Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:25][C:20]=2[O:19][CH2:18]1.Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:26]([C:24]3[CH:23]=[CH:22][C:21]4[O:17][CH2:18][O:19][C:20]=4[CH:25]=3)(=[O:27])=[O:28])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccc4c(c3)OCO4)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
A mixture of 0.5 g 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.52 g of benzo[1,3]dioxol-5-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 100 ml of 60% ethanol yielded 0.30 g of benzo[1,3]dioxol-5-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide as yellowish crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:29]([O-:31])=[O:30])=[C:19]([CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:20]=1>CN(C)C(=O)C>[N+:29]([C:18]1[CH:17]=[CH:16][C:15]([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]#[N:11])=[CH:20][C:19]=1[CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)([O-:31])=[O:30]
Reactant: N#CCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1COC1CCCCO1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: N#CC(c1ccccc1)c1ccc([N+](=O)[O-])c(COC2CCCCO2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a mixture of 7.13 parts of a dispersion of sodium hydride in mineral oil (50%) and 94 parts of N,N-dimethylacetamide was added dropwise a solution of 9.1 parts of benzeneacetonitrile in 18.8 parts of N,N-dimethylacetamide. After the hydrogen evolution had ceased, there were added 1.28 parts of tris-2,2,2-(2-methoxyethoxy)ethanamine and a solution of 20.2 parts of intermediate 54, namely 2-[(5-chloro-2-nitrophenyl)methoxy]-tetrahydro-2H-pyran, in 28.2 parts of N,N-dimethylacetamide. After 15 minutes, the reaction mixture was poured into ice-water and the whole was neutralized. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated, yielding 26.2 parts (100%) of 4-nitro-α-phenyl-3-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]benzeneacetonitrile (interm. 55).
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(O[Cl:15])(C)(C)C>CO>[Cl:15][N:4]1[C:3]([CH2:2][Cl:1])([CH3:9])[CH2:7][O:6][C:5]1=[O:8]
Reactant: CC(C)(C)OCl
Reactant: CC1(CCl)COC(=O)N1
Solvent: CO
Product: CC1(CCl)COC(=O)N1Cl
Temperature: 25 °C

Procedure:
A solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (13.39 g, 89.52 mmol) in MeOH (100 ml) was cooled to 0° C., and tert-butylhypochlorite (12.0 ml, 101 mmol) was added dropwise over 15 min. The solution was warmed to RT over 45 min, and concentrated in vacuo. The residue was crystallized by dissolution in ˜80 ml CH2Cl2 followed by careful layering of 60 ml hexanes to afford the title compound as white, fan-shaped crystals (12.31 g, 66.89 mmol, 75%). 1H NMR (CDCl3, 400 MHz) δ1.50 (s, 3H), 3.55 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.0 Hz, 1H), 4.19 (d, J=8.8 Hz, 1H), 4.53 (d, J=8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz) δ 20.4, 46.7, 64.1, 155.7. LRMS (ESI/APCI): 225 [M+H+CH3CN]+, 191 [M+H−Cl+CH3CN]+, 184 [M+H]+, 150 [M+H−Cl]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Mg].[CH3:15][Si:16]([CH3:25])([CH3:24])[C:17]1[O:21][CH:20]=[C:19]([CH:22]=[O:23])[CH:18]=1>O1CCCC1>[OH:23][CH:22]([C:19]1[CH:18]=[C:17]([Si:16]([CH3:25])([CH3:24])[CH3:15])[O:21][CH:20]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: CCCCCCCCCCCCBr
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
A mixture of 1-bromododecane (2.97 g, 11.9 mmol) and magnesium turnings (300 mg, 12.5 mmol) in tetrahydrofuran (20 ml) was refluxed under argon for 30 minutes. On cooling, a solution of 5-trimethylsilyl-3-furaldehyde (1g, 5.9 mmol) in tetrahydrofuran (THF) (2 ml) was added. After 30 min., the reaction mixture was quenched with saturated ammonium chloride. Extraction (ethyl ether), drying (magnesium sulfate) and evaporation afforded an oil, which was purified by flash chromatography on silica using 15% ethyl ether/hexane. Fractions with Rf of about 0.25 on evaporation gave the title alcohol as a pale yellow oil, which solified into a colorless solid on storage at -20°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24](O)=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=3)[C:8]2=[O:23])[S:4][C:3]=1[C:24]([NH:58][CH2:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)=[O:25]
