Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[NH:10][CH3:11].[C:17](OC)(OC)(OC)[CH:18]([CH3:20])[CH3:19]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:17]1[CH:18]([CH3:20])[CH3:19]
Reactant: COC(OC)(OC)C(C)C
Reactant: CNC(Cc1ccccc1N)c1cccs1
Solvent: CC(=O)O
Product: CC(C)C1=Nc2ccccc2CC(c2cccs2)N1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
A stirred solution of 3.45 g of 2-amino-N-methyl-α-(2-thienyl)benzeneethaneamine and 13.34 g of trimethyl orthoisobutyrate was treated rapidly with 3.8 ml of glacial acetic acid. The reaction mixture was refluxed for 8 hours and cooled to room temperature overnight. The mixture was concentrated on a rotary evaporator at 70° C. After standing overnight under refrigeration, the residue was dissolved in 60 ml of 10% hydrochloric acid solution and .extracted with diethyl ether (2×50 ml). The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2×75 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by HPLC (Water's Associates Prep LC/System 500; silica gel; sample applied in dichloromethane; methanol as eluent). Concentration of the appropriate fractions yielded 1.08 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(2-thienyl)-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[C:12](=[O:22])[CH:13]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[O:15][C:10]=2[C:9]=1[CH2:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[C:12](=[O:22])[CH:13]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[O:15][C:10]=2[C:9]=1[CH2:25][CH2:26][CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1c(Cc2ccccc2)ccc2c(=O)cc(CCC(=O)OC)oc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(Cc2ccccc2)ccc2c(=O)cc(CCC(=O)O)oc12
Yield: 72.8 %

Procedure:
Methyl 3-[7-benzyl-4-oxo-8-propyl-4H-1-benzopyran-2-yl]propionate (1.0 g) was refluxed with ethanol (50 ml) containing 10% aqueous sodium carbonate solution (10 ml) for 30 minutes. The mixture was diluted with water, washed with ethyl acetate, and acidified to give a solid, which crystallised from ethanol to give the propionic acid (0.7 g), mp 160°-161°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.N1C=CC=CC=1.[CH:39]1[C:51]2[CH:50]([CH2:52][O:53][C:54](Cl)=[O:55])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]=2[CH:42]=[CH:41][CH:40]=1.Cl>C(Cl)Cl.O>[CH:39]1[C:51]2[CH:50]([CH2:52][O:53][C:54]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([S:8][C:9]4[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=4[N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=3)=[O:55])[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:43]=2[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
A suspension of the product of Example 52A (1.00 g, 3.445 mmol) in anhydrous methylene chloride (40 mL) was treated with N,O-bis(trimethylsilyl)acetamide (1.77 mL, 7.234 mmol) dropwise, and the resulting orange-colored solution was stirred at room temperature for 30 minutes under a nitrogen atmosphere. Anhydrous pyridine (0.557 mL, 6.89 mmol) was then added, followed by solid 9-fluorenylmethoxycarbonyl chloride (1.114 g, 4.306 mmol) in three portions. The reaction was stirred for 30 minutes, then poured into water (75 mL) and adjusted the pH to 1 with 1N aqueous hydrochloric acid. After stirring for 15 minutes at room temperature, the mixture was transferred to a separatory funnel and extracted with ethyl acetate (500 mL, followed by 2×150 mL). The combined organic extracts were washed with water (2×50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Trituration with methylene chloride provided the title compound as a yellow solid (1.29 g, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.[CH2:36](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH:35][C:14](=[O:16])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][C:11]([CH3:12])([CH3:13])[CH3:36])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(F)cc3)C[C@@H]21
Product: CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(F)cc3)C[C@@H]21

Procedure:
tert-butyl(S)-1-((3aR,4S,6aS)-2-(4-fluorophenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-ylamino)-4,4-dimethyl-1-oxopentan-2-ylcarbamate was prepared by substituting (S)-2-(tert-butoxycarbonylamino)-4,4-dimethylpentanoic acid for N-(tert-butoxycarbonyl)-L-leucine and (3aR,4S,6aS)-2-(4-fluorophenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 261 Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.70 (d, J=7.0, 1H), 8.14 (d, J=8.7, 1H), 7.99 (dd, J=8.6, 5.2, 2H), 7.32 (t, J=8.6, 2H), 4.75-4.65 (m, 1H), 4.27-4.18 (m, 1H), 3.74 (dd, J=9.9, 2.7, 1H), 3.10 (ddd, J=13.9, 9.6, 5.4, 2H), 2.92 (dd, J=9.4, 7.7, 1H), 2.61-2.47 (m, 2H), 2.15 (dd, J=14.2, 4.7, 1H), 1.89-1.73 (m, 3H), 1.56-1.45 (m, 10H), 1.28-1.18 (m, 1H), 0.98 (s, 9H); MS (ESI+) m/z 512 (M+H)+.
