Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[CH:12]([CH3:14])[CH3:13].C(Br)C.[Mg].[CH3:19][C:20]([CH:27]=[O:28])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl>C1COCC1>[OH:28][CH:27]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[C:3]=1[CH:12]([CH3:14])[CH3:13])[C:20]([CH3:19])=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1ccc(Br)c(C(C)C)c1OC
Reactant: CCOC(=O)C=C(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCOC(=O)C=C(C)C(O)c1ccc(OC)c(OC)c1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
Compound 7 (10.0 g, 38.6 mmol) and ethyl bromide (0.60 g, 5.5mmol) were added to magnesium turnings (1.20 g, 49.4 mg atom) in 100 mL of dry THF in a 520 mL round bottom flask equipped with a reflux condenser and magnetic stirrer. The mixture was refluxed with stirring under a static nitrogen atmosphere for 1 h. The reaction mixture was cooled to 0° C. and 7a (6.90 g, 48.5mmol) in 25 mL of dry THF at 0° C. was added. The mixture was stirred at ambient temp for 1 h and poured into 100 g of ice and 25 ml of 6M HCl. The organic layer was extracted into ether and the ether was washed with water and brine and dried over MgSO4. The ether was evaporated and the byproducts distilled bulb to bulb (120° C./1 torr) to leave 9.8 g (30.4 mmol, 79%) of 8 as a residual oil: IR 3440 (alcohol), 1722 (ester), 1655 (alkene) cm-1 ; 1H NMR δ1.31 (t, J=7.1 Hz, 3H), 1.37 (d, J=7.0 Hz, 6H), 1.99 (s, 3H), 3.40 (br s, 1H), 3.75-3.85 (m, 1H), 3.847 (s, 3H), 3.853 (s, 3H), 4.19 (q, J+7.1 Hz, 2H), 5.39 (s, 1H), 6.26 (s, 1H), 6.75 (d, J=8.6 Hz, 1H), 6.94 (d, J=7.1 Hz, 1H). Anal. (C18H26O5) C,H.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reaction time: 0.5 h

Procedure:
N-methylpiperazine 3.6 mL, N,N-diisopropylethylamine 5.7 mL and tetrahydrofuran 31 mL were mixed and dropped into a solution of 4-chloro-3-nitrobenzenesulfonyl chloride 8.19 g in tetrahydrofuran 51 mL, under cooling with ice, followed by stirring for 30 minutes under cooling with ice. The stirring was then continued for 17 hours at room temperature. The solvent was distilled off and the residue was poured in water, of which pH was raised to 9 with saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate-tetrahydrofuran mixed solvent. The organic layer was washed with saturated brine, dried over magnesium sulfate, and from which the solvent was distilled off. Recrystallizing the crude product from ethyl acetate-hexane mixed solvent, 4.29 g of the title compound was obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH:12][C:13](OC(C)(C)C)=O)=[C:7]([N+:20]([O-:22])=[O:21])[CH:6]=1)(=[O:4])=[O:3].[C:23]1(=O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30]C=2)[CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)(C(F)(F)F)=O.ClCCl>[C:13]1(=[N:12]/[NH:11][C:8]2[CH:9]=[CH:10][C:5]([S:2]([NH2:1])(=[O:3])=[O:4])=[CH:6][C:7]=2[N+:20]([O-:22])=[O:21])/[CH2:30][CH2:29][CH2:28][C:27]2[C:32]/1=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CC(C)(C)OC(=O)NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: O=C1CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(N/N=C2\CCCc3ccccc32)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A room temperature solution of Example 73A (145 mg,0.44 mmol) in 1:1 TFA/dichloromethane (10 mL) was stirred for 4 hours and concentrated. The concentrate was dissolved in ethanol (2 mL), treated with 3,4-dihydro-1(2H)-naphthalenone (8.2 mg, 0.06 mmol) and pyridinium p-toluenesulfonate (2 mg, 0.008 mmol), heated to reflux, stirred for 2 hours, cooled to room temperature, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 359 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].F[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16]>C1COCC1>[CH3:3][O:4][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16]
Reactant: CO
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Using the procedure for Example 113C, in a 100 mL round bottomed flask, sodium hydride (276 mg. 11.5 mmol) was suspended in 30 ml, of a dry THF and cooled to 0° C. To this solution methanol (427 μL, 10.56 mmol) was added and stirred for 30 minutes. This solution 2-fluoro-4-nitro-1-trifluoromethyl-benzene (2.0 g, 9.6 mmol) was added as a 2 mL THF solution. The reaction was allowed to warm to room temperature overnight with stirring. The reaction was concentrated and then partitioned between ethyl acetate and water, extracting twice. The extracts were dried with magnesium sulfate, filtered and concentrated. The nitro compound was purified by silica gel chromatography using a gradient of ethyl acetate/hexane 0-50% over 60 minutes. The main peak was collected, and concentrated to afford 2-methoxy-4-nitro-1-trifluoromethyl-benzene as an oil weighing 1.16 g. 1H NMR (300 MHz, DMSO-d6) δ 8.0-7.9 (m, 3H), 3.9 (s, 3H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH3:25])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 23, Step 1, using the following starting materials: (6-methoxy-2′-methylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:7]=1[Cl:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(N)c(Cl)c1)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
