Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>CN(C)C=O>[CH3:21][S:22]([O:14][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[C:5]([S:9][CH2:10][CH:11]([CH3:12])[CH3:13])[N:4]=1)(=[O:24])=[O:23]
Reactant: CC(C)CSc1nc(O)c(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CSc1nc(OS(C)(=O)=O)c(Cl)cc1Cl
Temperature: 50 °C
Yield: 73.8 %

Procedure:
6.0 g of 3,5-dichloro-6-isobutylthio-2-pyridinol and 3.0 g of anhydrous sodium carbonate were suspended in 25 ml of N,N-dimethylformamide, followed by stirring. 3.3 g of methanesulfonyl chloride was added dropwise to the suspension at 10° C. The obtained mixture was allowed to stand to lower the temperature to room temperature, heated to 50° C. and stirred for 2.5 hours. The reaction mixture was poured into 200 ml of chilled water and extracted with ether twice. The ether layer was washed with 5% aqueous caustic soda and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (with n-hexane and toluene) to obtain 5.8 g of objective 3,5-dichloro-6-isobutylthio-2-pyridyl methanesulfonate as a colorless oil (yield: 73.8%).
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3].S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:17][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(=O)NCc1ccc(C(C)O)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)NCc1ccc(C(C)Cl)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-(1-hydroxyethyl)phenylmethyl)acetamide (5.26 g) in chloroform (40 ml) was added dropwise a solution of thionyl chloride (2.1 ml) in chloroform (10 ml) at below 5° C. over 20 min. The mixture was stirred at 30° C. for 1 hr. The mixture was poured into a saturated sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (elution solvent; methanol:chloroform=4:96) to give the title compound (4.08 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[CH:19]=2)[NH:16][C:15]([C:24](O)=[O:25])=[CH:14]3)=[CH:6][CH:5]=1.O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[OH-].[NH4+]>O.CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]([CH3:22])[CH3:23])[CH:19]=2)[NH:16][C:15]([C:24]([NH2:28])=[O:25])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: On1nnc2ccccc21
Reactant: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C(=O)O)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Oc2cc(OC(C)C)c3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A mixture of 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(1-methylethoxy)-1H-indole-2-carboxylic acid (1.43 g), 1-hydroxybenzotriazole (810 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.15 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 30 min. An aqueous solution of ammonium hydroxide (25%, 5 mL) was added to the mixture. The whole was stirred at room temperature for 4.5 days. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and brine, dried (MgSO4) filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound (1.05 g, 74%) as pale brown crystals. MS 356 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH:13]([NH2:16])([CH3:15])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: CC(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Br)c(F)c1
Yield: 92.5 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and isopropylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-3-fluoro-N-isopropylbenzenesulfonamide (0.40 g, 93%) was provided after purification. HRMS: calcd for C9H11BrFNO2S, 294.96779; found (EI, M+.), 294.9665. HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:2]([CH3:12])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:15])=[O:14]
Reactant: CC1(C)CNc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1,2,3,4-Tetrahydro-3,3-dimethylquinoline (51 mg, 0.32 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (14 mL, 0.32 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 39 mg (58%) of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.40 (dd,J=8.3, 2.1, 1H), 7.29 (d,J=1.8, 1 H), 7.01 (d,J=8.3H, 1H), 4.25 (s, 1H), 2.98 (s, 2H), 2.54 (s, 2H), 1.01 (s, 6 H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]1([CH3:15])[C:9]([CH3:14])=[CH:10][CH:11]=[CH:12][CH:13]=1>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:10][CH2:9][CH2:8][CH2:13][CH2:12][CH2:11][CH2:14][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:8][CH3:15].[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: Cc1ccccc1C
Agent: O=C1C=CC(=O)O1
Product: C=CCCCCCCCCCCCCCCCC

Procedure:
5.6 g PA-18 (0.02 equivalents as maleic anhydride, hereinafter "anhydride equivalents") and 100 ml xylene were mixed in a 250 ml flask equipped with a nitrogen atmosphere and a Dean Stark trap. This mixture was refluxed for 30 minutes to dry the polymer. The mixture was cooled slightly and Flame Retardant A (of Example 1) (5.1 g, 0.01 mole) was added. The mixture was refluxed for 2 hours with azeotropic removal of water as it formed. The 30 solvent was stripped using aspirator and high vacuum systems to yield 10.4 g of yellow crystals. The infrared spectrum of this compound showed the N-(acylamino)imide carbonyl bands merged at 1710 cm-1 and a small residual anhydride carbonyl band at 1770 cm-1. The hydrazide carbonyl for the starting material was not observed in the product spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: BrCc1ccncc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccncc2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-pyridine following the procedure of Example 478: MS (ESI) m/z 485.
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=[O:8].OC1C(=O)[N:15]([CH:26]([CH3:28])[CH3:27])[S:16](=[O:25])(=[O:24])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(Cl)Cl>[Cl:11][C:6]1[C:7](=[O:8])[N:15]([CH:26]([CH3:28])[CH3:27])[S:16](=[O:24])(=[O:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)N1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 50 °C
Yield: 46.8 %

