Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:9]([CH3:25])([O:14][N:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]1([CH3:24])[CH3:23])[CH2:10][CH2:11][CH2:12][OH:13])#[N:8].C(N(CC)CC)C.O>C(OCC)C>[C:1]([O:13][CH2:12][CH2:11][CH2:10][C:9]([C:7]#[N:8])([O:14][N:15]1[C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][C:16]1([CH3:24])[CH3:23])[CH3:25])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C#N)(CCCO)ON1C(C)(C)CCCC1(C)C
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCC(C)(C#N)ON1C(C)(C)CCCC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Methacryloyl chloride (174 mg, 1.7 mmol) in diethyl ether (5 ml) was slowly added to a cooled (0° C.) solution of 1-(1-cyano-4-hydroxy-1-methylbutoxy)-2,2,6,6-tetramethylpiperidine (Example 6) (150 mg, 0.56 mmol) in diethyl ether (10 ml) containing triethylamine (339 mg, 3.3 mmole). The reaction was stirred at ambient temperature for 1 hr after which was added triethylamine (2 ml) and water (10 ml) and stirred for a further hour. The layers were separated and the ether layer washed with saturated bicarbonate, water, brine, dried over magnesium sulphate and concentrated. Chromatography using silica gel and dichloromethane as eluent gave the title compound as a colourless oil (132 mg, 70% yield). 1H NMR δ (CDCl3): 1.1 (9H, s), 1.3 (4H, s), 1.5 (5H, broad s), 1.95 (7H, m), 4.2 (2H, m, OCH2), 5.5 (1H, m, olefinic CH2), 6.1 (1H, broad s, olefinic CH2). Mass spectrum CI (CH4) m/e: 337 (MH+), 156, 140.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:21])=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:22])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(C1C=CC(C2C3C(C)=CC(C)=C(C)C=3OC2C)=CC=1)(C)C.BrC1C(C)=C(C)C2OC(C)C(C3C=CC(C(C)C)=CC=3)C=2C=1C.C(NC1C(C)=C(C)C2OC(C)C(C3C=CC(C(C)C)=CC=3)C=2C=1C)C1C=CC=CC=1.C(C1C=CC(C2C3C(C)=C(N)C(C)=C(C)C=3OC2C)=CC=1)(C)C.C(CC(Cl)=O)(C)(C)C.C(C1C=CC(C2C3C(C)=C([NH:149][C:150](=[O:156])[CH2:151][C:152]([CH3:155])([CH3:154])[CH3:153])C(C)=C(C)C=3OC2C)=CC=1)(C)C>CCCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:21])=[C:16]([NH:149][C:150](=[O:156])[CH2:151][C:152]([CH3:155])([CH3:154])[CH3:153])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C@H:11]2[CH3:22])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)C(C)O2
Reactant: Cc1cc(C)c2c(-c3ccc(C(C)C)cc3)c(C)oc2c1C
Agent: CC(C)(C)CC(=O)Cl
Agent: Cc1c(C)c2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)C(C)O2
Agent: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)O2
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)[C@H](C)O2
Yield: 18 %

Procedure:
Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran obtained in Reference Example 347, a mixture of cis isomer and trans isomer (3:2) of 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was synthesized in the same manner as in Reference Example 199. Using the mixture as it is as the compound, a mixture of cis isomer and trans isomer of 5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was obtained in the same manner as in Reference Example 23. Using the compound, a mixture of cis isomer and trans isomer of N-benzyl-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)amine was obtained in the same manner as in Reference Example 24. Using the compound, (3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)amine was synthesized in the same manner as in Reference Example 30. Using the compound and tert-butylacetyl chloride, a mixture of cis isomer and trans isomer of N-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide was obtained in the same manner as in Example 1. The compound was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to synthesize the title compound. Yield: 18%. Melting point: 143-144° C. (hexane)
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[O:19]=[C:20]1[NH:25][CH:24]([C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:26]([CH:24]2[NH:25][C:20](=[O:19])[CH2:21][CH2:22][CH2:23]2)=[O:27])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C1CCCC(C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C2CCCC(=O)N2)CC1
Temperature: 25 °C
Yield: 47 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (500 mg), 6-oxopiperidine-2-carboxylic acid (261 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (403 mg), 1-hydroxy-1H-benzotriazole monohydrate (322 mg), triethylamine (0.627 mL), and N,N-dimethylformamide (5 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 1 M sodium hydroxide solution, saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (280 mg, 47%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH2:10][CH3:11])=[CH:5][C:6]=1[C:7]([OH:9])=O.CN(C(ON1N=N[C:22]2[CH:23]=[CH:24][CH:25]=[N:26][C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C.O.C(#N)C>[Br:1][C:2]1[S:3][C:4]([CH2:10][CH3:11])=[CH:5][C:6]=1[C:7]([N:26]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)=[O:9]
Reactant: CCc1cc(C(=O)O)c(Br)s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCc1cc(C(=O)N2CCCCC2)c(Br)s1
Reaction time: 3 h
Yield: 63.4 %