Reaction SMILES: C(OC([NH:8]C(C1C=CC=CC=1)(O)CC)=O)(C)(C)C.[ClH:19].[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O:27]1CCO[CH2:29][CH2:28]1>>[ClH:19].[NH2:8][C@@H:29]([CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:28][OH:27]
Reactant: C1COCCO1
Reactant: Cc1ccccc1
Reactant: CCC(O)(NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Product: N[C@H](CO)Cc1ccccc1

Procedure:
A solution of 20.10 g (80.00 mmol) of (S)-2-(tert-butoxycarbonylamino-1-phenyl-propan-1-ol [J. Med. Chem. 33, 2707 (1990)] in 200 ml of a 4N solution of gaseous hydrogen chloride in anhydrous dioxane is stirred at room temperature for 30 minutes. Thereafter, 60 ml of toluene are added and the mixture is concentrated in vacuo. This operation is repeated twice more, and the residue is then titrated with a little ether, filtered off with suction and dried under a high vacuum over KOH. 14.14 g (94% of theory) of the title compound are obtained as colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][CH2:18][NH2:19].C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: NCCc1cccs1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1cccs1)c1cc(Cl)ccc1Cl
Yield: 66.7 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (164 mg, 0.85 mmol) in thionyl chloride (2 mL) then with 2-thiopheneethylamine (50 μL, 0.42 mmol) in presence of triethylamine (0.5 mL) in THF (3 mL) according to method B gave 2,5-dichloro-N-(2-thiophen-2-yl-ethyl)-benzamide (83 mg, 0.28 mmol, 66% yield) as a off-white powder after purification on silica gel (eluent: EtOAc/hexane 5/95 to 20/80).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCCCCC1CCOCC1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCOCC1

Procedure:
Prepared similarly to Intermediate 220 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1([CH3:22])[CH2:14][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][C:11]1=[O:21])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)C(C)C)(C)C.[C:32](Cl)([Cl:34])=[O:33].C1(C)C=CC=CC=1.Cl>ClCCl>[C:1]([O:8][CH2:9][C:10]1([CH3:22])[CH2:14][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([C:32]([Cl:34])=[O:33])[C:11]1=[O:21])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCCCCC(=O)OCC1(C)CN(c2ccccc2)NC1=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCC(=O)OCC1(C)CN(c2ccccc2)N(C(=O)Cl)C1=O
Reaction time: 2 h

Procedure:
A solution of hexanoic acid, 4-methyl-3-oxo-1-phenyl-pyrazolidin-4-ylmethyl ester (0.74 g, 0.0024 mol) and N,N-diisopropylethylamine (0.36 g, 0.0028 mol) in dichloromethane (8 ml) was added dropwise over 30 min to a stirred solution of a 20% phosgene in toluene solution (1.5 ml, 0.0028 mol) and dichloromethane (8 ml) under an atmosphere of argon. The reaction mixture was cooled using an acetone-solid carbon dioxide bath such that the initial temperature was −30° C. and the reaction remained below −20° C. during the addition. The reaction was stirred for 2 hr at between −30° C. and −20° C. Dilute aqueous hydrochloric acid (8 ml) was added to the cold reaction. The organic layer was washed with saturated aqueous sodium chloride (8 ml), dried over magnesium sulfate, and concentrated in vacuo to give a yellow viscous oil. Analysis was consistent with the desired product. The total yield of product was 0.83 g (96%).
