solution was stirred for 25 minutes. Then, a solution of 2,3,4-tribenzyloxy-5-(benzyloxy-methyl)cyclohexanone (200 mg, 0.373 mmol) in THF (0.70 mL) was added dropwise thereto and the reaction mixture was stirred for 75 minutes. To the reaction mixture was added a saturated ammonium chloride aqueous solution and the mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. The solvent was concentrated and the obtained residue was purified by silica gel chromatography [developing solution=ethyl acetate:n-hexane (2:5)] to obtain the title compound (80 mg, 27%) as a mixture of 1R-isomer and 1S-isomer.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[C:17]([OH:24])=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>O1CCCC1>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:18]([CH2:19][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:17]=1[OH:24]
Reactant: C1COCCN1
Reactant: O=Cc1cccc(Br)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1c(Br)cccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (3.18 g) was added to a solution of 3-bromo-2-hydroxybenzaldehyde (2.0 g) and morpholine (1.04 ml) in tetrahydrofuran (30 ml) and the mixture stirred at ambient temperature for 18 h. After filtering from a little insoluble material, the filtrate was evaporated. The residue was partitioned between dichloromethane and water and the solvent phase was washed with water, dried and evaporated to an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[C:22]([N:24]3[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]3)[CH:21]=[CH:20][C:19]=2[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=1.BrC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.[F:59]C1C=C(N)C=CC=1F>>[F:59][C:5]1[CH:4]=[C:3]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH:28]=[C:27]([CH2:29][CH2:30][OH:31])[N:26]=[N:25]4)[CH:21]=[CH:20][C:19]=3[CH3:32])=[O:17])=[C:12]([CH3:33])[CH:11]=2)[CH:2]=[CH:7][C:6]=1[F:8]
Reactant: Nc1ccc(F)c(F)c1
Reactant: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Agent: Cc1cc(Br)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1cc(Nc2ccc(F)c(F)c2)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 452 (0.13 mmol) and 3,4-difluoro-phenylamine (0.13 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM/petroleum ether (40-60) 0:50:50, 0:100:0 and 5:95:0 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 196.4, 149.6 (dd), 147.5, 145.7, 144.7 (dd), 142.3, 142.2, 138.4 (dd), 135.3, 135.2, 134.4, 132.1, 127.0, 120.7, 120.5, 118.4, 117.9 (d), 117.7, 116.0 (dd), 111.4, 108.5 (d), 60.2, 29.2, 22.0, 18.9
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[F:26])[C:20](Cl)=[O:21]>C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([F:26])=[C:17]([F:16])[CH:18]=2)=[CH:3][N:4]=1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: Nc1cnc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cnc(Cl)nc1)c1ccc(F)c(F)c1
Yield: 61.8 %

Procedure:
A solution of 450 g (3.49 mol) of 5-amino-2-chloropyrimidine and 790 g (6.98 mol) of triethylamine in anhydrous THF was cooled to less than 5° C. in an ice bath. To this solution was added 3,4-difluorobenzoyl chloride at a rate (2 h) that maintained the temperature of the reaction mixture below 10° C. Once the addition was complete the reaction was monitored for full conversion of the starting material to product by HPLC. Following confirmation of complete conversion, the reaction mixture was concentrated under reduced pressure. The viscous residue was dissolved in ethyl acetate (4 L) and washed with water (4 L) and 2M HCl (4 L). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in ethanol (4 L) and 250 g of charcoal was added. The mixture was heated to reflux for 10 minutes and filtered through a bed of Celite® and the filtrate was concentrated under reduced pressure. The solids were recrystallized twice from acetonitrile (1 L) to yield 580 g (61.8%) of the desired product as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]([NH:29][C:30](=[O:39])[O:31]CC1C=CC=CC=1)[CH2:13][CH2:14][C@@H:15]1[C@@H:17]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([CH3:28])[CH:19]=2)O1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C@H:12]1[N:29]2[C:30](=[O:31])[O:39][C@H:17]([C:18]3[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[C:20]([CH3:28])[CH:19]=3)[C@@H:15]2[CH2:14][CH2:13]1
Reactant: Cc1cc([C@H]2O[C@@H]2CC[C@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc([C@H]2OC(=O)N3[C@H](c4cc(C(F)(F)F)ccc4Br)CC[C@@H]23)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To benzyl [(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]-3-{(2R,3R)-3-[3-methyl-5-(trifluoromethyl)phenyl]oxiran-2-yl}propyl]carbamate (100 mg, 0.162 mmol) in DMF (2 mL) was added LiHMDS (1.0 M, 0.324 mL, 0.324 mmol) at 0° C. The mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The resultant residue was purified by preparative TLC to yield (1R,5S,7aS)-5-[2-bromo-5-(trifluoromethyl)phenyl]-1-[3-methyl-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one (75 mg, 0.148 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 2H), 7.46 (s, 1H), 7.44 (d, J=8.8 Hz, 3H), 6.06 (d, J=8.1 Hz, 1H), 5.33 (t, J=8.0 Hz, 1H), 4.57 (m, 1H), 2.99 (m, 1H), 2.48 (s, 3H), 1.68 (m, 1H), 1.57 (m, 1H), 1.38 (m, 1H).
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([CH3:9])[C:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])(S(C3C=CC=CC=3)(=O)=O)[CH2:4]2)[O:2]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O>[OH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:5]1[CH:6]([CH3:9])[CH2:7][CH2:8][C:3](=[O:2])[CH:4]=1
Reactant: CC1CCC2(CC1(CCCCCCCCCCCCCCO)S(=O)(=O)c1ccccc1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC1CCC(=O)C=C1CCCCCCCCCCCCCCO

