Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:77][N:78]([CH3:82])[CH2:79][CH2:80][NH2:81]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:81][CH2:80][CH2:79][N:78]([CH3:82])[CH3:77])=[O:28])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCN
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)NCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
To a mixture of 0.0604 g (0.131 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) and 4 mL of dimethylformamide was added 0.0309 g (0.229 mmole) of 1-hydroxybenzotriazole, 0.0825 g (0.229 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1113 g (0.862 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0172 g (0.197 mmole) of N,N-dimethylethylenediamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0631 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(2-dimethylamino-ethyl)-3-ethoxy-benzamide (I-219) as a white solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C@@H:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])[CH3:35]
Reactant: C[C@H](N)c1ccccn1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with (S)-1-amino-1-(2-pyridyl)-ethane (51 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 76 mg of the title compound. Optical Rotation [α]D=+63.90° (c=0.39 mg/ml; CH3OH)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: c1ccsc1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: O
Product: Brc1ccc(-c2cccs2)cc1
Temperature: 85 °C
Yield: 98 %

Procedure:
As shown in the following Reaction 8,130 mg (0.6 mmol) of 4-bromophenyl boronic acid was melted in 15 mL of thiophene, and 500 mg (3.22 mmol, 3 eq) of manganese(III) acetate dihydrate was added thereto, and then the reaction solution was refluxed for 1 hour at temperature of 85° C. Next, the reaction solution was filtered with hexane using a funnel charged with silica gel, and dehydrated with magnesium sulfate and distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase: n-hexane) to obtain 140 mg of 2-(4-bromo-phenyl)-thiophene with a yield of 98%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 7.50 (m, 4H), 7.25 (d, 2H), 7.07 (t, 1H)].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[NH:27][C:26]2=[O:34])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>C1COCC1.CO>[O:34]=[C:26]1[N:25]([CH:22]2[CH2:21][CH2:20][N:19]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9](=[O:18])[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:11])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27]1
Reactant: O=C(C(=O)c1ccc(CBr)cc1)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(C(=O)c1ccc(CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1)c1ccccc1

Procedure:
A mixture of 1-[4-(bromomethyl)phenyl]-2-phenylethane-1,2-dione (6.06 g, 20.0 mmol), 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (4.56 g, 21.0 mmol), PS-DIEA (20 g, 74 mmol), and TEA (50 mg, 0.5 mmol) was stirred overnight at rt in THF-MeOH (1:1, 300 mL). After this time, the resin (PS-DIEA) was filtered and washed with MeOH (2×100 mL). The combined solution was concentrated to afford the desired product. This product is pure enough (by LCMS) for next step reaction. Analytical LCMS: single peak (ELSD), 2.483 min.
Reaction SMILES: [Na].[CH3:2][O-:3].[Na+].[O:5]1[C@H:7]2[CH2:8][C@H:9]3[C@:24]([CH3:26])([CH2:25][C@@H:6]12)[C@@H:23]1[C@H:12]([C@H:13]2[C@:20]([CH3:28])([CH2:21][C:22]1=[O:27])[C@@H:16]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3.Cl>CO.O>[OH:3][C@@H:2]1[C@@H:6]([O:5][CH3:7])[CH2:25][C@@:24]2([CH3:26])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:23]2[C:22](=[O:27])[CH2:21][C@@:20]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:19])[CH3:18])[CH2:8]1
Reactant: C[O-]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
Sodium (70 mg.) was dissolved in dry methanol (5 ml.), and to the resulting solution of sodium methoxide (about 166 mg,) was added 2α,3α-epoxy-5α-pregnane-11,20-dione (100 mg). The solution was refluxed for 5 days, then water was added, and the mixture was neutralised with dilute hydrochloric acid and extracted into chloroform. The extract was dried over sodium sulphate and evaporated to a brown oil which was purified by preparative TLC in ethyl acetate/petrol (1/1). The title compound was recrystallised from ethyl acetate/petrol (21 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].C(N(CC)CC)C>O1CCCC1.CO.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3cccs3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 (12.0 g) obtained in Example 120-(1) was dissolved in tetrahydrofuran (120 ml) and methanol (360 ml), and added thereto were triethylamine (24.2 ml) and 10% palladium carbon catalyst (wet, 3.6 g), and the mixture was stirred at room temperature for 18 hours under hydrogen atmosphere under normal pressure. The insoluble materials were filtered off, washed with tetrahydrofuran, and the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, washed successively with a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and water, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-methyl-3(2-thienylmethyl)benzene (7.79 g) as colorless crystals. APCI-Mass m/Z 536 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[CH:3]=1.[N:15]([O-])=[O:16].[Na+].O>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=[O:16]
Reactant: O=N[O-]
Reactant: CCCCCn1c(N)cc(=O)[nH]c1=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 1 h

