Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3=[C:15]([O:28][CH3:29])[C:16]([C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:19])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1.[CH3:31]NCCN1CCCC1.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3=[C:15]([O:28][CH3:29])[C:16]([C:18]([N:20]([CH3:31])[CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:19])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1
Reactant: COc1c(C(=O)NCCN2CCCC2)cn2ncnc(Nc3ccc(Br)cc3F)c12
Reactant: CNCCN1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)CCN2CCCC2)cn2ncnc(Nc3ccc(Br)cc3F)c12
Yield: 86.1 %

Procedure:
To a solution of Compound A of Example 98 (20 mg, 0.052 mmol) in DMF (1 mL) was added 1-(2-methylaminoethyl)-pyrrolidine (10 mg, 0.078 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (25 mg, 0.056 mmol). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC, the product was collected, converted to its HCl salt and lyophilized to provide 22 mg (80%) of the title compound. MS: [M+H]+=491,493 (1:1);1H NMR (CD3OD): δ 8.27 (s, 1H), 7.83 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.65–7.55 (m, 2H), 4.09 (s, 3H), 3.99–3.96 (m, 4H), 3.85 (br s, 2H), 3.58–3.51 (m, 2H), 3.29–3.15 (m, 5H), 2.19–2.07 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH3:14])=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Br:20][C:21]1[CH:22]=[C:23]([C:28](Cl)=[O:29])[C:24]([Cl:27])=[N:25][CH:26]=1.BrC1C=C(C(O)=O)C(O)=NC=1.O=S(Cl)Cl>CC#N>[Cl:27][C:24]1[C:23]([C:28]([NH:1][C:2]2[C:3]([NH:12][CH2:13][CH3:14])=[N:4][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:7]=2)=[O:29])=[CH:22][C:21]([Br:20])=[CH:26][N:25]=1
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: CCNc1nc(C(F)(F)F)ccc1N
Agent: O=C(O)c1cc(Br)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCNc1nc(C(F)(F)F)ccc1NC(=O)c1cc(Br)cnc1Cl
Reaction time: 0.08 h

Procedure:
To a cooled solution of 3-amino-2-(ethylamino)-6-trifluoromethyl pyridine (1 g, 4.9 mmol) in MeCN (24 mL) was added solid NaHCO3 (906 mg, 11 mmol). After 5 min, crude 5-bromo-2-chloro-3-pyridinecarbonyl chloride (prepared from 5-bromo-2-hydroxy-3-pyridinecarboxylic acid and SOCl2 [as described by T. W. Gero et al. in Synth. Commun. 1989,19,553-559 (incorporated herein by reference) but with omission of the aqueous work-up] was added (1 equiv., 4.9 mmol). After 2 h, the reaction mixture was poured over ice/H2O (1.5 L) and the resulting solid was filtered, rinsed with H2O and then hexane. After drying under reduced pressure overnight, the title compound was obtained as a light brown solid (1.6 g, 77% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([C:35]2[NH:39][N:38]=[N:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:39]4[C:35]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:36][N:37]=[N:38]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: c1ccc(-c2cnn[nH]2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4nncc4-c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 5-phenyl-1H-[1,2,3]triazole.