Procedure:
Paratoluenesulfonic acid (20 mg) was added to a solution of 235 mg of 1,1-(ethylenedioxy)-3-(14-hydroxytetradecyl)-4-methyl-3-(phenylsulfonyl)-cyclohexane in 20 ml of chloroform and 4 ml of acetone. The resulting mixture was reacted at 50° C. for 24 hours. To the reaction mixture was added 10 ml of a saturated aqueous solution of sodium bicarbonate, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column while using hexane-ethyl acetate, whereby 3-(14-hydroxytetradecyl)-4-methyl-2-cyclohexen-1-one was obtained in the form of a colorless oil (yield: 75%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:8][CH:9]=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>O1CCCC1.O>[Cl:20][C:14]1[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=1[O:12][C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)c1cncnc1Oc1cc(Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cncnc1Oc1cc(Cl)ccc1Cl
Temperature: 80 °C
Yield: 82.3 %

Procedure:
To a solution of 515 mg (1.64 mmol) 4-(2,5-dichloro-phenoxy)-pyrimidine-5-carboxylic acid ethyl ester in 10 mL tetrahydrofuran/water (2/1 v/v) was added 3.29 mL (3.28 mmol) 1M aqueous sodium hydroxide solution and the resulting solution was heated by microwave irradiation (Emrys Optimizer, Personal Chemistry) 30 minutes at 80° C. Solvents were evaporated under vacuum and the residue extracted three times with ethyl acetate and 1M aqueous hydrochloric acid. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 385 mg (57%) of the desired compound as an off-white powder. MS (ESI): m/z=238.8 [M−H]−.
Reaction SMILES: [NH2:1][C:2]([C@@H:4]1[CH2:9][C@H:8]([N:10]([C:15]([C:17]2[C:18]([NH:27][CH2:28][C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:21][CH:22]=2)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)=[O:3].C(OCC)(=O)C.[ClH:47]>>[ClH:47].[ClH:47].[NH2:1][C:2]([C@@H:4]1[CH2:5][NH:6][CH2:7][C@H:8]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:15]([C:17]2[C:18]([NH:27][CH2:28][C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[N:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[N:21][CH:22]=2)=[O:16])[CH2:9]1)=[O:3]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1CNC[C@@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl (3R*,5S*)-3-(aminocarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-1-carboxylate (230 mg) was dissolved in 1 M hydrogen chloride-ethyl acetate (4 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, ethyl acetate was added and the precipitate was collected by filtration and washed with ethyl acetate to give the object compound (218 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: OCCCC1CCCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC1CCCc2ccccc21
Yield: 102 %

Procedure:
Compound 94-1 (140 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (212 mg) and N-bromosuccinimide (144 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature 16 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (190 mg) as a colorless oil.