Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>>[C@@H:11]1([OH:12])[C@@H:2]([OH:1])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
The results on batch culture behavior of the YS2 strain in a balanced synthetic nutrient medium containing 50 g/l of glucose are presented in FIG. 2 and Table 2. The ammonium sulfate concentration was 10 g/l. FIG. 2 illustrates glucose concentration 10 (g/l, left vertical axis), cell mass level 20 (g/l, left vertical axis), ethanol concentration 30 (g/l, left vertical axis), and inositol concentration 40 (g/l, right vertical axis) over time (hours, horizontal axis). Once again, two phases of microbial growth are apparent in FIG. 2. In the first phase (0--23 h) glucose is consumed to produce cell mass and ethanol. Once again, in the glucose consumption phase no detectable amount of inositol was produced. In the second phase, ethanol was consumed to produce cell mass. As in the previous experiment, about 170 mg/l of inositol was produced toward the end of the second phase.
Reaction SMILES: [CH2:1]([N:8]([C:23](=[O:26])[CH2:24]I)[C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+]>C1COCC1>[CH2:1]([N:8]1[C:23](=[O:26])[CH2:24][O:22][CH:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][CH:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(Cc2ccccc2)C(=O)CI)[C@H](O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2C(C1)OCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-tert-butyl 4-[benzyl(iodoacetyl)amino]-3-hydroxypiperidine-1-carboxylate (172 g, 363 mmol) in THF (1500 mL) was added t-BuOK (48.72 g, 435 mmol) in portions at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was poured into ice-water (400 mL) and extracted with EtOAc (200 mL×2). The organic layer was washed with brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give tert-butyl 1-benzyl-2-oxooctahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate as a mixture of trans diastereomers, which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][C:3]12[CH2:8][C:7]1([CH3:9])[CH2:6][NH:5][CH2:4]2.Cl[CH2:11][C:12]#[C:13][CH2:14][OH:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][C:3]12[CH2:8][C:7]1([CH3:9])[CH2:6][N:5]([CH2:11][C:12]#[C:13][CH2:14][OH:15])[CH2:4]2
Reactant: CC12CNCC1(C)C2
Reactant: OCC#CCCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC12CN(CC#CCO)CC1(C)C2
Temperature: 25 °C

Procedure:
To a stirring solution of 1,5-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride (0.3 gm, 2 mmol) in chloroform (50 ml), 1-chloro-4-hydroxy-2-butyne (0.11 gm, 1 mmol), followed by triethylamine (0.3 gm, 3 mmol) were added. The reaction mixture was refluxed for 3 hours and then allowed to cool to room temperature. The solvents were evaporated in vacuo. The residual oil was purified by column chromatography using silicagel (100-200 mesh), eluting the compound with 50-50 ethyl acetate-hexane mixture.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](=[O:30])[CH2:18][C:19](=[O:29])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>O1CCCC1>[NH2:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17](=[O:30])[CH2:18][C:19](=[O:29])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Reaction time: 1 h
Yield: 34.9 %

Procedure:
To a solution of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (22 mg, 54 μmol, synthesized in Example 278) in 1 mL of tetrahydrofuran was added 2 mL of 4N HCl/dioxane at room temperature. After being stirred at the same temperature for 1 h, the reaction mixture was neutralized with saturated NaHCO3 aqueous solution. The mixture was extracted with chloroform, and the organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 50/50) to obtain the title compound as a solid (5.8 mg, 35%) having the following characteristics.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[P:33](=[O:40])([O:37]CC)[O:34][CH2:35][CH3:36])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:20])([CH3:21])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[P:33](=[O:37])([OH:40])[O:34][CH2:35][CH3:36])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOP(=O)(O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 45 °C
Yield: 64.2 %