Reaction SMILES: C([O:5][C:6]1[CH:7]=[C:8]([C@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)(C)(C)C.S(=O)(=O)(O)O.[OH-].[Na+].C1(O)C=CC=CC=1>O>[NH2:14][C@@H:12]([C:8]1[CH:7]=[C:6]([OH:5])[CH:11]=[CH:10][CH:9]=1)[CH3:13]
Reactant: C[C@@H](N)c1cccc(OC(C)(C)C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Oc1ccccc1
Product: C[C@@H](N)c1cccc(O)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
(R)-1-(3-tert-Butoxyphenyl)ethylamine (5 g, 25.9 mmol) was suspended in water (10 ml) and admixed with 38% sulfuric acid up to a pH of 1. The mixture was heated to 85° C. and stirred at this temperature for another three hours, after which the gas evolution had stopped. The colorless mixture was allowed to cool to room temperature and then 20% NaOH was added dropwise up to a pH of 9.1, whereupon the protected phenol precipitated out in the form of a white powder. This was filtered off with suction and dried overnight in a drying cabinet. 2.6 g (73%) of (R)-3-(1-aminoethyl)phenol were obtained in the form of a pale yellow powder.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH2:4][C:5](=O)[C:6]([F:9])([F:8])[F:7].[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:16]=1[NH:25][NH2:26]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:6]([F:9])([F:8])[F:7])[N:25]([C:16]2[C:17]([Cl:24])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[Cl:14])[N:26]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: NNc1c(Cl)cc([N+](=O)[O-])cc1Cl
Solvent: CO
Product: O=[N+]([O-])c1cc(Cl)c(-n2nc(C(F)(F)F)cc2C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1,1,5,5,5-Hexafluoro-2,4-pentanedione (0.56 g, 2.70 mmol) is added to a solution of 2,6-dichloro-4-nitrophenylhydrazine (0.30 g, 2.35 mmol) in 20 ml of methanol chilled in an ice bath. The mixture is stirred overnight at RT, after which the methanol is removed in vacuo. The residue is dissolved in toluene and a catalytic amount of p-toluenesulfonic acid (pTSOH) added. The mixture is heated under reflux and stirred for 2 hours, after which it is allowed to cool to RT and the solvent is removed in vacuo. The resulting crystals are dissolved in xylene, 40 mg of pTSOH is added and the mixture is heated under reflux for 2 hours. The resulting mixture is cooled, washed with methylene chloride, concentrated in vacuo and purified by flash chromatography to give 3,5-bis(trifluoromethyl)-1-(2,6-dichloro-4-nitrophenyl)pyrazole. Following the procedure of Example 5, the nitrophenylpyrazole is reduced by treatment with platinum dioxide and hydrogen to give 3,5-dichloro-4-[3,5-bis-(trifluoromethyl)-1-pyrazolyl]aniline.
Reaction SMILES: [NH2:1][C:2]1([CH2:15][NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH2:6][CH2:5][N:4]([C:7]2[C:12](Br)=[C:11]([NH2:14])[N:10]=[CH:9][N:8]=2)[CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1([CH2:15][NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH2:6][CH2:5][N:4]([C:7]2[C:12]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[C:11]([NH2:14])[N:10]=[CH:9][N:8]=2)[CH2:3]1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ncnc(N2CCC(N)(CNC(=O)c3ccc(F)cc3F)C2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc(N2CCC(N)(CNC(=O)c3ccc(F)cc3F)C2)c1-c1ccc(F)cc1
Temperature: 100 °C
Yield: 61 %

Procedure:
A mixture of N-{[3-amino-1-(6-amino-5-bromopyrimidin-4-yl)pyrrolidin-3-yl]methyl}-2,4-difluorobenzamide (70.0 mg; 0.16 mmol; 1.0 eq.), 4-fluorophenylboronic acid (45.8 mg; 0.33 mmol; 2.0 eq.), palladium acetate (1.8 mg; 0.01 mmol; 0.05 eq.), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (6.7 mg; 0.02 mmol; 0.10 eq.) and cesium carbonate (160.1 mg; 0.49 mmol; 3.0 eq.) in dioxane (4 ml) and water (0.5 ml) in the microwave vial was heated at 100° C. for 30 min. The reaction mixture was workup and the crude was purified by pre-HPLC (Waters, acetonitrile/0.1% NH4OH in water) to afford the title compound in 61% yield. LC-MS: (M+1=443, obsd.=443).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:19](OC)=[O:20])=[C:7]([CH2:17][CH3:18])[N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][C:9]=12)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[OH-].[Na+]>ClCCl.CCOCC.O>[CH2:17]([C:7]1[N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][C:9]2=[C:5]([CH2:3][OH:2])[C:6]=1[CH2:19][OH:20])[CH3:18]
