Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:35]([C:38]1[CH:43]=[CH:42][C:41]([C@H:44]2[CH2:49][CH2:48][C@H:47]([CH2:50][CH2:51][C:52]3[CH:59]=[CH:58][C:55]([CH:56]=O)=[CH:54][CH:53]=3)[CH2:46][CH2:45]2)=[CH:40][CH:39]=1)[CH2:36][CH3:37].O>C1COCC1>[CH2:35]([C:38]1[CH:43]=[CH:42][C:41]([C@H:44]2[CH2:45][CH2:46][C@H:47]([CH2:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([CH:56]=[CH:7][C:6]4[CH:5]=[CH:4][C:3]([Cl:2])=[CH:28][CH:27]=4)=[CH:58][CH:59]=3)[CH2:48][CH2:49]2)=[CH:40][CH:39]=1)[CH2:36][CH3:37]
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C=O)cc3)CC2)cc1
Reactant: Clc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C=Cc4ccc(Cl)cc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspension of 11.8 g of 4-chlorobenzyltriphenyl-phosphonium bromide in 100 ml of THF was stirred under nitrogen gas stream, and 2.8 g of potassium-t-butoxide was added to the suspension at room temperature. After stirred at room temperature for 1 hour, a solution of 7 g of the 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzaldehyde in 50 ml of THF was added dropwise. After stirred at room temperature for 2 hours, 300 ml of water was added and extracted with 300 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under a reduced pressure, and then 200 ml of heptane was added. Precipitate thus separated was filtered off, and subjected to a column chromatography over a silica gel by using ethyl acetate/heptane (1/5) as an eluent. Solvent was distilled off under a reduced pressure to obtain 5.6 g 4-(2-(4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)phenyl)ethenyl)chlorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]#[N:16])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)c[nH]c2c1
Temperature: 0 °C
Yield: 84.6 %

Procedure:
A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) is cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture is stirred at this temperature for I h. The dark solution is poured into ice water (600 mL) and the light brown solid is collected by filtration, washed with additional H2O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1>C(OCC)(=O)C.[Pt]>[F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2cccc(F)c2)c(F)c1
Yield: 98.1 %