Reaction SMILES: C(O[CH:4](OCC)[CH:5]1[C:14]2([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[O:13][C:12]2[C:7](=[CH:8][C:9]([F:27])=[CH:10][CH:11]=2)[C:6]1=O)C.[ClH:32].[CH3:33][NH:34][NH2:35]>>[ClH:32].[F:27][C:9]1[CH:10]=[CH:11][C:12]2[O:13][C:14]3([C:5]4[C:6](=[N:35][N:34]([CH3:33])[CH:4]=4)[C:7]=2[CH:8]=1)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3
Reactant: CCOC(OCC)C1C(=O)c2cc(F)ccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Reactant: CNN
Agent: Cl
Product: Cn1cc2c(n1)-c1cc(F)ccc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To tert-butyl 3-(diethoxymethyl)-6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (3.81 g, 8.71 mmol) was added hydrochloric acid (32.7 mL of 4.0 M in dioxane, 130 mmol). The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under vacuum, and the obtained solid was azeotroped with EtOH (1×30 mL). The resulting solid was suspended in EtOH (30.5 mL) and was treated with methylhydrazine (556 μL, 10.5 mmol) at 40° C. for 4 h. The mixture was then heated at 80° C. for 1 h resulting in a yellow solution with an off white precipitate. The solid was collected to give 8-fluoro-2-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] hydrochloride (798 mg, 26%). ESI-MS m/z calc. 273.1, found 274.5 (M+1)+. Retention time 0.83 minutes (3 min run). Note: The yellow mother liquor was evaporated to give a mixture of methyl regioisomers (1.71 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Cl)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Cl)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of methyl 3-(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (125 mg, 0.28 mmol) in methanol (30 ml) and water (1.0 ml) was added sodium hydroxide (44.6 mg, 1.11 mmol). The reaction was stirred overnight at room temperature. Then the reaction mixture was concentrated in vacuo, dissolved in water (30 ml), adjusted to pH 5 with aqueous hydrochloric acid (3 N) to give a precipitate, which was collected by filtration to afford 3-(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (90 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>CS(C)=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:30])[N:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1nnc2ccc(CN3CCOCC3)cc2c1O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 0.25 h
Yield: 39 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-cinnolinecarboxamide [Preparation 12] (200 mg) in dry DMSO (15 mL) is added lithium bis(trimethylsilyl)amide (0.51 mL of a 1 M solution in hexanes). The mixture is stirred for 15 min over which time everything dissolves. Methyl iodide (0.032 mL) is then added and the reaction is stirred for an additional 2 h. The mixture is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine, dried and condensed. The crude product is chromatographed on silica (gradient CH2Cl2, 1% MeOH/CH2Cl2, 2% MeOH/CH2Cl2, 3% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The residue from the column is dissolved in CH2Cl2. Hexanes are added to precipitate the product. The resulting solid is collected and dried to yield 0.079 g (39%) of the title compound as a white solid. Physical characteristics are the same as reported above.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1.[H][H]>CO.[C].[Pd]>[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=2[O:2]1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCc1ccc2c(c1)OCO2

Procedure:
In 5 ml of absolute methanol was dissolved 500 mg of 3,4-methylenedioxy-cinnamic acid, followed by adding thereto 50 mg of 10% palladium-carbon, and the reaction was carried out with stirring in a hydrogen stream at room temperature for 5 hours.