Reactant: CCc1c(C(=O)OC)c(C(=O)OC)c2n1-c1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CCc1c(CO)c(CO)c2n1-c1ccccc1C2
Reaction time: 0.25 h

Procedure:
A solution of 3-ethyl-8H-3a-aza-cyclopenta[a]indene-1,2-dicarboxylic acid dimethyl ester (2.5 g, 8.35 mmol) in anhydrous dichloromethane (30 mL) was added dropwise to a stirred suspension of LiAlH4 (0.793 g, 20.87 mmol) in anhydrous ether (30 mL) at 0° C. The mixture was stirred for 15 min after the addition was completed. The excess hydride was carefully decomposed by the slow, sequential addition of water (1.3 mL), 15% NaOH aqueous solution (1.3 mL), and water (3.6 mL). The solid inorganic salt was filtered and washed with dichloromethane. The combined filtrate and washings was concentrated in vacuo to dryness. The solid residue was triturated with ether, collected the solid product by filtration, and dried in vacuo to yield (3-ethyl-2-hydroxymethyl-8H-3a-azacyclopenta[a]inden-1-yl)-methanol (DA-1099), 1.31 g (64%): mp 131-133° C.; 1H NMR (DMSO-d6) δ 1.18 (3H, t, J=7.3 Hz, Me), 2.89 (2H, q, J=7.3 Hz, CH2), 3.81 (2H, s, CH2), 4.36 (2H, d, J=5.2, CH2O), 4.45 (2H, d, J=5.2 Hz, CH2O), 4.47 (1H, t, J=5.2 Hz, exchangeable, OH), 4.63 (1H, t, J=5.2 Hz, exchangeable, OH), 7.06-7.09 (1H, m, ArH), 7.30-7.34 (1H, m, ArH), 7.37-7.39 (1H, m, ArH), 7.45-7.46 (1H, m, ArH). Anal. Calcd for C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C, 73.22; H, 6.94; N, 5.71.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN1CCCC1=O>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: c1ccc2c(c1)CCCCCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCCCCc4ccccc43)c2cc1OC
Yield: 67 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 67% yield from 1,2,3,4,5,6-hexahydro-benzo[b]azocine (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 204°-207° C.; GC-MS: 349 (M+); anal. RP18-HPLC RT: 5.25 min.).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[H-].[Na+].[CH3:15]I>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:15]
Reactant: CI
Reactant: Oc1ccc2ccccc2c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ccccc2c1Br
Temperature: 25 °C

Procedure:
1-Bromo-2-naphthol (2.0 g, 8.97 mmol) was dissolved in THF (20 mL), and the solution was cooled to 0 deg in an ice bath. NaH was added thereto (60% dispersion of in mineral oil, 430 mg 10.8 mmol), followed by MeI (1.2 mL, 19.6 mmol) as bubbling subsided. The reaction mixture was heated to reflux overnight, cooled to room temperature, and water added dropwise thereto until bubbling subsided. The reaction mixture was diluted with EtOAc, and the organic layer was washed once each with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 10% to 50% EtOAc/hexanes to afford 1-bromo-2-methoxynaphthalene as a solid. LC/MS (ES MS, M+H+ found: 238) and proton NMR (400 MHz, CDCl3) δ 4.04 (s, 3H), 7.28 (d, J=9 Hz, 1H), 7.42 (t, J=7 Hz, 1H), 7.58 (t, J=6.8 Hz, 1H), 7.8 (dd, J=9 Hz, 2H), 8.2 (d, J=8.6 Hz, 1H).
Reaction SMILES: C([N:3]1[CH2:17][CH2:16][C:15]2[C:6](=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH3:18])[CH2:5][CH2:4]1)C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([N:3]1[CH2:17][CH2:16][C:15]2[C:6](=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH3:18])[CH2:5][CH2:4]1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCN1CCc2nc3ccccc3c(C)c2CC1
Product: CCOC(=O)N1CCc2nc3ccccc3c(C)c2CC1
Yield: 10 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 3-ethyl-1,2,4,5-tetrahydro 11-methyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 59.