Procedure:
A solution of intermediate 187, diethyl 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorophenylphosphonate (0.115 g, 0.20 mmol) in tetrahydrofuran (3 ml)/ethanol (3 mL) was treated with 1 N aqueous sodium hydroxide (1.0 ml, 1.0 mmol) and the resulting mixture heated at 45° C. for 2 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified on a Shimadzu automated preparative HPLC system (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) to give 0.070 g (64% yield) of the title material as a clear oil. 1HNMR 400 MHz (CDCl3) δ ppm: 1.37 (3H, t, J=7.1 Hz, CH3), 1.62 (6H, s, 2×CH3), 4.04 (4H, m, 2×CH2), 4.18 (2H, m, OCH2), 4.75 (2H, broad d, J=5 Hz, NCH2), 5.32 (2H, s, OCH2), 7.21 (1H, m, aromatic), 7.30–7.33 (3H, m, aromatics), 7.38–7.40 (2H, m, aromatics), 7.47–7.52 (1H, m, aromatic), 7.56–7.63 (1H, m, aromatic), 8.56 (1H, broad t, NH). HRMS (ESI+) calculated for C26H30FN3O7P [M+H+]: 546.1805. found: 546.1786.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12](C)[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:21][C:22]1[C:23]([CH:32]2[CH2:34][O:33]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]>>[F:21][C:22]1[C:23]([CH:32]([OH:33])[CH2:34][N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[C:7](=[O:11])[O:8][CH2:9][C:10]=4[C:2]=3[CH3:1])[CH2:19][CH2:18]2)=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=1)[C:27]#[N:28]
Reactant: COc1cc(C2CO2)c(F)cc1C#N
Reactant: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O
Product: COc1cc(C(O)CN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)c(F)cc1C#N

Procedure:
5-fluoro-4-(1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-(methyloxy)benzonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-(1-methyl-2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one and 5-fluoro-2-(methyloxy)-4-oxiran-2-ylbenzonitrile.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[C:11]([C:16]2[C:20]([Cl:21])=[C:19]([O:22][CH:23]([F:25])[F:24])[N:18]([CH3:26])[N:17]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[Cl:21][C:20]1[C:16]([C:11]2[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([N:8]([S:28]([CH3:27])(=[O:30])=[O:29])[S:28]([CH3:27])(=[O:30])=[O:29])[CH:10]=2)=[N:17][N:18]([CH3:26])[C:19]=1[O:22][CH:23]([F:24])[F:25]
Reactant: Cn1nc(-c2ccc(Cl)c(N)c2)c(Cl)c1OC(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(-c2ccc(Cl)c(N(S(C)(=O)=O)S(C)(=O)=O)c2)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g (22 mmol) of triethylamine were added to a solution of 3 g (10 mmol) of 3-(3-amino-4-chlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole in 50 ml of dichloromethane. 2.5 g (21 mmol) of methanesulfonyl chloride were added dropwise to this mixture at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then washed with water. The organic phase was subsequently dried over magnesium sulfate and concentrated. The solid product was washed with a little diethyl ether. Yield: 3.1 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>C(Cl)Cl.O>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:12][C:6]2([C:4]([O:3][CH3:2])=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NS(=O)(=O)c2ccc(OC)cc2)CCCCC1
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid methyl ester hydrochloride (32 g, 165 mmol) was suspended in DCM (1000 ml), and diisopropylethylamine (84.9 ml, 496 mmol) was added thereto. A solution of 4-methoxybenzenesulfonyl chloride (51.2 g, 248 mmol) dissolved in DCM (150 ml) was added dropwise at 0° C., and stirring was carried out overnight at room temperature. Aqueous 1 M HCl (150 ml) and water (50 ml) were added and the phases were separated. The organic phase was dried over sodium sulfate and concentrated to dryness. The product was purified by column chromatography on silica gel (DCM/methanol 99:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH2:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27](O)=[O:28])=[CH:15][CH:14]=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[NH:11][C:27]([C:20]1[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:24][C:23](=[O:25])[NH:22][C:21]=1[CH3:26])=[O:28]
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1
Reactant: Nc1cc2cn[nH]c2cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2Cl)C(c2ccc(Cl)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.2 %

Procedure:
6-Chloro-1H-indazol-5-amine (64 mg, 0.382 mmol, 1.0 equiv) was combined with the product from Example 4, Step 2 (101 mg, 0.382 mmol, 1.0 equiv), EDC (88 mg, 0.458 mmol, 1.2 equiv) and Et3N (64 μL, 0.458 mmol, 1.2 equiv) in DMF (1 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was concentrated en vacuo. The residue was purified by flash chromatography (0-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (15-98% CH3CN/H2O, adjusted to pH 10 w/NH4OH over 13 minutes, retention time 6.56 min) to provide 40 mg (25%) of the title compound as a white solid. MS (ES+) m/e 416 [M+H]+
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[CH2:25]([NH:27][C:28]1([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29]1)[CH3:26]>C(O)CO>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:10][C:5]2[N:6]([C:2]([N:30]3[CH2:31][CH2:32][C:28]([NH:27][CH2:25][CH3:26])([C:33]([NH2:35])=[O:34])[CH2:29]3)=[N:3][N:4]=2)[N:7]=1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Reactant: CCNC1(C(N)=O)CCNC1
Solvent: OCCO
Product: CCNC1(C(N)=O)CCN(c2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 26.9 %