Reaction SMILES: [O-][CH2:2]C.[Na+].[CH:5]1([O:10][C:11]2[C:16]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]([O:23][CH3:24])[CH:14]=[CH:13][C:12]=2[C:25](=[O:31])[CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:9][CH2:8][CH2:7][CH2:6]1.Br[CH2:33][CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)C>[CH2:36]([O:35][CH2:34][CH2:33][CH:26]([C:25](=[O:31])[C:12]1[CH:13]=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]=1[O:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9]1)[C:27]([O:29][CH2:30][CH3:2])=[O:28])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC[O-]
Reactant: COC(=O)CC(=O)c1ccc(OC)c(OC2CCCC2)c1OC1CCCC1
Reactant: BrCCOCc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCOCc1ccccc1)C(=O)c1ccc(OC)c(OC2CCCC2)c1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium ethoxide (2.0 g, 29 mmol) was added to a solution of methyl 3-(2,3-bis(cyclopentyloxy)-4-methoxyphenyl)-3-oxopropanoate (11 g, 29 mmol) and ethanol (150 mL) at rt. After refluxing for 1 h, ((2-bromoethoxy)methyl)benzene (12.5 g, 57.8 mmol) was added and refluxing was continued overnight. The reaction was allowed to cool to rt, concentrated, diluted with ethyl acetate (300 mL), and then washed with brine (50 mL×2). The organic layer was dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate:petroleum ether) to give ethyl 4-(benzyloxy)-2-(2,3-bis(cyclopentyloxy)-4-methoxybenzoyl)butanoate: MS (ESI): 525.
Reaction SMILES: [CH3:1][S:2]([C:5]1([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].C([Li])CCC.[Br:16][C:17]1[CH:18]=[C:19](/[C:24](=[N:26]/[S@@:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28])/[CH3:25])[C:20]([F:23])=[N:21][CH:22]=1.C[Al](C)C>C1COCC1.C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:18]=[C:19]([C@:24]([NH:26][S:27]([C:29]([CH3:30])([CH3:32])[CH3:31])=[O:28])([CH3:25])[CH2:1][S:2]([C:5]2([C:9]#[N:10])[CH2:8][CH2:7][CH2:6]2)(=[O:4])=[O:3])[C:20]([F:23])=[N:21][CH:22]=1
Reactant: CS(=O)(=O)C1(C#N)CCC1
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cc(Br)cnc1F
Agent: C[Al](C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)S(=O)N[C@@](C)(CS(=O)(=O)C1(C#N)CCC1)c1cc(Br)cnc1F
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
A solution of 1-(methylsulfonyl)cyclobutanecarbonitrile (8 g, 50.4 mmol) in THF (50 mL) was brought to −78° C. followed by the dropwise addition of butyllithium solution, 2.5M in hexanes (20.17 mL, 50.4 mmol). The resulting mixture was stirred at this temperature for 20 min. A solution of (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (9.0 g, 28.02 mmol) in toluene (40 mL) at −78° C. was treated with trimethylaluminum solution, 2.0 M in toluene (14 ml, 28.02 mmol) for 10 min. This solution was added dropwise to the previous mixture containing the nitrile and the resulting mixture was stirred at −78° C. for 1 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes to afford an off-white solid as N—((R)-2-(5-bromo-2-fluoropyridin-3-yl)-1-((1-cyanocyclobutyl)sulfonyl)propan-2-yl)-2-methylpropane-2-sulfinamide (7.07 g, 14.72 mmol, 59.1% yield). LC/MS (ESI+) m/z=479.8 (M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[O:3]1.[O:13]=[C:14]1[CH2:23][CH2:22][CH2:21][C:20]2[C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=[CH:16][C:15]1=2.[Se](=O)=[O:29]>>[O:13]=[C:14]1[CH2:23][CH2:22][CH2:21][C:20]2[C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=[CH:16][C:15]1=2.[C:8]1(=[O:12])[C:9]2[C:4](=[CH:1][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:29].[CH3:27][O:26][C:24]([C:19]1[C:20]2[CH:21]=[CH:22][C:23](=[O:3])[C:14](=[O:13])[C:15]=2[CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: CC1C=CC2=C(CCCC2=O)O1