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([O:1][CH:2]([C:4]1[C:13]2[O:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:10][C:9](=[O:20])[C:8]=2[CH:7]=[C:6]([CH3:21])[CH:5]=1)[CH3:3])(=[O:32])=[O:31]
Reactant: Cc1cc(C(C)O)c2oc(-c3ccncc3)cc(=O)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(C)OS(C)(=O)=O)c2oc(-c3ccncc3)cc(=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8-(1-hydroxyethyl)-2-(4-pyridinyl)-6-methyl-4H-1-benzopyran-4-one (2.4 g) in dichloromethane (100 ml) in an ice bath, was treated with triethylamine (1.3 ml) followed by methanesulfonylchloride (0.67 ml) and the mixture stirred at 0° C. for 30 minutes. The solution was then washed with 0.1N HCl (aq) (2×30 ml), dried (Na2SO4) and the solvent removed to yield a oily brown solid, which was not further purified.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:19][C:20]1[C:25](B(O)O)=[CH:24][CH:23]=[C:22]([F:29])[N:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[F:19][C:20]1[C:25]([C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]3)=[CH:13][CH:14]=2)=[CH:24][CH:23]=[C:22]([F:29])[N:21]=1
Reactant: OB(O)c1ccc(F)nc1F
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(F)nc3F)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 0,05 M of 4-(trans-4-pentylcyclohexyl)bromobenzene, 0,06 M of 2,6-difluoropyridine-3-boronic acid, 1,25 g of Pd(PPh3)4, 100 ml of toluene, 40 ml of ethanol and 50 ml of 2 M Na2CO3 -solution is heated at 60 ° C under stirring for 2 hours. Customary work-up and recrystallisation from ethanol gives 2,6-difluoro-3-[4-(trans-4-pentylcyclohexyl)phenyl]-pyridine with C 58° N 107° I.
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCN(c2ccc(C(F)(F)F)cn2)C[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 115 °C
Yield: 47 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride was dissolved in dimethyl sulfoxide (1.0 mL). 2-Chloro-5-(trifluoromethyl)pyridine (36.0 mg, 0.198 mmol, 1.9 equivalents) and sodium carbonate (82.0 mg, 0.774 mmol, 7.5 equivalents) were added, and the resulting suspension was heated to 115° C. for 14 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, and then dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified via silica chromatography on 2 sequentially linked 4 g silica cartridges, eluted with 25:75 to 0:100 heptanes:ethyl acetate to give the titled compound (26 mg, 0.055 mmol, 47% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (s, 1H), 8.06 (s, 1H), 7.95 (s, 1H), 7.66 (dd, J=9.0, 2.2 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 5.56-5.20 (m, 1H), 4.63 (d, J=14.4 Hz, 1H), 4.34 (d, J=15.2 Hz, 1H), 4.03 (td, J=9.3, 3.7 Hz, 1H), 3.90 (d, J=12.0 Hz, 1H), 3.83 (dd, J=16.0, 8.0 Hz, 1H), 3.56-3.41 (m, 1H), 3.36 (dd, J=14.4, 9.7 Hz, 1H), 2.72 (dd, J=12.1, 7.3 Hz, 2H), 2.66 (ddd, J=14.2, 9.1, 5.1 Hz, 1H), 2.15 (d, J=14.0 Hz, 1H), 2.06-1.91 (m, 1H), 1.04-0.88 (m, 4H); 1H NMR (400 MHz, pyridine-d5) δ ppm 8.64 (s, 1H), 8.25 (d, J=1.2 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.79 (dd, J=9.1, 2.4 Hz, 1H), 6.90 (d, J=9.1 Hz, 1H), 5.53-5.38 (m, 1H), 4.67 (d, J=14.3 Hz, 1H), 4.46 (d, J=15.4 Hz, 1H), 4.14 (d, J=13.2 Hz, 1H), 4.04 (ddd, J=18.1, 11.2, 4.4 Hz, 2H), 3.57-3.40 (m, 2H), 2.96-2.80 (m, 2H), 2.62 (ddd, J=14.1, 9.0, 5.3 Hz, 1H), 2.16 (dd, J=14.0, 3.3 Hz, 1H), 2.04 (td, J=8.2, 4.1 Hz, 1H), 1.15-1.04 (m, 2H), 1.04-0.83 (m, 2H); MS (ESI+) m/z 434.1 (M+H)+; [α]D24.6=37.3 (c=0.85, CH3OH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1.[Na+].[Cl-]>CN1C(=O)CCC1>[CH3:52][O:51][C:49](=[O:50])[C:48]1[CH:53]=[CH:54][C:45]([NH:44][C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])=[CH:46][CH:47]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(NC(=O)CCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