Procedure:
2-Bromo-5-ethyl-thiophene-3-carboxylic acid (0.44 g, 1.88 mmol) was dissolved in DMF (10 mL). HATU (1.88 mmol) and piperidine (10 mmol) were added and the reaction mixture stirred for 3 hours. The mixture was diluted with water and acetonitrile and the product was purified by HPLC, eluting with 0%-95% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.36 g). LCMS m/z 304.00 [M+H]+ RT=10.91 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 6.6 (s, 1H), 3.7 (m, 2H), 3.35 (m, 2H), 2.75 (q, 2H), 1.65 (m, 4H), 1.55 (m, 2H), 1.27 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[C:25]([CH2:27][O:28][C:29]2[C:33](/[CH:34]=[CH:35]/[C:36]3[N:37]=[C:38]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[S:39][C:40]=3[CH3:41])=[CH:32][N:31]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[N:30]=2)[CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])[O:10][C:11]=1[CH3:12].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][O:2][C:3]1[CH:26]=[C:25]([CH2:27][O:28][C:29]2[C:33](/[CH:34]=[CH:35]/[C:36]3[N:37]=[C:38]([N:42]4[CH2:43][CH2:44][O:45][CH2:46][CH2:47]4)[S:39][C:40]=3[CH3:41])=[CH:32][N:31]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:30]=2)[CH:24]=[CH:23][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])[O:10][C:11]=1[CH3:12]
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCOCC5)sc4C)cc3OC)c(C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCOCC3)sc2C)ccc1OCc1nc(-c2cccc(C(=O)O)c2)oc1C
Yield: 72.8 %

Procedure:
To a mixture of methyl 3-[4-({2-methoxy-4-[({4-[(E)-2-(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (0.35 g), tetrahydrofuran (50 mL) and methanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was heated under reflux for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the precipitated crystals were collected by filtration and washed with diethyl ether to give 3-[4-({2-methoxy-4-[({4-[(E)-2-(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]phenoxy)methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as brown crystals (0.25 g, yield 71%). Recrystallization from acetone-hexane gave brown prism crystals. melting point: 215-217 (dec) ° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[O:25]1[CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:36]3[NH:35][N:34]=[CH:38][CH:37]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23][CH2:24]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(Br)c1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCOCC2)c(-c2ccn[nH]2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
5-Bromo-6-morpholino-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 18.1, 100 mg, 0.224 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (125 mg, 0.448 mmol), Pd(Ph3P)4 (25.9 mg, 0.022 mmol) and K3PO4 (190 mg, 0.896 mmol) and toluene (1.121 mL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred for 16 h at 110° C. The RM was diluted with DME (2 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 93 mg, 0.134 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc from 10% to 60% EtOAc). The fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was treated with TFA (500 μL, 6.49 mmol) and DCM (1.5 mL) and then stirred at RT for 4.5 h. The RM was diluted with DCM (30 mL) and washed with water, sat. aq. NaHCO3, brine and dried over Na2SO4. The solvent was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC (Column Diol, from 20% to 25% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.0 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.07-3.25 (m, 4H) 3.55-3.75 (m, 4H) 6.62-6.82 (m, 1H) 7.36 (d, J=8.53 Hz, 2H) 7.54-7.88 (m, 1H) 7.85-7.92 (m, 2H) 8.20-8.40 (m, 1H) 8.76 (d, J=2.13 Hz, 1H) 10.44 (br. s, 1H) 13.02-13.31 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:13]=2)=[CH:4][N:3]=1.[ClH:35].O1CCOCC1>CO.C1(C)C=CC=CC=1>[ClH:35].[ClH:35].[NH:26]1[CH2:27][CH:24]([N:21]2[C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[N:13]=[C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)[C:9]=3[CH2:23][CH2:22]2)[CH2:25]1
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CN(C(=O)OC(C)(C)C)C1)CC2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N(C1CNC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-{4-(2-aminopyrimidin-5-yl)-2-[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}azetidine-1-carboxylate (760 mg, 1.62 mmol) in methanol (8 mL), was added 4 N HCl in 1,4-dioxane (8 mL, 32 mmol). The reaction was stirred at room temperature for 1 h. The mixture was diluted with toluene and the solvent was removed under reduced pressure to give a foamy residue. The residue was triturated in acetone to get a free flowing tan solid which was collected by filtration to give the title compound in quantitative yield. The material was taken directly in the next step without purification. 1H NMR (400 MHz, CD3OD) δ 8.78 (br s, 2 H), 5.32 (br s, 1 H), 4.62 (br s, 3 H), 4.34 (br s, 2 H), 4.19-3.99 (m, 4 H), 3.85-3.72 (m, 2 H), 3.64-3.46 (m, 2 H), 3.23 (br s, 2 H), 1.41 (d, J=5.5 Hz, 3 H).
Reaction SMILES: C1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)C=CC=CC=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH2:29])[CH2:27][CH2:28][C@H:23]2[CH2:22]1.C(N1C[C@H]2C(N)CC[C@H]2C1)C1C=CC=CC=1>>[F:33][C:16]([F:15])([F:34])[C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[CH2:20][N:21]1[CH2:25][C@H:24]2[C@@H:26]([NH:29][C:12]([CH:7]3[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:27][CH2:28][C@H:23]2[CH2:22]1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Agent: NC1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Product: O=C(N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)C1CCCC1