Reactant: O=[Se]=O
Agent: COC(=O)c1cccc2c1CCCC2=O
Product: COC(=O)c1cccc2c1C=CC(=O)C2=O
Product: O=C1C=Cc2ccccc2C1=O

Procedure:
Methyl 5-oxo-5,6,7,8-tetrahydro-1-naphthoate was prepared according to the literature (J. Org. Chem. 1976, p2918) from 2-methyl-2,6,7,8-tetrahydro-chromen-5-one (Tetrahedron Letters, 1975, p3407). Treatment of methyl 5-oxo-5,6,7,8-tetrahydro-1-naphthoate with selenium dioxide as described in Reference Example 1A yielded the corresponding 1,2-naphthoquinone, 5,6-dioxo-5,6-dihydro-naphthalene-1-carboxylic acid methyl ester, which was coupled with 2,3-diamino-benzoic acid, diacetate salt, as described in Reference Example 1A to yield the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1.[NH3:17].C1COCC1>S(Cl)(Cl)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([NH2:17])=[O:16])[CH2:10][CH2:9]1
Reactant: N
Reactant: O=C(O)[C@H]1CC[C@@H](Nc2ccccn2)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@@H](Nc2ccccn2)CC1
Reaction time: 1 h

Procedure:
cis-4-(pyridin-2-ylamino)cyclohexanecarboxylic acid (0.22 g, 1.00 mmol) was dissolved in thionyl chloride (2 ml) at room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to yield the crude acid chloride, which was added to liquid ammonia/THF (1:1, 15 ml) and allowed to stir at room temperature. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure to afford 100 mg of cis-4-(pyridin-2-ylamino)cyclohexanecarboxamide as off white solid.
Reaction SMILES: [P:1]([O:6]C)([O:4][CH3:5])[O:2][CH3:3].[CH2:8]1[O:12][C@@H:11]2[C@H:13]([O:16][N+:17]([O-:19])=[O:18])[CH2:14][O:15][C@@H:10]2[C@H:9]1[OH:20].C(Br)(Br)(Br)Br>N1C=CC=CC=1>[P:1]([O:20][C@H:9]1[CH2:8][O:12][C@@H:11]2[C@H:13]([O:16][N+:17]([O-:19])=[O:18])[CH2:14][O:15][C@H:10]12)([O:4][CH3:5])([O:2][CH3:3])=[O:6]
Reactant: COP(OC)OC
Reactant: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: BrC(Br)(Br)Br
Solvent: c1ccncc1
Product: COP(=O)(OC)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trimethyl phosphite (2.95 mL, 25.0 mmol) was added dropwise over ca. 1 hour to a stirred 0° C. mixture of isosorbide-5-mononitrate (3.82 g, 20.0 mmol) and carbon tetrabromide (7.30 g, 22.0 mmol) in pyridine (10 mL), and the mixture was stirred at room temperature for 3 hours. The reaction was partitioned between 1M hydrochloric acid and diethyl ether/ethyl acetate (1:1). The aqueous phase was extracted with diethyl ether. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate and brine, dried (sodium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 50-100% ethyl acetate/hexane afforded the title compound as an orange solid. 1H NMR (500 MHz, CD3OD) δ 5.46 (td, J=5.5, 2.2 Hz, 1H), 5.02 (t, J=5.3 Hz, 1H), 4.82 (dd, J=6.8, 2.7 Hz, 1H), 4.58 (d, J=5.1 Hz, 1H), 4.10 (d, J=10.7 Hz, 1H), 3.99 (dd, J=11.5, 2.1 Hz, 1H), 3.91 (dd, J=11.4, 5.2 Hz, 1H), 3.88 (dt, J=11.0, 2.4 Hz, 1H), 3.80 (d, J=2.7 Hz, 3H), 3.78 (d, J=2.7 Hz, 3H); LC-MS: m/z 300.0 (M+H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([C:18](OC)=[O:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][CH:16]=[C:15]([CH2:18][OH:19])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCc1c[nH]c(-c2ccc(C3CCCCC3)cc2)c1
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a solution of methyl 5-(4-cyclohexylphenyl)-1H-pyrrole-3-carboxylate (3.0 g) in absolute tetrahydrofuran (40 mL) was added dropwise a 1.5 mol/L solution (21.0 mL) of diisobutylaluminum hydride in toluene at −78° C. The mixture was further stirred at the same temperature for 2 hr. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1) to give the title compound as crystals (yield 1.07 g, 40%).