Procedure:
A suspension of 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (113 mg, 0.3 mmol) and 3-(ethylamino)pyrrolidine-3-carboxamide (94 mg, 0.6 mmol) in ethylene glycol (2 mL) was stirred at 110° C. for 2 h. Analysis by HPLC/MS indicated the reaction was not complete. Additional 3-(ethylamino)pyrrolidine-3-carboxamide (47 mg, 0.3 mmol) was added. The reaction continued at 110° C. for 1 h more. After cooling to room temperature, the reaction mixture was loaded onto a silica gel cartridge (12 g), eluted with a gradient of MeOH (0-6%) in CH2Cl2 to obtain 40 mg of desired product with 90% purity. The product was further purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 40% to 90% B, 8 min gradient, 90% B hold for 3 min, (A=90% H2O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H2O, 90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detection at 220 nm) to yield the product as a TFA salt. The product was dissolved in EtOAc, washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was lyophilized in acetonitrile to afford 30 mg (20%) of the title compound as a yellow powder. HPLC/MS (method A): retention time=2.75 min, (M+H)+=496.2. 1H NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H), 7.28-7.38 (m, 4H), 7.19-7.26 (m, 2H), 7.01-7.07 (m, 2H), 5.39 (s, 1H), 4.00-4.15 (m, 5H), 2.54-2.65 (m, 3H), 2.12 (m, 1H), 1.40-1.55 (m, 1H), 1.10 (t, J=7.09 Hz, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].C1C(=O)N([Cl:21])C(=O)C1>CO>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:21])=[C:8]([CH3:13])[C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1scc(C)c1C(N)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CO
Product: CC(=O)Nc1sc(Cl)c(C)c1C(N)=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-acetylamino-4-methylthiophene-3-carboxylic acid amide (2 g, 10.1 mmol) is dissolved in MeOH (40 mL). NCS (1.47 g, 11.1 mmol) is added and the resulting suspension is stirred at 60° C. for 1 h. The mixture is then concentrated under vacuo, the obtained residue is dissolved in DCM and washed with aqueous NaHCO3. The organic phase is then dried over MgSO4, filtered and concentrated under vacuo to yield the desired compound which is used as such.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=2[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:15][CH2:16]2)=[O:21])=[C:23]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[CH:24]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3N3CCOCC3)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3N3CCOCC3)CC2)c(C)c1
Yield: 98.2 %

Procedure:
To a mixture of ethyl 2-chloro-4-nitrobenzoate (1.5 g), palladium acetate (73.3 mg), 2-(dicyclohexylphosphino)biphenyl (229 mg), tripotassium phosphate (1.94 g) and morpholine (0.57 mL) was added 1,2-dimethoxyethane (23 mL), and the mixture was stirred with heating under reflux for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give ethyl 2-(morpholin-4-yl)-4-nitrobenzoate (220 mg). The obtained ethyl 2-(morpholin-4-yl)-4-nitrobenzoate (220 mg) and 1-(2,4-dimethylphenyl)piperazine (149 mg) were dissolved in ethanol (3.5 mL), 1N aqueous sodium hydroxide solution (1.1 mL) was added, and the mixture was stirred at 50° C. To the reaction mixture was added 1N hydrochloric acid (1.1 mL), 1-(2,4-dimethylphenyl)piperazine (149 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (218 mg) were added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, the obtained residue was purified by silica gel column chromatography to give [4-(2,4-dimethylphenyl)piperazin-1-yl][2-(morpholin-4-yl)-4-nitrophenyl]methanone (206 mg). Then, to a solution of ethanol (3 mL) and water (1 mL) were added ammonium chloride (294 mg) and iron (211 mg), and the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl][2-(morpholin-4-yl)-4-nitrophenyl]methanone (206 mg) was added while stirring at 60° C.-70° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (188 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][O:23]C)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].B(Br)(Br)Br.C(=O)(O)[O-].[Na+].CCCCCCC>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([NH:20][CH2:21][CH2:22][OH:23])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O
Product: O=c1onc(-c2nonc2NCCO)n1-c1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 729.8 %