Methyl (2S)-3-(4-aminophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (1.0 g, 3.22 mmol) and N-chlorosuccinimide (474 mg, 3.55 mmol) were dissolved in DMF (20 mL) and allowed to stir under an atmosphere of nitrogen for 24 h. The reaction was quenched with water and diluted with ethyl acetate (100 mL). The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column (5–20% ethyl acetate/hexanes) to afford the product as a clear oil (645 mg, 61%). 1H NMR (400 MHz, CD3OD): δ 7.05 (s, 1H), 6.90–6.87 (m, 1H), 6.76–6.74 (m, 1H), 4.27–4.23 (m, 1H), 3.68 (s, 3H), 2.97–2.92 (m, 1H), 2.78–2.72 (m, 1H), 1.39 (s, 9H); LCMS found for C10H14ClN2O2 (M+H)+: m/z=229.
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([NH:29][CH2:2][CH2:3][OH:4])[CH2:27][CH2:28]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: N[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: OCCN[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 24 to obtain the title compound.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@@H:9](O)[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3].C(N(S(F)(F)[F:27])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[N:1]([CH2:4][C@@H:5]1[C@H:9]([F:27])[CH2:8][N:7]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=NC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Process (A): (3R,4R)-3-Azidomethyl-1-benzyloxycarbonyl-4-hydroxypyrrolidine (1.20 g) was dissolved in dichloromethane (40 mL). While this solution was cooled on a sodium chloride/ice bath, diethylaminosulfur trifluoride (1.20 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. The reaction vessel was again cooled on a sodium chloride/ice bath and diethylaminosulfur trifluoride (0.57 mL) was again added dropwise. The mixture was then stirred at room temperature for 2 hours. While the reaction mixture was cooled on an ice bath, a saturated aqueous solution of sodium hydrogen carbonate (40 mL) was added dropwise and the dichloromethane layer was separated. The dichloromethane layer was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate (2×20 mL) and water (20 mL), followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was purified on a silica gel column (eluant=hexane:ethyl acetate=2:1) to give 726 mg of (3R,4S)-3-azidomethyl-1-benzyloxycarbonyl-4-fluoropyrrolidine as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:35](=[O:59])[NH:36][C@H:37]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=1)[C:38]([O:40]CC1C=CC=CC=1)=[O:39])[CH2:10][CH2:11][C:12](=[O:34])[N:13]([CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.O.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:35](=[O:59])[NH:36][C@H:37]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=1)[C:38]([OH:40])=[O:39])[CH2:10][CH2:11][C:12](=[O:34])[N:13]([CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of (12S,15R)-benzyl 12-(tert-butoxycarbonylamino)-8-(2-(tert-butoxycarbonylamino)ethyl)-2,2-dimethyl-4,9,13-trioxo-15-(4-(trifluoromethyl)benzyl)-3-oxa-5,8,14-triazahexadecan-16-oate (3 g, 3.58 mmol) in a mixture of EtOH/H2O (18 mL/2 mL) was added palladium (wet) on carbon (catalytic amount). The reaction mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The catalyst was filtered through a pad of Celite. The filtrate was evaporated under reduced pressure to give (12S,15R)-12-(tert-butoxycarbonylamino)-8-(2-(tert-butoxycarbonylamino)ethyl)-2,2-dimethyl-4,9,13-trioxo-15-(4-(trifluoromethyl)benzyl)-3-oxa-5,8,14-triazahexadecan-16-oic acid (CLXVI) as white crystals (2.66 g, 3.56 mmol, 99% yield). 1H NMR (DMSO-d6) δ ppm 1.32 (s, 27H), 1.52-1.78 (m, 2H), 2.07-2.26 (m, 2H), 2.9-3.03 (m, 4H), 3.14-3.23 (m, 4H), 3.31 (brs, 2H), 3.83-3.92 (m, 1H), 4.4-4.46 (m, 1H), 6.74-6.85 (m, 2H), 6.88-6.94 (m, 1H), 7.38 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H), 7.94-8.01 (m, 1H); 19F NMR (DMSO-d6) δ ppm −60.24 (s, 3F); ESIMS found for C34H52F3N5O10 m/z 748.9 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1([CH2:15][O-:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+]>>[CH2:15]([O:16][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: [O-]Cc1ccccc1
Agent: [Na+]
Product: Nc1cc(OCc2ccccc2)ncn1
Yield: 27 %

Procedure:
6-Chloropyrimidin-4-amine (500 mg, 3.86 mmol) and sodium phenylmethanolate (1 M solution in benzyl alcohol, 4.67 mL, 4.67 mmol) were heated at 120° C. for 16 hrs. 6-(Benzyloxy)pyrimidin-4-amine (210 mg, 27% yield) was isolated as clear oil following HPLC purification (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA). The purified material (a TFA salt) was converted to its free base by dissolving in ethyl acetate (20 mL) and washing with saturated NaHCO3 (20 mL) for use in the next step. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=0.96 (M+H=202.24).