Procedure:
DMF (25 mL) and oxalyl chloride (0.2 mL, 2.29 mmol) were added separately to a solution of 4-hydroxy-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.5 g, 1.87 mmol) in DCM (25 mL) at 0° C. The reaction mixture was then heated at 50° C. for 4 h, water was added and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, then brine and evaporated. The residue was purified by silica gel column chromatography using a 4:1 mixture of hexane and EtOAc as eluant to give the title compound (0.25 g, 46%) as a solid; 1H NMR (200 MHz, CDCl3): δ 8.10-7.94 (m, 2H), 7.61-7.50 (m, 3H), 4.50 (sep, 1H), 1.61 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[CH:4](=[N:8][CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:5]([CH3:7])[CH3:6]>C(O)C>[CH:9]([NH:8][CH:4]([P:1]([OH:3])[OH:2])[CH:5]([CH3:7])[CH3:6])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[PH2]O
Reactant: CC(C)C=NC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Reaction time: 1 h

Procedure:
Hypophosphorous acid (100%, 15.8 parts) dissolved in absolute ethanol was added to a stirred solution of 41.3 parts isobutylidenebenzhydrylamine in absolute ethanol. An exothermic reaction occurred. After standing one hour the reaction was filtered and the white solid dried in vacuo. There was obtained DL-1-benzhydrylamino-2-methylpropanephosphonous acid, melting point 191° (dec.).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C@@H:14]2[CH2:18][O:17][CH2:16][C@H:15]2[OH:19])=[CH:11][CH:10]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C(Cl)Cl>[CH3:22][S:23]([O:19][C@H:15]1[C@H:14]([O:13][C:12]2[CH:20]=[CH:21][C:9]([Br:8])=[CH:10][CH:11]=2)[CH2:18][O:17][CH2:16]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Triethylamine (181.9 mL, 1.31 mol) was added to a solution of trans-4-(4-bromophenoxy)tetrahydrofuran-3-ol from the previous step (354 g, assumed 300.6 g, 1.16 mol) in methylene chloride (2 L), and the reaction was cooled to 0° C. in an ice bath. Methanesulfonyl chloride (101.3 mL, 1.31 mol) was then added drop-wise, while keeping the reaction temperature below 5° C., and the reaction was stirred at room temperature for 18 hours. Water (1.5 L) was added, and the aqueous layer was extracted with methylene chloride. The organics were combined and dried over sodium sulfate, filtered and concentrated in vacuo to afford product as a brown oil. Yield: 399.6 g, 1.18 mol, quantitative. Material from a smaller-scale experiment carried out in similar fashion was triturated with ethanol for characterization. 1H NMR (400 MHz, CDCl3) δ 3.10 (s, 3H), 4.00 (br dd, J=10.4, 1.9 Hz, 1H), 4.07 (m, 1H), 4.16 (dd, J=11.1, 3.9 Hz, 1H), 4.23 (dd, J=10.5, 4.6 Hz, 1H), 4.98 (br d, J=4.6 Hz, 1H), 5.20 (m, 1H), 6.85 (d, J=9.1 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1.[Cl:21]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Cl:21])[CH:9]=[C:10]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1ccc2c(N)ncnn12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1c1cc(Cl)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 9 (52 mg) in anhydrous DMF (2 mL) under Ar was chilled to 0° C. and treated dropwise with a solution of N-chlorosuccinimide in anhydrous DMF (27 mg in 1 mL). The mixture was warmed to RT and stirred for 1 h. The mixture was concentrated then eluted through a silica column with 0-10% MeOH:EtOAc to give Compound 12 (5.3 mg): ESI-MS m/z 407.1 ([M+H]+); 1H NMR (d6-DMSO): δ 0.83 (s, 3H); 3.60 (m, 1H); 3.70-3.74 (m, 4H); 4.74 (s, 1H); 4.84 (t, 1H, J=5.0 Hz); 4.91 (d, 1H, J=6.4 Hz); 5.36 (s, 1H); 6.86 (s, 1H); 7.83 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[N:24]([CH2:30][CH2:31]Br)[C:25]([Br:29])=[C:26]([Br:28])[N:27]=1)[CH:2]=[CH2:3].C(Cl)Cl>C[O-].[Na+]>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:5]1[C:23]1[N:24]([CH:30]=[CH2:31])[C:25]([Br:29])=[C:26]([Br:28])[N:27]=1)[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2nc(Br)c(Br)n2CCBr)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1c(-c2nc(Br)c(Br)n2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 65 °C