Procedure:
The title compound was prepared by substituting cyclopentanecarboxylic acid for 1-phenylcyclopentanecarboxylic acid and (3aS*,4S*,6aR*)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 122 Step E for (3aS*,6aR*)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described for Example 1: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.82 (d, J=6.9, 1H), 7.71 (s, 1H), 7.61 (d, J=7.7, 1H), 7.55 (d, J=7.7, 1H), 7.46 (t, J=7.7, 1H), 4.48-4.41 (m, 1H), 4.07 (q, J=7.1, 1H), 2.82 (ddd, J=2.9, 7.8, 16.7, 1H), 2.72 (dd, J=2.9, 9.5, 1H), 2.66 (p, J=7.9, 1H), 2.50-2.42 (m, 1H), 2.37 (dd, J=2.9, 9.0, 1H), 2.34-2.29 (m, 1H), 2.21 (dd, J=7.5, 9.4, 1H), 2.03 (dt, J=7.0, 15.3, 1H), 1.86 (dddd, J=7.4, 12.3, 20.5, 23.4, 3H), 1.75-1.60 (m, 5H), 1.53-1.41 (m, 2H), 1.30 (td, J=4.7, 11.1, 1H), 1.11 (t, J=7.1, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]3[CH:31]=[C:32]([Cl:36])[C:33]([NH2:35])=[CH:34][C:22]=3[N:21]=2)[CH:19]=1)=[O:14])[CH3:11].NC1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2C=1.[Br:56][CH2:57][C:58](Br)=[O:59]>CCOC(C)=O.O.C1COCC1>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:24]([CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]3[CH:31]=[C:32]([Cl:36])[C:33]([NH:35][C:58](=[O:59])[CH2:57][Br:56])=[CH:34][C:22]=3[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2nc3cc(NC(=O)CBr)c(Cl)cc3n2COCCOC)c1
Temperature: 23 °C
Reaction time: 0.42 h
Yield: 42.5 %