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a stirred mixture of 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)-imidazolidin-1-yl)thiophene-2-carboxylic acid (3.68 g, 9.56 mmol), 1-hydroxybenzotriazole (1.94 g, 14.36 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (2.75 g, 14.3 mmol) in N,N-dimethylformamide (40 mL) was added N,N-diisopropylethylamine (5.00 mL, 5.00 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.97 mL, 9.57 mmol). The resulting reaction mixture was stirred for 16 h, then was diluted with ethyl acetate (300 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×100 mL), water (100 mL) and brine (100 mL). The combined water/brine layer was extracted with dichloromethane (200 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by recrystallization from 50% ethyl acetate in hexanes to afford the title compound as a colorless solid (2.48 g, 55%): mp 102-104° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.29-7.22 (m, 1H), 6.20 (t, J=5.6 Hz, 1H), 6.10 (s, 1H), 4.58 (d, J=5.6 Hz, 2H), 4.50 (s, 2H), 3.85-3.77 (m, 2H), 3.50-3.42 (m, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 155.8, 149.1, 148.7, 142.3, 141.4, 140.1, 135.5, 134.2, 130.1 (d, JC-F=32.6 Hz), 128.4, 125.7 (q, JC-F=3.8 Hz), 123.5, 122.1, 119.2, 112.5, 47.7, 42.7, 41.6, 41.1, 16.0; MS (ES+) m/z 475.3 (M+1).
Reaction SMILES: [C:1](=O)([O:47]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@H:14]([NH:35][C:36]([O:38][C@@H:39]2[C@H:46]3[C@H:42]([O:43][CH2:44][CH2:45]3)[O:41][CH2:40]2)=[O:37])[C@H:15]([OH:34])[CH2:16][N:17]([S:22]([C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH2:30][O:31][C:27]=3[CH:26]=2)(=[O:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:9][CH:8]=1.[CH3:58][NH2:59].O1CCCC1>>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([S:22]([N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:16][C@@H:15]([OH:34])[C@@H:14]([NH:35][C:36](=[O:37])[O:38][C@@H:39]3[C@H:46]4[C@H:42]([O:43][CH2:44][CH2:45]4)[O:41][CH2:40]3)[CH2:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][C:1]([NH:59][CH3:58])=[O:47])=[CH:12][CH:11]=3)(=[O:24])=[O:23])=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: CN
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCOC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CNC(=O)OCCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1

Procedure:
3-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)propyl 4-nitrophenyl carbonate was treated with 2M methylamine/tetrahydrofuran as described above to provide the title compound as a white solid. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.84 (3H, d), 1.1-1.2 (1H, m), 1.2 (1H, br quintuplet), 1.9-2.0 (3H, m), 2.17 (1H, t), 2.45 (3H, d), 2.6-2.8 (3H, m), 2.83-3.00 (2H, m), 3.4-3.6 (5H, m), 3.7 (1H, br s), 3.8 (1H, br s), 3.9 (2H, br s), 4.0 (2H, br s), 4.8-4.9 (1H, m), 5.0 (1H, d), 5.5 (1H, d), 6.17 (2H, s), 6.7-6.8 (2H, m), 6.9 (1H, br s), 7.0-7.1 (3H, m), 7.2-7.4 (3H, m); MS: 708 (MH+);
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32]([NH:36][CH2:37][CH2:38]O)[CH2:33][CH2:34][CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH2:38][CH2:37][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH2:38][CH2:37][NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CCCCNCCO
Solvent: CCO
Product: CCCCNCCOB(c1ccccc1)C(OC(B(OCCNCCCC)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (35 mg) was obtained by allowing 40.6 mg of bis(4,4′-(phenylhydroxyboryl)benzyl) ether and 23 mg of N-n-butylethanolamine to act in 1 mL of ethanol.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:29]#[N:30])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:29]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:32])([CH3:31])[C:4]([OH:33])=[O:3])=[O:9])[N:11]=1)#[N:30]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc3c(O)c(C(=O)NCC(C)(C)C(=O)O)nc(C#N)c3c2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-[(1-Cyano-4-hydroxy-7-p-tolyloxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid ethyl ester (18 mg, 0.04 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 9 mg. MS: (−) m/z 417.99 (M−1).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:24][O:25][C:26]([C:28]1([NH2:40])[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]1)=[O:27].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][O:25][C:26]([C:28]1([NH:40][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=2)=[O:14])[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:29]1)=[O:27]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