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11]>O1CCCC1>[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH2:1])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1CCl
Reactant: N
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1CCl

Procedure:
A solution of ammonia (5.2 ml) in tetrahydrofuran (250 ml) at -70° was contacted rapidly with a solution of 2-(chloromethyl)benzenesulfonyl chloride (21.8 g) in tetrahydrofuran (125 ml). The stirred mixture was allowed to warm to 0° and volatiles were removed under vacuum. The residue was contacted with ethyl acetate and a small volume of water. The organic layer was dried (MgSO4) and evaporated to give 19.8 g of white solid, m.p. 156°-157.5°. Recrystallization from toluene/ethyl acetate gave a sample with m.p. 157°-160°.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([N+]([O-])=O)=[CH:10][CH:11]=2)[NH:6][C:5](=[O:16])[C:4]1=[O:17])[CH3:2].C[N:19](C)C=O>[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]2[C:7]([NH:6][C:5](=[O:16])[C:4](=[O:17])[N:3]2[CH2:1][CH3:2])=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: CCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Product: CCn1c(=O)c(=O)[nH]c2ccc(N)cc21
Yield: 81 %

Procedure:
8.3 g (35 mmol) of 1-ethyl-6-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 300 ml of dimethylformamide and, after addition of 2 g of palladium/carbon (10%), were hydrogenated. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 5.9 g (81%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](O)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O.CCOC(C)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([Cl:20])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccc(Cl)cc2CCc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Yield: 71.6 %

Procedure:
To a mixture of 13.3 g (54 mmol) of 8-chloro-6,11-dihydro-11-hydroxy-5H-benzo[5,6]cyclohepta[1,2-b]pyridine in 290 mL of toluene at -15° C. and under an atmosphere of nitrogen was added via syringe pump over a period of 1 hour 6.20 mL (85.7 mmol) of thionyl chloride. The extent of reaction was monitored by TLC (50% EtOAc in hexanes). When completed the mixture was poured into 300 mL of 1.0N aqueous NaOH and extracted with EtOAc (5×). The combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in EtOAc, quickly filtered through basic alumina, and concentrated again to yield a product which was triturated with pentane to yield 10.22 g of the title compound as a tan solid.
Reaction SMILES: [C:1]1([C@@H](NC(=O)C[C@H](O)C[C@H](O)/C=C/C2N(C(C)C)C3C(C=2C2C=CC(F)=CC=2)=CC=CC=3)C)C=CC=CC=1.[OH-].[Na+:40].[CH:41]1([C:44]2[C:53](/[CH:54]=[CH:55]/[C@@H:56]([OH:64])[CH2:57][C@@H:58]([OH:63])[CH2:59][C:60]([OH:62])=[O:61])=[C:52]([C:65]3[CH:70]=[CH:69][C:68]([F:71])=[CH:67][CH:66]=3)[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]=2)CC1.Cl>>[Na+:40].[F:71][C:68]1[CH:69]=[CH:70][C:65]([C:52]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([CH:44]([CH3:1])[CH3:41])[C:53]=2/[CH:54]=[CH:55]/[C@@H:56]([OH:64])[CH2:57][C@@H:58]([OH:63])[CH2:59][C:60]([O-:62])=[O:61])=[CH:66][CH:67]=1
Reactant: O=C(O)C[C@H](O)C[C@H](O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)N[C@@H](C)c2ccccc2)c(-c2ccc(F)cc2)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)n1c(/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
can be prepared from (E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoic acid ((S)-1-phenyl-ethyl)-amide by hydrolysis with sodium hydroxide according to the procedure described above for the preparation of (E)-(3R,5S)-7-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3,5-dihydroxy-hept-6-enoic acid. After completion of the hydrolysis, excess sodium hydroxide is neutralised by addition of hydrochloric acid and the solvent is evaporated under reduced pressure. As a work-up variant, the residue is dissolved in water at 60-70° C. and the solution is allowed to cool down to room temperature. Crystallisation occurs. The formed suspension is cooled down to 5° C., stirred for several hours at this temperature to complete the crystallisation and the product is isolated by filtration. (E)-(3R,5S)-7-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt is obtained as beige to yellow crystalline product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])cnc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-4-methyl-3-nitropyridine (25.6 g, 167 mmol) in conc. H2SO4 (50 mL) at 0° C. was added HNO3 (7.77 mL, d=1.49) drop-wise over 30 min. The mixture was warmed to r.t. for 1 h then heated to 50° C. for 60 min. The reaction mixture was cooled and poured into 500 g of ice. The resulting precipitate was filtered, washed with 50 mL of H2O, and air dried to give 2-amino-4-methyl-3,5-dinitro-pyridine as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Product: COc1ccc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol) and 5-methoxy-2-nitroaniline (39 mg, 0.230 mmol), similar to Example 180 and was isolated as an off white solid (35 mg, 58%). 