Procedure:
6-Amino-1-pentyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (8.0 g, 0.038 mol) was mixed with sodium nitrite (3.1 g, 0.045 mol) in acetic acid (120 mL). The mixture was stirred at 75° C. for 1 h. The color of the reaction mixture became pink and then purple. The solution was allowed to cool down to room temperature, and water (40 mL) was added. The solid was collected by suction filtration and washed with water (50 mL) to produce the desired product, which was used directly for next step without further purification. LCMS calculated for C9H15N4O2S: (M+H) 243.1; found 243.1.
Reaction SMILES: C1(NC(=S)N[C@@H](CC2C=CC=CC=2)C([NH:13][C@H:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]([CH2:31][C:32]3[NH:36][N:35]=[N:34][N:33]=3)[C:15]2=[O:37])=O)C=CC=CC=1.[ClH:46]>O1CCCC1.C(OCC)(=O)C>[ClH:46].[NH2:13][C@H:14]1[N:20]=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]([CH2:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[C:15]1=[O:37]
Reactant: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Reaction time: 10 h

Procedure:
To a solution of (3S)-3-[[(2S)-2-[N'-(phenyl)-thioureido]-3-phenylpropanoyl]amino]-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.10 g) in tetrahydrofuran (84.6 ml) was added dropwise 4N-hydrogen chloride in ethyl acetate (84.6 ml) below 6° C. After stirring under the same conditions for 10 hours, the resultant precipitates were collected by filtration, and then the collected precipitate was suspended in chloroform and stirred for 1 hour at room temperature. The objective product was collected by filtration to give (3S)-3-amino-1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1, 4-benzodiazepin-2-one hydrochloride (7.15 g).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: OC1CCNCC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCC(O)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidin-4-ol (38 mg), and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 41%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:30])[C:3]([NH:5][C@@H:6]([CH:27]([CH3:29])[CH3:28])[C:7]([N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[CH2:11][C@H:10]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:8])=[O:4].[O:31]1CC(O)O[CH2:33][CH:32]1O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:21]1([NH:20][C:18]([C@H:10]2[N:9]([C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:33][CH2:32][OH:31])[CH3:30])[CH:27]([CH3:29])[CH3:28])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Reactant: OC1COC(O)CO1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)NCCO)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 146.2 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-((S)-2-aminopropanamido)-3-methylbutanoyl)-N-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carb ox amide (55 mg, 134 μmol, Eq: 1.00) was combined with MeOH (3 mL) to give a colorless solution. 1,4-Dioxane-2,5-diol (8.87 mg, 73.9 μmol, Eq: 0.55) was added followed by acetic acid (8 μL, 134 μmol, Eq: 1.00) and sodium cyanoborohydride (13 mg, 210 μmol, Eq: 1.5). The reaction was stirred at rt for 4 h and then quenched by dropwise addition of 1 M aqueous HCl. The reaction mixture was basified with 0.1 M aqueous NaOH, extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to give (S)-1-{(S)-2-[(S)-2-(2-Hydroxy-ethylamino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a white solid (49 mg), m/z=454.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22](OC2C=CC=CC=2)=[O:23])C(=O)OC2C=CC=CC=2)[CH:7]=1.Cl.Cl.[CH3:52][N:53]([CH2:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[CH3:54].C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH2:55][CH:56]1[CH2:61][CH2:60][N:59]([C:22]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:38][CH2:39]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:23])[CH2:58][CH2:57]1)[CH3:54]
Reactant: CN(C)CC1CCNCC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 50.2 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(dimethylaminomethyl)piperidine dihydrochloride (67.0 mg), triethylamine (0.0523 ml) and water (0.050 ml), followed by stirring at room temperature for 10 hr. To the reaction mixture were added triethylamine (0.0523 ml) and water (0.050 ml), followed by further stirring at room temperature for 24 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added hexane, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (22.4 mg, 50.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:50])[CH:5]=[C:6]([Cl:49])[C:7]=1[CH2:8][C@@H:9]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12].N1C=CC=CC=1.[C:57](Cl)(=[O:67])[O:58][C@@H:59]1[CH:64]2[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]2)[CH2:60]1>Cl>[CH:11]([OH:12])=[O:10].[Cl:1][C:2]1[CH:3]=[N+:4]([O-:50])[CH:5]=[C:6]([Cl:49])[C:7]=1[CH2:8][C@@H:9]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[O:10][C:11]([C@H:13]1[N:17]([C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:57]([O:58][C@@H:59]3[CH:64]4[CH2:65][CH2:66][N:61]([CH2:62][CH2:63]4)[CH2:60]3)=[O:67])[CH:20]=2)[CH2:16][CH2:15][S:14]1)=[O:12]
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1C(=O)c1cccc(CNc2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@@H]1SCCN1C(=O)c1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Product: O=CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.3 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-((phenylamino)methyl)benzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (120 mg, 0.161 mmol) was dissolved in Pyridine (1 ml, 12.36 mmol). (R)-quinuclidin-3-yl carbonochloridate (76 mg, 0.403 mmol) was added under N2 atmosphere and at 0° C. The reaction was stirred at RT for two days to achieve completion. The reaction mixture was diluted with HCl 1N and the precipitate was filtered, washed with Water and purified by preparative HPLC to give 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-3-(3-((phenyl(((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)benzoyl)thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide formate salt (20 mg, 0.022 mmol, 13.82% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24]#[N:25]>C(#N)C>[CH3:13][S:12][C:4]1[N:5]=[C:6]([Cl:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:20][C:21]2[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:28]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:3]=1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1nc(Cl)c([N+](=O)[O-])c(Oc2cc(C#N)ccc2OCc2ccccc2)n1
Reaction time: 16 h
Yield: 56.1 %