Procedure:
12.68 g (47.8 mmol) of 3-fluoro-4-(3-fluoro-benzyloxy)-nitrobenzene in 150 ml ethyl acetate is treated with 1.27 g of 5% platinum on charcoal and hydrogenated for 6 h at room temperature and normal pressure. The catalyst is filtered and the solution evaporated to yield 11.03 g (98%) of dark brown oil. MS: m/e=235.1 (M+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[P:11]([O-:16])([O:14]C)[O:12][CH3:13].C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[PH:11](=[O:14])([O:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)[O:12][CH3:13]
Reactant: COP([O-])OC
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CO[PH](=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
1-Iodo-3-nitrobenzene (249 mg, 1 mmol) was dissolved in 10 mL of acetonitrile. Tetrakis(triphenylphosphine)palladium (58 mg, 3 mol %), dimethyl phosphite (0.138 ml, 1.5 mmol) and triethylamine (0.28 ml, 2 mmol) were added thereto and stirred at 70° C. overnight. After removing a solvent, the mixture was purified in accordance with the purification process A to obtain a mixture (0.222 g) of monomethyl (3-nitrophenyl) phosphonate and dimethyl ester. The obtained monomethyl phosphonate was dissolved in 10 mL of methanol. Pd/C in catalyst quantity was added thereto and stirred under hydrogen atmosphere overnight. After filtering out the catalyst, a solvent was removed to obtain a mixture of monomethyl (3-aminophenyl) phosphonate and dimethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH2:24])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1.[N:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH:24][C:38]([C:35]4[CH:36]=[CH:37][N:32]=[N:33][CH:34]=4)=[O:39])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(N)CC2)no1
Reactant: O=C(O)c1ccnnc1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-amide (example 32) has been coupled with pyridazine-4-carboxylic acid to yield the title compound as light yellow solid. MS: 551.1 (MH+, 1Cl).
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][N:20]1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:37][O:38][C:39]1[C:40]([O:48][CH2:49][CH2:50][CH3:51])=[C:41]([CH:45]=[CH:46][CH:47]=1)[CH2:42]CN.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH3:37][O:38][C:39]1[C:40]([O:48][CH2:49][CH2:50][CH3:51])=[C:41]([CH:45]=[CH:46][CH:47]=1)[CH2:42][N:20]([CH3:19])[C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]1[CH:9]=[N:10][C:11]2[NH:12][C:3](=[O:2])[CH2:4][CH2:5][C:6]=2[CH:7]=1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CCCOc1c(CCN)cccc1OC
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)cccc1OC
Yield: 22 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting (3-methoxy-2-propoxy-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (193 mg, 22%) was prepared as a white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.6 (s, 1H), 8.35 (d, J=14.1 Hz, 1H), 8.09-8.01 (m, 1H), 7.50 (dd, J=15.2, 2.5 Hz, 1H), 7.24 (d, J=15.3 Hz, 1H), 7.07-6.94 (m, 2H), 6.67-6.62 (m, 1H), 5.43 (br s, 1H), 4.79-4.64 (m, 2H), 3.87 (q, J=6.9 Hz, 2H), 3.79 (s, 3H), 3.10-2.86 (m, 5H), 2.56-2.45 (m, 2H), 1.71 (app sextet, J=7.1 Hz, 2H), 0.97 (q, J=7.3 Hz, 3H); MS (ESI) nm/e 410 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:30])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: COc1ccc2c(c1)CCC(N)C(=O)N2
Product: COc1ccc2c(c1)CCC(NC(=O)CC(C)(C)NC(=O)OC(C)(C)C)C(=O)N2

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step D by the procedure described in Example 1, Step F. 1H NMR (200 MHz, CDCl3): 1.32 (s,6H), 1.38 (s,9H), 1.86 (m,1H), 2.4-3.0 (m,5H), 3.77 (s,3H), 4.49 (m,1H), 5.25 (br s,1H), 6.68 (d,8 Hz,1H), 6.70 (s,1H), 6.89 (d,8 Hz,1H), 7.55 (br s,1H). FAB-MS: calculated for C21H31N3O5 405; found 428 (M+Na,100%), 406 (M+H,23%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[H-].[Na+].[Na].[CH:19](Br)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.CO>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][O:4]1
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CO
Product: FC(F)(F)C1(C(F)(F)F)OCC(COC(c2ccccc2)c2ccccc2)O1

Procedure:
A sample of 12 grams (0.05 mols) of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane in 50 ml toluene is treated with 1.93 grams sodium hydride - mineral oil (53.4%, 0.043 mols) at 25°-33° C. The sodium salt is stirred for 2 hours at 35° C. Benzhydryl bromide, 10.6 grams, (0.043 mols) is added at 37° C. and then the temperature is raised to 75°-95° C. for 3 hours. The mixture is filtered and the filtrate washed with water. Vacuum-stripping gives an oil which is dissolved in methanol and clarified by filtration through Super Cel. Yield of product is 17.0 grams at this point. A forerun is distilled in a 4 inch column filled with stainless steel packing, the remainder without packed column. The product obtained is distilled at 137° C. under 0.45 mm of mercury pressure to yield 2,2-bis(trifluoromethyl)-4-diphenylmethoxymethyl-1,3-dioxolane.
Reaction SMILES: Cl.Cl.[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[N:10]1[CH2:15][CH2:14][C:13]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:11]1.C(OC(N1CCC(N2CCC3(C4C(=CC=CC=4)CCC3)CC2)C(O)C1)=O)(C)(C)C.C(OC(N1CCC(O)C(N2CCC3(C4C(=CC=CC=4)CCC3)CC2)C1)=O)(C)(C)C.[I:83][C:84]1[CH:85]=[C:86]([CH:89]=[CH:90][CH:91]=1)[CH2:87]Br>CCO.C(N(CC)CC)C>[I:83][C:84]1[CH:85]=[C:86]([CH:89]=[CH:90][CH:91]=1)[CH2:87][N:7]1[CH2:8][CH2:9][CH:4]([OH:3])[CH:5]([N:10]2[CH2:15][CH2:14][C:13]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH2:12][CH2:11]2)[CH2:6]1
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Reactant: BrCc1cccc(I)c1
Agent: CC(C)(C)OC(=O)N1CCC(N2CCC3(CCCc4ccccc43)CC2)C(O)C1
Agent: CC(C)(C)OC(=O)N1CCC(O)C(N2CCC3(CCCc4ccccc43)CC2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2cccc(I)c2)CC1N1CCC2(CCCc3ccccc32)CC1