Hexadecanedioic acid mono-tert-butyl ester (0.4 g, 1.17 mmol) was dissolved in NMP (6 mL). N-Ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.223 g, 0.1.17 mmol) and 1-hydroxy-7-azabenzotriazole (0.159 g, 1.17 mmol) was added and the mixture was stirred at 50° C. for 1 hour and then allowed to cool to room temperature. Diisopropylethylamin (0.6 mL, 3.5 mmol) was added followed by methyl 4-aminobenzoate (0.353 g, 2.34 mmol). The mixture was stirred overnight under nitrogen at room temperature. The mixture was poured into saturated aqueous NaCl (50 mL), washed with diethylether (3×100 mL between ethyl acetate. The organic phases were collected, dried (Na2SO4) and solvent removed in vacuo. The crude material was purified on silica using ethyl acetate/heptane (50:50), to give pure 4-(15-tert-Butoxycarbonylpentadecanoylamino)benzoic acid methyl ester (235 mg, 42%)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:18]1[CH:19]=[CH:20][C:15]([F:14])=[CH:16][C:17]=1[F:21])=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: Fc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(F)cc1F

Procedure:
6-Bromohexanoyl chloride (2 g), 1,3-difluorobenzene (20 ml) and aluminum chloride (1.31 g) were reacted and treated in the same manner as in Preparation Example 105 to give 1.16 g of 6-bromo-1-(2,4-difluorophenyl)-1-hexanone.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([OH:29])[CH3:28].N(C(OCC)=O)=NC(OCC)=O.[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1O)=[O:45]>C1COCC1.CN(C=O)C>[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1[O:29][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH3:28])=[O:45]
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1O
Reactant: CC(O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Triphenyl phosphine (124 mg, 0.47 mmol, 1.5 Eq.) was added to a stirred solution of 1-(2-Chloro-phenyl)-ethanol (74 mg, 0.47 mmol, 1.5 Eq.) in anhydrous THF (5 mL) at 0° C. under nitrogen. The reaction was stirred at this temperature for 30 minutes, then diethyl azodicarboxylate (75 μL, 0.47 mmol, 1.5 Eq.) was added dropwise and the reaction stirred at 0° C. for a further 1 hour. 3-Hydroxy-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl ester (100 mg, 0.32 mmol, 1.0 Eq.) in anhydrous DMF (2 mL) was added and the reaction stirred for a further 1 hour at 0° C. then allowed to warm to ambient temperature overnight. The crude reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (2×20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (88 mg, 0.19 mmol, 73%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.93 (3H, s), 5.84 (1H, q), 6.70 (1 h, br s), 6.74 (1H, s), 7.02 (1H, t), 7.21-7.40 (5H, m), 7.51 (1H, d), 7.63 (1H, d), 8.12 (1H, s).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][OH:22])=[CH:12][C:7]=2[O:6][CH2:5]1.N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>ClCCl>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:21]([OH:22])[C:30](=[O:31])[O:32][CH3:33])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: CON=C1COc2cc(OCc3ccccc3NO)ccc21
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON=C1COc2cc(OCc3ccccc3N(O)C(=O)OC)ccc21
Reaction time: 8 h
Yield: 35.8 %

Procedure:
A solution of 4.8 g of N-[2-(3-methoxyimino-2,3-dihydro-benzofuran-6-yloxymethyl)phenyl]-N-hydroxyamine and 1.3 g of pyridine in 50 ml of dichloromethane was cooled to 0° C. 1.4 g of methyl chloroformate was dropped into the solution. The temperature was slowly elevated to room temperature, and the reaction was further carried out for 8 hours. After the completion of the reaction, the reaction liquid was washed with a dilute aqueous hydrochloric acid solution and aqueous NaCl solution and then dried over anhydrous magnesium sulfate. After the concentration under reduced pressure, the obtained residue was dissolved in a mixed solution of 30 ml of methanol and 20 ml of tetrahydrofuran. 1.4 g of anhydrous potassium carbonate was added to the obtained solution, and they were stirred for 4 hours. Water and diethyl ether were added to the reaction solution, and the resultant mixture was neutralized with a dilute aqueous hydrochloric acid solution. After the extraction with diethyl ether, the extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (hexane:ethyl acetate) to obtain 1.9 g of methyl N-[2-(3-methoxyimino-2,3-dihydrobenzofuran-6-yloxymethyl)phenyl]-N-hydroxycarbamate [1H-NMR (CDCl3) (ppm): 3.77 (3H, s), 3.93 (3H, s), 5.03 (2H, s), 5.13 (2H, s), 6.49-7.50 (m)].