Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].[NH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:37][CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])=[O:9])=[O:4]
Reactant: CC(C)(O)CN
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(O)CNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 4, 35 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 1-amino-2-methylpropan-2-ol (12.42 mg, 0.139 mmol), 4-methylmorpholine (0.046 mL, 0.418 mmol), and BOP (61.6 mg, 0.139 mmol). This was stirred for 1 h and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21.2×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=33.2 min) to give single enantiomer 3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-(2-hydroxy-2-methylpropyl)propanamide (15.3 mg, 0.026 mmol, 36.8% yield): LC/MS=574.3 [M+H)+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.69 (4 H, d, J=8.14 Hz), 7.52-7.65 (3 H, m), 5.11 (1 H, s), 3.52 (2 H, t, J=6.71 Hz), 3.31 (3 H, dt, J=3.25, 1.57 Hz), 2.48 (2 H, t, J=6.71 Hz), 1.16 (6 H, d, J=1.76 Hz). HPLC Peak RT=9.0 min (Analytical Method D).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][S:36]([C:33]3[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=3)(=[O:37])=[O:38])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1)OCC

Procedure:
2-Ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) was esterified with 4-nitrobenzenesulfonyl chloride using the same method as in Example 26 (c) to give 2-ethoxy-3-(4-{2-[4-(4-nitrobenzenesulfonyloxy)phenyl]-ethoxy}phenyl)propanoic acid ethyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:28])[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[C:9]([CH3:19])[O:10]2)(=[O:3])[CH3:2].[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:28])[C:8]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[C:9]([CH2:19][Br:29])[O:10]2)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2c(C)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2c(CBr)oc3cc(OC(C)=O)cc(OC(C)=O)c3c2=O)cc1
Yield: 111.9 %

Procedure:
A solution of 5,7-diacetoxy-4'-methoxy-2-methylisoflavone (2 g), benzoyl peroxide (0.1 g) and N-bromosuccinimide (1.4 g) in 120 ml carbon tetrachloride was heated under reflux for 20 hours, the solvent was distilled off under reduced pressure, and the solid residue was treated with water. The crude product collected by filtration was recrystallized from methanol, affording 2.7 g of 5,7-diacetoxy-4'-methoxy-2-bromomethylisoflavone.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:21]([Cl:22])=[CH:20][C:7]([C:8]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:18][CH3:19])=[O:9])=[C:6]([O:23][CH3:24])[CH:5]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:21]([Cl:22])=[CH:20][C:7]([C:8]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:32])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:14][C@H:13]2[O:18][CH3:19])=[O:9])=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCNC[C@H]1OC
Reactant: O=C(CCCCCBr)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCC(=O)c2ccccc2)C[C@H]1OC
Yield: 60.8 %

Procedure:
cis-4-Amino-5-chloro-2-methoxy-N-((3-methoxypiperidin-4-yl)methyl)-benzamide dihydrochloride (0.88 g) as a starting compound, 6-bromo-1-phenyl-1-hexanone (0.67 g) and potassium carbonate (1.37 g) were reacted and purified in the same manner as in Example 172 to give 0.67 g of cis-4-amino-5-chloro-2-methoxy-N-((3-methoxy-1-(6-oxo-6-phenylhexyl)-piperidin-4-yl)methyl)benzamide, m.p. 99°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)[N:6]=[C:5]2[OH:20].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)=[O:31])=[CH:10][CH:9]=2)[C:5]([OH:20])=[N:6]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: Nc1ccc2c(c1)c(O)nn2Cc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)c(O)nn3Cc2ccc(Cl)c(Cl)c2)cc1

Procedure:
1.54.g 5-amino-1-(3,4-dichlorobenzyl)-1H-indazole-3-ol and 1.12 g 4-methoxyphenyl isocyanate are stirred in 75 ml tetrahydrofuran for 5 hours at room temperature. the solution is concentrated to one third of its volume under vacuum and the precipitate crystallized out after cooling is filtered off under suction. It is recrystallized from n-butanol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][C:12]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([F:14])[F:13])=[N+]=[N-].[ClH:23].CCOCC>CCO.[OH-].[Pd+2].[OH-]>[ClH:23].[NH2:1][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][C:12]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([F:14])[F:13]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN=[N+]=[N-]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Reaction time: 8 h