In a round-bottomed flask were combined 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (180 mg, 0.54 mmol), 3-amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (214 mg, 0.87 mmol), EDC (114 mg, 0.59 mmol), and HOBt (80 mg, 0.59 mmol). Then added DMF (2.4 mL) followed by i-Pr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with Et2O (2×). The combined organics were washed with H2O (2×) and brine then dried over Na2SO4 and concentrated. The residue was purified by chromatography over 24 g of SiO2 using EtOAc/hexanes (gradient: 0-40% EtOAc) to afford 276 mg (91%) of 3-{[2-Cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:21]1[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[CH:22]=1>C1COCC1>[Br:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[CH:25][N:24]=[C:23]([Cl:30])[CH:22]=2)=[C:2]([Cl:1])[CH:8]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C(O)c1cnc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cc1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of 2-chloro-4-bromoaniline (6.776 g, 33.1 mmol) in 50 ml anhydrous THF was added LHMDS (50 ml, 50 mmol, 1M/THF) over a period of 15 min at −78° C. It was stirred for an additional 30 min., then a solution of 4,6-dichloronicotinic acid (3 g, 15.7 mmol) in 50 ml THF was added dropwise. After complete addition the mixture was gradually allowed to warm to room temperature and the reaction mixture was stirred for an additional 12 hours. The mixture was quenched with H2O and 1N HCl was added (pH 0-1) followed by brine. It was extracted using THF and dried with Na2SO4. The solvent was removed and the solid crude product was suspended in 200 ml EtOAc. The suspension was heated with stirring at the reflux temperature for 5 min. It was cooled to room temperature and the precipitate was filtered and washed with EtOAc and dried at 50° C. for 5 h in oil pump vacuo to obtain the title compound as an off-white solid (4.05 g, 72%). Rf (CHCl3/MeOH 10:1)=0.3. 1H-NMR (500 MHz, DMSO-D6): δ=10.12 (s, 1H), 8.65 (s, 1H), 7.88 (s, 1H), 7.62-7.57 (dd, 1H), 7.55-7.48 (dd, 1H), 6.67 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@@H:11]1/[CH:16]=[CH:17]/[C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[Li+].Cl>CO.C1COCC1.O>[OH:24][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])/[CH:17]=[CH:16]/[C@H:11]1[CH2:12][CH2:13][C:14](=[O:15])[N:10]1[CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]([OH:25])=[O:2]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC[C@H](O)/C=C/[C@H]1CCC(=O)N1CCCCOCC(=O)O
Temperature: 45 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a solution of {4-[(R)-2-((E)-(S)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic acid methyl ester (0.14 g, 0.4 mmol) in a mixture of 2 mL of methanol and 2 mL THF at room temperature under a nitrogen atmosphere was added an aqueous solution of lithium hydroxide (0.066 g, 1.6 mmol) in 1 mL of water. The reaction was stirred at 45° C. overnight, cooled to room temperature and treated with aqueous hydrochloric acid (1 M) until acidic. The residue was diluted with water (10 mL) and extracted with ethyl acetate. The organic solution was dried (brine, Na2SO4), evaporated and purified by chromatography to yield 28 mg of {4-[(R)-2-((E)-(S)-3-hydroxy-oct-1-enyl)-5-oxo-pyrrolidin-1-yl]-butoxy}-acetic acid; ESMS: m/z (M+) 341.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([CH3:33])=[CH2:32])[CH:28]=[C:27]([Cl:34])[C:26]=1[Cl:35].Cl>CN(C=O)C.CC(=O)OCC.O>[CH3:14][C:4]1([CH3:15])[O:3][B:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:32][C:31]([CH3:33])([C:29]4[CH:28]=[C:27]([Cl:34])[C:26]([Cl:35])=[C:25]([Cl:24])[CH:30]=4)[O:13][N:12]=3)=[CH:10][C:5]1=2