Procedure:
A mixture of 21c and 22c derived from a mixture of 19c and 20c as described above (676 mg, 1.81 mmol), 3-iodobenzylbromide (2.17 mmol, 645 mg), and triethylamine (10 mL) in absolute EtOH (20 mL) was refluxed for 18 h. Volatiles were removed under reduced pressure and the red residue was treated with water. After extraction in dichloromethane (3×30 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a dark red semi-solid residue. Chromatographic purification (silica gel, 50% ethyl acetate-hexanes) afforded 276 mg (30%) of the crude product as a yellow oil. The two regioisomers were separated by HPLC (Silica gel, Hexane/Isopropanol/Triethylamine: 98/2/0.02) and 13d was obtained as a white crystalline solid (166 mg, 18%). Only a trace of the other isomer was recovered. The hydrochloride of 13d was prepared in satd methanolic saturated HCl and subsequently recrystallized from 50% i-PrOH-hexanes to provide a white powder; mp 245° C. 1H NMR (CDCl3)δ1.59-2.06 (m, 8, 2 N-CH2 --CH2), 2.41-2.48 (m, 2, Ar-CH2 --CH 2), 2.52-2.62 (m, 2, CH2CHOH), 2.75-2.78 (m, 4, Ar-CH2 --CH2 --CH2), 2.83-2.92 (m, 2, CH2 --CH2 --CHOH), 3.01-3.06 (d, 2, N-CH2 --CHN, J=10.0 Hz), 3.38-3.56(m, 3, Ar-CH2 --N+CH-N), 3.85 (s, 1, CH--OH), 7.02-7.31 (m, 5, arom.), 7.44-7.48(d, 1, arom., J=7.8 Hz), 7.58-7.62 (d, 1, arom., J=7.9 Hz), 7.68 (s, 1, arom.).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4](C)[C:3]=1[C:13]([OH:15])=[O:14].[CH2:16](N(CC)CC)[CH3:17].[NH3:23].O1CCOCC1>ClCCl>[CH2:16]([O:15][C:13]([C:3]1[CH:4]=[N:5][C:6]([Cl:11])=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:23])=[O:14])[CH3:17]
Reactant: CCN(CC)CC
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C(=O)O
Reactant: N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1N
Reaction time: 8 h