Procedure:
To a solution of diethyl 3-(2-(2-azidoethoxy)ethoxy)-1,1-difluoropropylphosphonate (1 eq) in EtOH (2 M) solution was added palladium hydroxide (0.05 eq) and 2 M HCl in ether (1.1 eq). The reaction mixture was stirred under hydrogen (1 atm) overnight. The palladium was filtered off and the filtrate was concentrated en vaccuo. The crude mixture was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:37][CH2:38][CH3:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH2:37][CH2:38][CH3:39])=[C:5]([CH:27]=[CH:28][C:29]=1[C:30]([N:32]1[CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:31])[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([CH2:24][CH2:25][CH3:26])=[C:13]([CH:21]=[CH:22][CH:23]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)N3CCCC3)c(OC)c2CCC)cccc1OCC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)N3CCCC3)c(OC)c2CCC)cccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 49 (150 mg, 0.2769 mmol) and 1M lithium hydroxide (554 μl, 0.5538 mmol) were added to 2.0 ml of methanol and the reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, 2.0 ml of water was added, then the solution was acidified with 10% hydrochloric acid. The solution was extracted three times with ethyl acetate and the combined extracts were dried and filtered. The solvent was removed under vacuum to give the product as a gum.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH:8]([CH2:11][OH:12])[CH2:9][OH:10])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:10][CH2:9][CH:8]([CH2:11][OH:12])[O:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1
Reactant: Cc1cc(OC(CO)CO)no1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OC(CO)COC2CCCCO2)no1

Procedure:
A solution of 11.26 g of 2-O-(5-methyl-3-isoxazolyl)glycerol (prepared as described in Preparation 20), 5.93 ml of dihydropyran and 0.15 g of pyridine p-toluenesulfonate in 110 ml of methylene chloride was stirred at room temperature for 14 hours. The solvent was removed by evaporation under reduced pressure, and then the residue was subjected to column chromatography through 350 g of silica gel. 3.32 g of the 1,3-ditetrahydropyranyl compound was first eluted with a 1:4 by volume mixture of ethyl acetate and hexane, and then 9.67 g of the title compound were isolated as a colorless oil from the fractions eluted with a 1:1 by volume mixture of ethyl acetate and hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([OH:26])=O)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1.Cl.[N:28]1([C:33]([NH2:35])=[NH:34])[CH:32]=[CH:31][CH:30]=[N:29]1.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:35][C:33](=[NH:34])[N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)=[O:26])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:17][CH:18]=2)[S:11][CH:12]=1
Reactant: N=C(N)n1cccn1
Reactant: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
[4-(2-Chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]acetic acid (0.630 g, 1.62 mmol) was dissolved in CH2CL2 (5 mL) and carbonyldiimidizole (1.31 g, 8.1 mmol) was added. The solution was stirred under argon at room temperature for thirty minutes. 1-H-Pyrazole-1-carboxamidine hydrochloride (2.37 g, 16.2 mmol) and diisopropyl ethylamine (4.23 mL, 3.14 g, 24.3 mmol) were added the solution was stirred overnight. The solvent was removed and the mixture was absorbed onto silica gel and purified by flash chromatography (20:1 CHCl3:MeOH to yield 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[imino(1H-pyrazol-1-yl)methyl]acetamide (0.421 g) as a white solid. mp 119-120 ° C.; 1H NMR (500 MHz, DMSO-d6) δ: 0.98 (t, 3H, J=7.3 Hz), 1.73 (m, 2H), 3.55 (s, 2H), 3.96 (t, 2H, J=6.4 Hz), 6.53 (m, 1H), 7.02 (d, 2H, J=8.7 Hz), 7.30 (m, 4H), 7.40 (s, 1H), 7.49 (d, 2H, J=8.5 Hz), 7.89 (s, 1H), 8.08 (s, 1H). MS (ES) m/z 479.1 ([M+H]+). MS (ES) m/z 957.2 ([2M+H]+). MS (ES) m/z 979.2 ([2M+NA]+). Anal. Calcd for C25H23ClN4O2S: C, 62.69; H, 4.84; N, 11.70. Found: C, 62.35; H, 4.86; N, 11.58.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[C:13]([CH3:16])=[CH:14][S:15][C:5]=12)[CH3:3].[CH3:17][O-:18].[Na+]>CO>[CH2:2]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6](/[C:13](/[CH3:16])=[CH:14]\[S:15][CH3:5])[C:17]1=[O:18])[CH3:3]
Reactant: C[O-]
Reactant: CC[n+]1c2ccccc2n2c(C)csc21
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCn1c(=O)n(/C(C)=C\SC)c2ccccc21
Temperature: 25 °C
Yield: 65.7 %