Procedure:
To a solution of diisopropylethylamine (0.86 mL, 4.95 mmol), 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.650 g, 1.65 mmol), and THF (8 mL) at 0° C., was added bromoacetyl bromide (0.244 mL, 2.81 mmol). The reaction mixture was allowed to slowly warm to 23° C. A second aliquot of bromoacetyl bromide (0.244 mL, 2.81 mmol) was added and the reaction mixture was kept at 23° C. for an additional 25 min. Water was added (20 mL) and the aqueous layer was extracted with EtOAc (2×75 mL). The combined organic layers were washed with brine (25 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.361 g, 42% yield) after trituration with EtOAc. A 3:2 mixture of regioisomers was observed in the 1H NMR spectrum. MS (ESI/CI): mass calcd. for C19H21BrClN5O5, 513.0; m/z found, 514.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.89 (s, 1H), 8.87 (br s, 1H), 8.71 (s, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 6.13 (s, 2H), 4.36 (q, J=7.2 Hz, 2H), 4.13 (s, 2H), 3.68-3.62 (m, 2H), 3.49-3.43 (m, 2H), 3.31 (s, 3H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([I:13])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.Cl>N1C=CC=CC=1.O>[C:16](/[CH:15]=[CH:1]/[C:3]1[CH:4]=[C:5]([I:13])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])([OH:18])=[O:17]
Reactant: COC(=O)c1cc(I)cc(C=O)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)c1cc(I)cc(/C=C/C(=O)O)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
The mixture of methyl 5-formyl-3-iodobenzoate (2.5 g), malonic acid (1.8 g) and piperidine (0.2 ml) in pyridine (25 ml) was stirred for 3 hours at 100° C. The mixture was added to water and adjusted to pH 2 with 6N-hydrochloric acid. The isolated precipitate was collected by filtration to give methyl 5-[(E)-2-carboxyethenyl]-3-iodobenzoate (2.4 g)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.[N:10]([O-])=O.[Na+].NC1C=CC=CC=1.S([O-])([O-])=O.[NH4+].[NH4+]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][NH2:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: Nc1ccccc1
Product: NNc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a 1 L flask were added finely powdered p-bromoaniline (69 g, 0.4 mol), water (200 mL) and conc. HCl (100 mL, 1.2 mol). The mixture was cooled in an ice bath to less than 5° C. A solution of sodium nitrite (30 g, 0.43 mol) in water (90 mL) was added dropwise to the aniline suspension over approx. 1 h, while maintaining the temperature at less than 5° C. The mixture was stirred for a further 30 min and then was gravity filtered through a No. 1 paper into a chilled flask. The solution was added in small portions to a solution of 92% ammonium sulfite (118 g, 0.8 mol) in water (250 mL), which had been chilled to 0° C., at a rate such that the temperature remained at less than 5° C. (approx. 1 h). During the addition a yellow solid formed in the mixture. After the addition was completed, stirring was continued for 1 h at 0° C. and the mixture was then allowed to warm to rt. The solid was filtered off and the filtrate was treated with conc. HCl (120 mL). The solution was heated to reflux during which time a solid formed and then mostly dissolved. The hot solution was filtered and then allowed to cool to rt before chilling in a refrigerator overnight. The crystals were filtered off and were washed with 1 M HCl (60 mL). The solid was added to a mixture of DCM (1 L) and 1N sodium hydroxide (600 mL) and the suspension was shaken until the solid dissolved. The layers were separated and the aqueous phase was washed again with DCM (2×400 mL). The combined organic solutions were dried (MgSO4), filtered and the solvent was evaporated in vacuo to afford p-bromophenylhydrazine (50.3 g, 67%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[S:17]([OH:20])(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:17]([OH:20])(=[O:19])=[O:18])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2ccccc2)c(S(=O)(=O)O)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 44.4 %

Procedure:
To a stirred solution of 4-nitrobiphenyl (50.00 g, 0.25 mol) in chloroform (750 mL) was added dropwise at room temperature chlorosulfonic acid (17 mL, 0.3 mol). The reaction mixture was stirred at 60° C. for 6 h. The white precipitate formed was collected by filtration and washed with cold chloroform. The product was air dried to give 31.00 g of 4-nitrobiphenylsulfonic acid (Yield 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.C(Cl)CCl.C1C=C2N=NN(O)C2=CC=1.O.C(Cl)Cl.[F:51][C:52]([F:59])([C:55]([F:58])([F:57])[F:56])[CH2:53]O.C(O)(C(F)(F)F)=O>>[F:51][C:52]([F:59])([C:55]([F:58])([F:57])[F:56])[CH2:53][O:29][C:28](=[O:30])[C@H:27]([OH:31])[CH2:26][N:15]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:32])=[CH:13][CH:12]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=1)=[O:18]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
(R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20 mg, 43 μmol), EDC (40.16 mg, 0.2587 mmol), and HOBt hydrate (39.62 mg, 0.2587 mmol) were combined in DCM (0.5 mL, 8 mmol) and stirred at room temperature. After 10 minutes, 2,2,3,3,3-pentafluoro-1-propanol (51.8 mg, 345 μmol) was added. The resulting mixture was stirred at room temperature overnight to yield the title compound (5.9 mg, purity 100%) as a TFA salt. MS m/z [M+H]+ calc'd for C24H20ClF6N3O6, 596.09. found 596.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2Cl.CC(O)C.S(=O)(=O)(O)O>O.CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[N:28][C:27]=2[NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: Clc1cnc2c(Cl)nccc2c1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: O
Product: NC1=N[C@](CF)(c2cc(Nc3nccc4cc(Cl)cnc34)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 55 °C
Reaction time: 16 h
Yield: 24.85 %

Procedure:
A sealable vial was charged with crude (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (345 mg, 1.116 mmol, step 1) and 3,8-dichloro-1,7-naphthyridine (Intermediate 2; 233 mg, 1.171 mmol). iPrOH (8 mL) was added and the suspension was briefly sonicated. Sulfuric acid (0.059 mL, 1.116 mmol, Aldrich) was added and the vial was sealed. The reaction was heated to 55° C. in an oil bath for one hour then cooled to RT and stirred for additional 16 hours. The reaction was diluted with water and EtOAc. The aqueous layer separated was basified to pH=12 by the addition of 1N NaOH. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel chromatography using a gradient of 0-50% EtOAc:Hexanes to afford the title compound as a white solid. (130.8 mg, 0.277 mmol, 24.85% yield). MS m/z=472.0 [M+H]+. Calculated for C20H15ClF5N5O: 471.811