Procedure:
Methyl 1-allyl-3-cyclohexyl-2-(4,5-dibromo-1-(2-bromoethyl)-1H-imidazol-2-yl)-1H-indole-6-carboxylate was dissolved in a solution of sodium methoxide (0.5 M in Methanol from Aldrich, 10 mL) and the light yellow solution was heated to 65° C. for 1 h. Methylene chloride (20 mL) was then added, followed by ice-water (50 mL). The aqueous layer was then adjusted to pH 5, and the organic layer was separated, dried (Na2SO4), filtered and evaporated to give the title compound in a form pure enough for use in the next step. 1H NMR (500 MHz, CDCl3) δ 0.8-1.90 (m, 10 H), 2.50 (m, 1H), 3.92 (s, 3H), 4.55 (dd, 1H, J=4.5, 16.5 Hz), 4.70 (dd, 1H, J=6.5, 16.5 Hz), 5.85 (dd, 1H, J=6.0, 17.5 Hz), 5.05 (d, 1H, J=10.5 Hz), 5.09 (d, 1H, J=9.0 Hz), 5.26 (d, 1H, J=13.5 Hz), 5.7-5.80 (m, 1H), 6.56 (dd, 1H, J=9.0, 16.0 Hz), 7.77 (d, 1H, J=8.0 Hz), 7.82 (d, 1H, J=8.0 Hz), 8.07 (s, 1H).
Reaction SMILES: C(=O)([O-])N.[C:5]([O:9][C:10]([N:12]([C:20]1[C:25]([CH3:27])([CH3:26])[S:24](=[O:29])(=[O:28])[C@@H:23]([CH2:30][C@@H:31]([OH:33])[CH3:32])[C@:22]([C:35]2[CH:40]=[C:39]([N+:41]([O-:43])=[O:42])[CH:38]=[CH:37][C:36]=2F)([CH3:34])[N:21]=1)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[CH3:27][C:25]1([CH3:26])[S:24](=[O:29])(=[O:28])[C@@H:23]2[CH2:30][C@H:31]([CH3:32])[O:33][C:36]3[CH:37]=[CH:38][C:39]([N+:41]([O-:43])=[O:42])=[CH:40][C:35]=3[C@@:22]2([CH3:34])[N:21]=[C:20]1[N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17]
Reactant: C[C@H](O)C[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: NC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A mixture of cis and trans isomers, tert-butyl N-tert-butoxycarbonyl-N-[2R,3R)-3-(2-fluoro-5-nitro-phenyl)-2-[(2S)-2-hydroxypropyl]-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate and tert-butyl N-tert-butoxycarbonyl-N-[(2S,3R)-3-(2-fluoro-5-nitro-phenyl)-2-[(2S)-2-hydroxypropyl]-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (1.8 g, 3.06 mmol) and cesium carbonate (4.99 g, 15.32 mmol) were combined in DMSO (15 ml) and stirred at room temperature for 6 h. The solution was diluted with water and the precipitate was collected by filtration, washed with water, and dried under vacuum. The product was purified via silica gel column chromatography (80 g column) using 10-50% ethyl acetate in heptane to afford to afford tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.62 g, 2.85 mmol, 93% yield). MS m/z=590 [M+Na].
Reaction SMILES: [ClH:1].Cl.N1CCOC(CN[C:11]([C:13]2[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[CH:18]=2)=[O:12])C1.[CH3:36][N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][CH:40]([NH2:45])[CH2:41]2.C(N(C(C)C)C(C)C)C>C1COCC1.C(OCC)C>[ClH:1].[ClH:1].[CH3:36][N:37]1[CH:42]2[CH2:43][CH2:44][CH:38]1[CH2:39][CH:40]([NH:45][C:11]([C:13]1[N:14]=[N:15][C:16]([CH2:32][CH2:33][CH2:34][CH3:35])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)=[CH:21][CH:20]=3)[CH:18]=1)=[O:12])[CH2:41]2
Reactant: CCCCc1nnc(C(=O)NCC2CNCCO2)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CN1C2CCC1CC(N)C2
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(C(=O)NC2CC3CCC(C2)N3C)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester hydrochloride (Example 90, 0.108 mmol, 60 mg), 8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamine (0.05 mL), ethyl-diisopropyl-amine (0.2 mL) in THF (2.0 mL) may be stirred at room temperature for 3 h. The reaction mixture may be diluted with diethyl ether, washed with water and 2 M aq. sodium hydroxide solution and dried over magnesium sulfate. The crude product may be purified by column chromatography on silica gel using 2-5% 2 M ammonia in MeOH in DCM and treated with 4 N HCl in dioxane. The organic solvents may be removed under reduced pressure, and the product dried overnight under high vacuum to provide the free base of the title compound. 1H NMR (free base, 400 MHz, CDCl3) δ 8.72 (1 H, d), 8.09 (1 H, s), 7.27 (2 H, d), 7.01 (2 H, d), 4.30-4.36 (2 H, m), 3.20 (2 H, bs), 3.08 (2 H, t), 2.32 (3 H, s), 1.26-2.35 (22 H, m), 0.87 (3 H, t).
Reaction SMILES: COC1C=CC(C([N:9]2[CH:14]([C:15]([OH:17])=[O:16])[CH:13]3[CH2:18][CH:10]2[CH2:11][CH2:12]3)=O)=CC=1.[C:21](Cl)(=O)[C:22](Cl)=O.CN(C)C=O.Cl.NO.C(N(CC)CC)C.Cl>ClCCl.O1CCCC1.O>[CH:10]12[CH2:18][CH:13]([CH2:12][CH2:11]1)[CH:14]([C:15]([O:17][CH2:21][CH3:22])=[O:16])[NH:9]2
Reactant: COc1ccc(C(=O)N2C3CCC(C3)C2C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: NO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1NC2CCC1C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution was 2-(4-methoxybenzoyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (217 mg, 0.787 mmol) in dichloromethane (3.0 ml) were added oxalyl chloride (0.14 ml, 1.65 mmol) and N,N-dimethylformamide (0.06 ml, 0.787 mmol) while being cooled with ice, and the mixture was stirred at room temperature for 30 minutes. Separately, to a suspension of hydroxylamine hydrochloride (219 mg, 3.15 mmol) in tetrahydrofuran (1.0 ml)-water (0.2 ml) was added triethylamine (0.67 ml, 4.80 mmol) at 0° C., and the mixture was stirred at 0° C. for 15 minutes. To this reaction mixture was added the acid chloride solution at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (2.5%–10% methanol/chloroform), to give the entitled compound (69.4 mg, 30% through the two steps of (b) and (c)).
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22](CCCCCCC(F)(F)C(F)(F)F)[C:23]([OH:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:70])([C:66]([F:69])([F:68])[F:67])[CH2:49][CH2:50][CH2:51]C(CCCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:51][CH2:50][CH2:49][C:48]([F:70])([F:47])[C:66]([F:69])([F:68])[F:67])[C:23]([OH:25])=[O:24])[C:11]2[C:10](=[CH:9][C:8]([OH:39])=[CH:7][CH:6]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate prepared in Example 6, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[C:23]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:19][CH2:20][CH2:21][CH3:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:25])[CH3:24]
Reactant: CCCCC(CC)CN(CCCCCCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCCC(CC)CN(CCCCCCOC(C)=O)c1ccccc1
Yield: 93.8 %