Procedure:
184 mg of 9-ethyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (0.533 mmol) were solubilised in methanol (35 mL), then 231 mg (8 eq) of NaOMe were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure to afford 1-ethyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a white powder (87 mg, 65%). Mp 74° C.; Rf=0.48 (CH2Cl2/AcOEt 8:2); 1H NMR (300 MHz, CDCl3) δ=1.35 (3H, t, J=7.2, CH3), 2.13 (3H, d, J=1.1, CH3), 2.22 (3H, s, SCH3), 3.94 (2H, q, J=7.2, CH2), 6.22 (1H, q, J=1.1, H5), 6.86 (1H, m, Ar), 6.99-7.09 (3H, m, Ar); 13C NMR (75 MHz, CDCl3) δ=13.46, 16.76, 20.28, 35.74, 107.58, 108.92, 120.81, 121.26, 126.59, 127.30, 127.50, 129.24, 151.75; HRMS m/z C13H17N2OS [M+H]+ calcd: 249.1056, found: 249.1056.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([NH2:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[C:8]([NH:10][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)=[O:21])=[O:9]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC(=O)c1c(Cl)cncc1Cl
Solvent: Cc1ccccc1C
Product: O=C(NC(=O)c1c(Cl)cncc1Cl)Nc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
A reaction vessel was charged with sixty-eight grams (0.36 mole) of 3,5-dichloro-4-pyridinecarboxamide, 55.5 grams (0.36 mole) of p-chlorophenyl isocyanate, and 1200 milliliters of xylene. The solution was heated under reflux with stirring for three hours. A small amount of impurity was removed by filtering the hot reaction mixture. On cooling in an ice water bath, a solid precipitated. The precipitated product was collected by suction filtration, washed with cold xylene and dried in a vacuum oven at about 70° C. The dried crude product was purified by recrystallization from 90 percent aqueous acetic acid. The yield was 81 grams (66 percent of theoretical) of white needles melting at 225°-227° C. Nuclear magnetic resonance spectral data confirmed the structure as being ##STR12##
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:22][N:23]([CH3:24])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with dimethylamine hydrochloride (CAN 506-59-2) in the presence of TBTU and DIEA to give the title compound as light yellow oil; MS (EI): m/e=312.4 [MH+].
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([OH:14])=[C:6]([N+:15]([O-])=O)[CH:5]=1>CO.[Zn]>[NH2:15][C:6]1[CH:5]=[C:4]([Br:3])[C:9]([C:10]([F:13])([F:11])[F:12])=[CH:8][C:7]=1[OH:14]
Reactant: O=[N+]([O-])c1cc(Br)c(C(F)(F)F)cc1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1cc(Br)c(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of zinc powder (16.23 g, 248 mmol) and ammonium chloride (13.28 g, 248 mmol) in MeOH (80 mL) was added 4-bromo-2-nitro-5-(trifluoromethyl)phenol (7.1 g, 24.8 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned between EtOAc (100 mL) and water (300 mL). The organic phase was separated and washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 2-amino-4-bromo-5-(trifluoromethyl)phenol as a black oil (5.9 g, 93%), which was used in the next step without further purification. 1H NMR (DMSO-d6, 400 MHz): δ 9.89 (brs 1H), 6.98 (s, 1H), 6.92 (s, 1H), 5.53 (brs, 2H).
Reaction SMILES: CN(C)S(C1C=C(C=C(C(F)(F)F)C=1)C([N:11]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=1)=O)(=O)=O.[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[N:49]=1)[C:44]([OH:46])=O>>[CH3:25][O:24][C:19]1[C:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:44](=[O:46])[C:43]2[CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[N:49]=[C:41]([C:40]([F:39])([F:55])[F:54])[CH:42]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1)c1cnccc1-c1cccnc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OC

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-ylamino)-acetic acid methyl ester (example 178, intermediate) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 48 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). Light yellow solid (55%). MS (ESI): m/z=515.114 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=O)(=[O:3])[CH3:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[C:1]([C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(=O)c1ncccc1C(=O)Cl
Product: CC(=O)c1ncccc1CN1CCOCC1