Procedure:
To a solution of 4,6-Dichloro-2-methyl-5-nitro-pyridine-3-carboxylic acid (15 g, 56.6 mmol) and triethylamine (7.9 mL, 57.3 mmol) in dichloromethane (84 mL) at 0° C. was added dropwise ammonia solution in dioxane (0.5 M, 113 mL, 56.5 mmol). The mixture was then stirred overnight. Removal of the solvent followed by column chromatography gave 9 as a yellow crystalline solid. (7.3 g). 1H-NMR δ: 1.32 (t, J=7.1 Hz, 3H), 4.33 (q, J=7.1 Hz, 2H), 8.06 (s, br, 2H), 8.62 (s, 1H).
Reaction SMILES: [Cl:1][O-].[Na+].[CH:4]12[CH2:10][C:9](=[O:11])[CH:8]1CC=C2.[CH3:12][C:13]([CH3:15])=[O:14]>[OH-].[Na+].S(=O)(=O)(O)O>[Cl:1][CH:15]1[CH:13]([OH:14])[CH2:12][CH:10]2[CH:4]1[CH2:8][C:9]2=[O:11]
Reactant: [O-]Cl
Reactant: O=C1CC2C=CCC12
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC2C1CC(O)C2Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1 N sodium hypochlorite in 0.1 N sodium hydroxide (478 ml) and 2 N sulphuric acid (425 ml) was added to a solution of bicyclo[3,2,0]hept-2-ene-6-one (23.0 g) in acetone (500 ml). The resulting solution was stirred at room temperature for 24 hours.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].O.[BH4-].[Na+]>O1CCCC1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C@@H:15]([OH:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.0 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 65 ml of tetrahydrofuran, and 2 ml of water and 0.6 g of fine sodium borohydride are added at room temperature. After 1 hour of stirring at room temperature, the reaction mixture is added to ice water, extracted three times with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried with sodium sulfate and concentrated by evaporation in a vacuum, raw yield 6.07 g.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1ncc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (0.32 g, 1.13 mmol), 2-methoxybenzeneboronic acid (0.19 g, 1.25 mmol), tetrakis(triphenylphosphine)palladium (65.5 mg, 0.057 mmol), and 2.0M sodium carbonate (3.0 mL, 6.00 mmol) in toluene (3.0 mL) and EtOH (1.0 mL) was heated to 70° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-25% EtOAc in hexanes) to afford a light yellow solid as 5-bromo-2-(2-methoxyphenyl)-3-nitropyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.93 (1H, d, J=2.0 Hz), 8.37 (1H, d, J=2.0 Hz), 7.66 (1H, dd, J=7.5, 1.7 Hz), 7.52 (1H, m), 7.16 (1H, td, J=7.5, 1.0 Hz), 6.92 (1H, dd, J=8.3, 0.7 Hz), 3.72 (3H, s).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:10]([NH:12][C@@H:13]([CH2:24][CH2:25][CH2:26][CH3:27])[C:14](=[O:23])[CH2:15][S:16][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[O:11])=O)(C)(C)C.[ClH:32].CCCCCC>C(OCC)(=O)C>[ClH:32].[NH2:8][C@@H:9]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:10]([NH:12][C@@H:13]([CH2:24][CH2:25][CH2:26][CH3:27])[C:14](=[O:23])[CH2:15][S:16][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[O:11]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)CSCc1ccco1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)CSCc1ccco1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59 %

Procedure:
(s)-3-((s)-2-tert-Butoxycarbonylamino-4-methylvalerylamino)-1-furfurylthio-2-heptanone (8.47 g) obtained in Example 1 was dissolved in ethyl acetate (25 ml), and 4N hydrogen chloride-containing ethyl acetate solution (25 ml) was added to the solution. After the mixture was stirred at room temperature for 50 minutes, hexane (50 ml) was added to the mixture. Then, the resultant crystals were filtered, and washed with hexane to give the titled product (4.31 g).
Reaction SMILES: C(O)CCCCC.[H-].[Na+].[C:10]1([O:16][C:17](=[O:51])[O:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][N:38]([C:41]5[C:49]6[CH:48]=[CH:47][S:46][C:45]=6[CH:44]=[CH:43][CH:42]=5)[CH2:37][CH2:36]4)[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:50])C=CC=CC=1.C[O-].[Na+]>O1CCCC1.O>[CH3:10][O:16][C:17](=[O:51])[O:18][CH2:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([C:41]4[C:49]5[CH:48]=[CH:47][S:46][C:45]=5[CH:44]=[CH:43][CH:42]=4)[CH2:37][CH2:36]3)[CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:50]
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCCO
Product: COC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Yield: 19.6 %