Reactant: C=C(C)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(C)(c4cc(Cl)c(Cl)c(Cl)c4)C3)cc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 37.4 %

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (500 mg, 2.44 mmol) in DMF (10 mL) at rt was added NCS (392 mg, 2.93 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(prop-1-en-2-yl)benzene (277 mg, 1.26 mmol) and TEA (140.4 mg, 1.39 mmol) in DMF (15 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at this temperature for 1 h and then at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2 and then poured into water followed by extraction with EA (100 ml×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE:EA (2:1) to give the final title compound (200 mg, yield 37.5%) as a white solid: 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 7.73-7.62 (m, 5H), 3.79-3.63 (q, 2H), 1.75 (s, 3 H), 1.46 (s, 6H). MS: m/z=424[M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[N:7]=1)=[O:5])C.C1COCC1.O>>[CH2:11]([C:9]1[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:32]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)[CH2:12][CH3:13]
Reactant: CCCc1cc(C(=O)OCC)nn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 88.8 %

Procedure:
5-Propyl-1-[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-pyrazole-3-carboxylic acid ethyl ester (400 mg, 607 μmol) was dissolved in THF (12.0 mL, 148 mmol). A solution of LiOH monohydrate (127 mg, 3.04 mmol) in water (4.0 mL, 222 mmol) was then added and the mixture was stirred at room temperature for about 19 hours. The mixture was then heated to 60° C. overnight. LCMS showed that the reaction was complete, but that two additional side products had also formed. The mixture was partitioned between EtOAc and a saturated ammonium chloride solution. The EtOAc layer was dried over Na2SO4 and concentrated to yield the title compound (340 mg). LCMS showed that the side products were no longer present.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13](Br)[N:12]=2)=[O:10])[NH:6][N:7]=1.NC1C(C(O)=O)=NC=C(C(F)(F)F)N=1.N1NC(N)=CC=1>>[N:7]1[NH:6][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[N:15][C:14]([C:18]([F:20])([F:21])[F:19])=[CH:13][N:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(C(F)(F)F)n[nH]1
Agent: Nc1ccn[nH]1
Agent: Nc1nc(C(F)(F)F)cnc1C(=O)O
Product: Nc1nc(C(F)(F)F)cnc1C(=O)Nc1ccn[nH]1

Procedure:
The title compound was prepared analogously to 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (5-trifluoromethyl-2H-pyrazol-3-yl)-amide (Example 1) using 3-amino-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 6) and 2H-pyrazol-3-ylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:4]3[CH:3]=[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[CH:7]=[CH:6][N:5]=3)=[O:9])[CH2:11][CH2:12]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CC1(C)OB(c2ccccn2)OC1(C)C
Reactant: O=C(c1cc(Br)ccn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: O=C(c1cc(-c2ccccn2)ccn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 120 °C
Yield: 1.3 %

Procedure:
In a 5 ml microwave vial were added 1-[(4-bromo-2-pyridinyl)carbonyl]-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 17) (150 mg, 0.314 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Description 5) (129 mg, 0.627 mmol), bis(triphenylphosphine)palladium(II) chloride (44.0 mg, 0.063 mmol), sodium carbonate (100 mg, 0.941 mmol), 1,2-dimethoxyethane (1.5 ml), ethanol (1.0 ml) and water (0.50 ml). The reaction mixture was heated for 20 minutes at 120° C. in the microwave. The crude material was diluted in EtOH and filtered through celite. The filtrate was concentrated in vacuo then diluted with MeOH and filtered through an SCX cartridge (1 g). All material came out with MeOH wash so product concentrated, diluted with MeOH and filtered through a 5 g SCX column (washed with MeOH, eluted with NH3 0.5M in MeOH). The eluted product was concentrated in vacuo then dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were combined and concentrated under vacuo to give the title compound (2 mg).