Procedure:
Following the procedures of Example 14, 2-acetylnicotinic acid chloride (1.0 g, 5.5 mmol) and morpholine (0.6 g, 6.7 mmol) are reacted together to give 4-(2-acetylnicotinyl)morpholine, which compound (1.0 g, 4.2 mmol) is then reacted with 4-(3-fluorophenyl)semicarbazide (0.7 g, 4.2 mmol) to give 4-(2-acetylnicotinyl)morpholine 4-(3-fluorophenyl)semicarbazone, m.p. 193°-195° compound 150).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][OH:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH2:19]=[C:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])O.[Na+]>ClCCl.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([CH2:16][O:17][C:20]1([CH3:19])[CH2:24][CH2:23][CH2:22][CH2:21]1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: C=C1CCCC1
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H](COC1(C)CCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
N-CBZ-L-serine methyl ester (3.15 g) was dissolved in 40 ml of dichloromethane at 0° C. under argon. Methylenecyclopentane (20 ml) was added, followed by 16 drops of concentrated sulfuric acid. The contents of the vessel were stirred at room temperature overnight then poured into dilute aqueous sodium hydrogen carbonate and extracted with chlorofrom (2×30 ml). The organic layer was dried over sodium sulfate and evaporated. The residual oil was chromatographed on silica gel with 50/50 petroleum ether/diethyl ether to give an oil (78% yield). The product, N-CBZ-O-(1-methylycyclopentyl)-L-serine methyl ester, was confirmed by NMR spectroscopy.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([F:11])([F:10])[F:9])[CH2:3][OH:4].[N:18]#[C:19]Br>>[F:11][C:8]([F:9])([F:10])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5][C@H:2]1[CH2:3][O:4][C:19]([NH2:18])=[N:1]1
Reactant: N[C@H](CO)CCC(c1ccccc1)C(F)(F)F
Reactant: N#CBr
Product: NC1=N[C@@H](CCC(c2ccccc2)C(F)(F)F)CO1

Procedure:
In analogy to example 1d (S)-2-amino-6,6,6-trifluoro-5-phenyl-hexan-1-ol was reacted with cyanogen bromide to give (4S)-4-(4,4,4-trifluoro-3-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 273.1 ([M+H]+))
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[F:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([S:39]([C:36]6[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=6)(=[O:41])=[O:40])[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(S(=O)(=O)c3ccc(F)cc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) in DMF (1 mL), was added 4-fluoro-benzenesulfonyl chloride (16 mg, 80 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by reverse phase chromatography (Method C) to afford 7 mg of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:26][CH:25]([N:27]([S:34]([CH2:37][CH2:38][CH2:39][CH3:40])(=[O:36])=[O:35])[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[O:24][N:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[Li+].[OH-]>C1COCC1>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:26][CH:25]([N:27]([S:34]([CH2:37][CH2:38][CH2:39][CH3:40])(=[O:36])=[O:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[O:24][N:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCC(COc2ccc(C3=NOC(N(CCC(=O)OC)S(=O)(=O)CCCC)C3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CCC(COc2ccc(C3=NOC(N(CCC(=O)O)S(=O)(=O)CCCC)C3)cc2)CC1

Procedure:
A solution of the impure methyl 3-(3-[4-{(butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionate less polar diastereomer (309 mg) in THF (5 mL) was saponified using 0.5M LiOH (2 mL, 1 mmol) over 6 hours as per Example 1, Part F. The crude carboxylic acid was purified using flash chromatography (CHCl3 --5-15% MeOH/CHCl3 step gradient) followed by crystallization from EtOAc/hexanes, affording 169 mg of the desired material; mp: 155° C. (dec); 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 7.56 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.80 (m, 1H), 3.96 (bd, J=13.2 Hz, 2H), 3.90 (d, J=6.3 Hz, 2H), 3.77 (bs, 3H), 3.52 (t, J=7.8 Hz, 1H), 3.38 (dd, J=14.4, 10.0 Hz, 1H), 2.98 (t, J=7.8 Hz, 2H), 2.76 (dt, J=12.2, 1.7 Hz, 2H), 1.95 (m, 2H), 1.75 (m, 4H), 1.41 (s, 9H), 1.38 (d, J=7.6 Hz, 1H), 1.25 (m, 4H), 0.88 (t, J=7.3 Hz, 3H).