Procedure:
To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) was added with stirring under ice-cooling 60% sodium hydride (18 mg) by small portions, and the mixture was stirred at the same temperature for 0.5 hr, to a solution of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was added with stirring under ice-cooling sodium methoxide (30 mg), and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester methyl ester (42 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:23][S:24][C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)[C:10]([S:11][C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[N:13]=2)=[C:9]([OH:21])[C:8](=[O:22])[O:7]1)=[O:5])C.C(=O)(O)[O-].[Na+]>O.C(O)C>[NH:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[S:11][C:10]1[C:6]([CH2:23][S:24][C:25]2[NH:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[N:29]=2)([C:4]([OH:5])=[O:3])[O:7][C:8](=[O:22])[C:9]=1[OH:21]
Reactant: CCOC(=O)C1(CSc2nc3ccccc3[nH]2)OC(=O)C(O)=C1Sc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1OC(CSc2nc3ccccc3[nH]2)(C(=O)O)C(Sc2nc3ccccc3[nH]2)=C1O
Yield: 54.7 %

Procedure:
3-(1H-benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid ethyl ester (32 g) prepared as described in Example 1 was suspended in water (400 mL) and ethanol (300 mL). The suspension was stirred continuously and aqueous sodium bicarbonate solution (23 g in 350 mL of water) was added dropwise during about 5 hours to maintain pH of around 7.5 to 8. The resulting mixture was stirred at 20° C. for 2 days. The milky mixture was put on a rotary evaporator to remove ethanol at a temperature below 40° C. under reduced pressure. The suspension became a clear solution soon after the evaporation started. During the evaporation process 400 mL of water were added to ensure complete removal of ethanol. The solution was adjusted to pH8 and allowed to stir at 40° C. for 18 hours. The product was precipitated out by acidifying the solution to pH 5-6 using acetic acid water solution (12 mL of acetic acid in 230 mL of water). The solid was filtered, washed with water (40 mL) and acetonitrile (40 mL), and dried under vacuum, giving 3-(1H-benzoimidazol-2-ylsulfanyl)-2-(1H-benzoimidazol-2-ylsulfanylmethyl)-4-hydroxy-5-oxo-2,5-dihydro-furan-2-carboxylic acid as a pale grey solid (16.5 g). 1HNMR (300 MHz, D2O) δ=7.10-6.70 (m, 8H), 3.80 (d, 1H), 3.60 (d, 1H) ppm. 13CNMR (75 MHz, D2O) δ=173.7, 173.2, 160.5, 156.6, 149.8, 149.3, 137.9, 122.2, 122.0, 113.7, 113.4, 104.5, 87.5, 37.4 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=O)=[CH:8][N:9]=1.N1C=CC=CC=1.Cl.[NH2:25][OH:26]>O>[Cl:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:10]=[N:25][OH:26])=[CH:8][N:9]=1
Reactant: NO
Reactant: COc1ccc(Oc2ncc(C=O)s2)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Oc2ncc(C=NO)s2)c(Cl)c1
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of Example 30B (13.05 g, 48.4 mmol) in pyridine (38.8 g, 484 mmol) was added hydroxylamine hydrochloride (33.7 g, 484 mmol). The mixture was heated at 80° C. for 0.5 hours, cooled to ambient temperature, treated with water (1000 mL) and filtered. The collected solids were dried in a vacuum oven to provide 13.2 g of the title compound (96%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.82 (s, 3H) 7.03 (dd, J=9.01, 3.13 Hz, 1H) 7.25 (d, J=2.94 Hz, 1H) 7.52 (d, J=8.82 Hz, 1H) 7.68 (s, 1H) 7.81 (s, 1H) 12.02 (s, 1H); MS (ESI) m/z 284.9 (M+H)+.