1H NMR (CDCl3): 9.69 (d, J=1.5 Hz, 1H), 8.83 (dd, J=1.5, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.08 (d, J=9.6 Hz, 1H), 7.11 (s, 1H), 6.27 (dd, J=2.7, 9.6 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.[CH3:20][C:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH2:22].S(=O)(=O)(O)O.[CH3:33][C:34]([C:41]1[CH:47]=[C:46]([OH:48])[CH:45]=[CH:44][C:42]=1[OH:43])([CH3:40])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37]>O>[CH3:22][C:21]([C:45]1[CH:44]=[C:42]([OH:43])[C:41]([C:34]([CH3:40])([CH3:33])[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:47][C:46]=1[OH:48])([CH3:20])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)CC(C)(C)c1cc(O)ccc1O
Reactant: C=C(C)CC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: Oc1ccc(O)cc1
Solvent: O
Product: CC(C)(C)CC(C)(C)c1cc(O)c(C(C)(C)CC(C)(C)C)cc1O
Temperature: 58 °C

Procedure:
To a 500 mL, 3-neck, round-bottom flask equipped with a stirrer, thermocouple and nitrogen are added 67 weight percent p-toluenesulfonic acid (PTSA) in water (33.5 g), hydroquinone (20.0 g, 0.18 moles), diisobutylene (101.8 g, 0.91 moles) and 95% aqueous sulfuric acid (11.2 g, 0.112 moles). This mixture is heated to 58° C. under a nitrogen blanket with stirring. After 14 hours reaction time at 58° C., diisobutylene (50 g) is added and the lower aqueous phase (containing PTSA, sulfuric acid, hydroquinone, mono-(1,1,3,3-tetramethylbutyl)hydroquinone and small amounts of other polar side products) is transferred to another reactor. The diisobutylene phase is washed with 150 g water two times at 50° C. and once at 85°. The remaining clear organic phase at 85° C. is cooled to 70° C. and eventually to 0-10° C. and the 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone product which crystallizes is collected by filtration. The product is washed with 60 g cold diisobutylene and dried at room temperature overnight. The 2,5-bis(1,1,3,3-tetramethylbutyl)hydroquinone product is obtained in a yield of 73% product and a purity greater than 98.5%.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:22])[N:4]=[C:3]1[N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].CCOC(C)=O>[Pd].CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[S:12][CH2:11][CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:38])([CH3:1])[C:3]([N:23]([C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[C:31](=[O:32])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[N:4][C@:5]3([CH3:22])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3SCC[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3SCC[C@H]2S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
A flask was charged with tert-butyl N-[(4aR,11bR)-3,3,11b-trimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzothiepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.18 g, 2.071 mmol), 10 wt. % Pd/C (0.220 g, 0.207 mmol), EtOAc (4.14 ml) and MeOH (4.14 ml). The flask was purged with nitrogen, evacuated, and filled with hydrogen. The reaction was stirred at RT under hydrogen atmosphere for 16 h. The reaction was incomplete, so another 100 mg of 10 wt. % Pd/C was added, and stirring under hydrogen was continued. After 8 h, the reaction was complete. The mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated to provide tert-butyl N-[(4aR,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzothiepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.00 g, 89%) as a dark foamy solid. LC/MS (ESI+) m/z=562.2 (M+Na). tert-Butyl N-[(4aS,11bR)-10-amino-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzothiepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate was prepared following the same hydrogenation procedure. The product was isolated as a dark foamy solid in 90% yield. LC/MS (ESI+) m/z=562.2 (M+Na).