Procedure:
To a solution of 4-(3-bromo-4-fluorophenyl)-3-(4-(2-methoxyethylamino)-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (can be prepared according to Example 1, steps A-G; 1232 g, 3.08 mol) in dichloromethane (12 L) stirring in a 22 L flask at 0° C. was added boron tribromide (354 mL, 3.67 mL) dropwise at a rate so that the temperature did not exceed 10° C. After stirring on ice for 1 h, a solution of saturated aqueous sodium bicarbonate (2 L) was carefully added at a rate so that the temperature did not exceed 20° C. (addition time 10 min). The resulting mixture was transferred to a 50 L separatory funnel, diluted with water (10 L), and the pH of the aqueous layer adjusted from 1 to 8 using solid sodium bicarbonate. The layers were separated, and the organic layer was washed with water (10 L), and the solvents removed in vacuo to afford a tan solid (24 mol processed in multiple runs, 9.54 kg, quant. yield). The material was slurried in 4 volumes of 7:1 heptane:ethyl acetate (4×22 L flasks), filtered, and dried to furnish the title compound as a tan solid (8679 g, 94%). The product was a mixture of the hydroxy- and the corresponding bromo-species.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6](Cl)[C:5]([F:10])=[C:4](Cl)[C:3]=1[F:12].C([O-])(=O)C.[Na+]>[Pd].O>[F:8][C:7]1[CH:2]=[C:3]([F:12])[CH:4]=[C:5]([F:10])[CH:6]=1
Reactant: Fc1c(Cl)c(F)c(Cl)c(F)c1Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Fc1cc(F)cc(F)c1
Temperature: 140 °C
Yield: 88.2 %

Procedure:
Palladium on carbon (10%, 410 mg), 100 g of water, 21.8 g of 1,3,5-trichloro-2,4,6-trifluorobenzene and 32.9 g of sodium acetate (4.5 equivalents) were placed in a pressure vessel. After flushing with nitrogen, the pressure vessel was heated to 140° C. and pressurized with 12 bar of hydrogen. A hydrogen pressure of 12 bar was maintained at 140° C. for about 12 hours while stirring vigorously. After cooling to 20-25° C., the pressure vessel was depressurized. The two-phase reaction solution was filtered and the phases were then separated. This gave a yield of 88.2% of 1,3,5-trifluorobenzene.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CCN(C(C)C)C(C)C.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[O:33])=[CH:35][CH:36]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)c2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (8) (6.27 g, 33.5 mmol) in DCM (100 mL) was added DIEA (8.75 mL, 50.3 mmol) and then 4-tert-butylbenzoyl chloride (8.0 mL, 43.6 mmol) in drop-wise manner. The mixture was stirred for 3 h at RT, diluted with DCM, washed with 1N NaOH, dried, and concentrated. The residue was subjected to flash column chromatography with 0 to 10% EtOAc in DCM to give (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (11.0 g, 91%). To a solution of (R)-tert-butyl 3-(4-tert-butylbenzamido)piperidine-1-carboxylate (850 mg, 2.36 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 190 mg, 4.72 mmol). The mixture was stirred at RT for 10 min and then iodomethane (0.44 mL, 7.08 mmol) was added. The mixture was stirred at RT for 1 h, and diluted with 150 mL EtOAc. The mixture was washed with water ×2, dried, and concentrated. The residue was subjected to flash column with 0 to 3% MeOH in DCM to afford (R)-tert-butyl 3-(4-tert-butyl-N-methylbenzamido)piperidine-1-carboxylate (9) in quantitative yield. It was treated with 15 mL 4N HCl in dioxane at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-4-tert-butyl-N-methyl-N-(piperidin-3-yl)benzamide (10) HCl salt in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[SH:10].Cl[C:12]([CH2:14]Cl)=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:3]2[S:10][C:12]([CH3:14])=[CH:13][C:4]=2[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(S)c(Br)cc1F
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2c(F)c(F)cc(Br)c2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
2-Bromo-4,5-difluorothiophenol (4.68 g, 20.8 mmol), 2,3-dichloro-1-propene (2.1 mL, 22.9 mmol), potassium carbonate (3.45 g, 24.9 mmol), and acetone (100 mL) were added, and stirred at 60° C. for 2 hours. The solvent was distilled away under reduced pressure, and after diluted with ethyl acetate, the resultant was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away, and to the resulting residue, dimethylaniline (50 mL) was added, and stirred at 220° C. overnight. After cooling, ethyl acetate and a 2 N hydrochloric acid aqueous solution were added to the reaction solution and stirred. After the insoluble material was filtered off, extraction was performed with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane) to thus obtain the title compound.