Procedure:
6-((2-ethylhexyl)(phenyl)amino)hexan-1-ol (8.0 g, 0.023 mol) and dichloromethane (100 ml) were loaded into a three-neck flask, stirred, and added with acetic anhydride (2.8 g, 0.028 mol) and pyridine (3.0 g, 0.038 mol). The mixture was allowed to react at 40° C. for 12 hours with stirring. The reaction product was transferred into a separate funnel, and was then added with water and dichloromethane, after which the organic layer was isolated therefrom, dehydrated using sodium sulfate, and then distilled under reduced pressure. Subsequently, the obtained viscous liquid was separated through silica column chromatography, thus obtaining 7.5 g of a yellowish transparent liquid.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:10][CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[CH2:4]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21].C(N(CC)C(C)C)(C)C>C(#N)C>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[N:8]1[CH2:9][CH:5]2[CH2:4][CH:3]([OH:2])[CH2:10][CH:6]2[CH2:7]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC1CC2CNCC2C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CC3CC(O)CC3C2)c(F)c1

Procedure:
The octahydro-5-hydroxycyclopenta[c]pyrrol hydrochloride (44.4 mmol) prepared in the step 1 was dissolved in 100 ml of acetonitrile, and 4.91 ml (44.4 mmol) of 1,2-difluoro-4-nitrobenzene and 23.20 ml (133.2 mmol) of N,N-diisopropylethylamine were added, and the mixture was heat to reflux for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was concentrated under reduced pressure to remove the solvent. The solvent-free concentrate was dissolved in ethyl acetate, and washed with distilled water, and then, the organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, of which NMR data is as follow.