Procedure:
To 4,6-dichloro-5-nitro-2-methylthiopyrimidine (5.0 g, 20.8 mmol) in 200 mL acetonitrile at 0° C. was added cesium carbonate (8.82 g, 27.1 mmol) followed by the addition of 3-hydroxy-4-benzyloxybenzonitrile (4.69 g, 20.8 mmol), and the resulting reaction mixture was stirred for 16 hours. The volatiles were evaporated and the residue chromatographed on silica gel (hexane/ethyl acetate, 2:1) to afford 5.0 g of 2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine, a compound of formula (C).
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.C[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.[C:18](=[O:20])=[O:19].O=O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:14]([OH:15])(=[O:1])[C:13]1[CH:12]=[CH:11][C:10]([C:18]([OH:20])=[O:19])=[CH:17][CH:16]=1
Reactant: O=C=O
Reactant: Cc1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
In this example, a solution of 0.1456 g (1.26 mmol) of N-hydroxysuccinimide, 0.089 g (0.73 mmol) of 4-methylbenzyl alcohol and 0.1509 g (0.61 mmol) of cobalt acetate tetrahydrate in 40 ml of acetic acid was kept to 22° C. in a Parr Hastelloy reactor with temperature and pressure transducer. After the temperature reached 22° C., 745 psi of CO2 was introduced into the reactor, then 120 psi of O2 was added slowly to the reactor. The mixture was stirred under pressure for 24 hours at 22° C., then the pressure was released, and the mixture was cooled to room temperature. The white solid TPA was filtered, and the filtrate analyzed by HPLC using biphenyl as the internal standard. The solid TPA product was washed with acetic acid (20 ml) and dried in an oven at 120° C. for six hours to yield pure white solid terephthalic acid (96% yield).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:20])[NH:14][NH:15][C:16]=2[CH:17]([CH3:19])[CH3:18])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].CC([O:24][CH2:25][C@H:26]1[O:31][C@H:30](Br)[C@H:29]([O:33]C(C)=O)[C@@H:28]([O:37]C(C)=O)[C@@H:27]1[O:41]C(C)=O)=O.[OH-].[Na+]>ClCCl>[C@@H:30]1([O:20][C:13]2[C:12]([CH2:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=3)=[C:16]([CH:17]([CH3:19])[CH3:18])[NH:15][N:14]=2)[O:31][C@H:26]([CH2:25][OH:24])[C@@H:27]([OH:41])[C@H:28]([OH:37])[C@H:29]1[OH:33]
Reactant: CC(C)Cc1ccc(Cc2c(C(C)C)[nH][nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)Cc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a suspension of 4-[(4-isobutylphenyl)methyl]-5-isopropyl-1,2-dihydro-3H-pyrazole-3-one (0.082 g), acetobromo-α-D-glucose (0.62 g) and benzyl(n-tributyl)ammonium bromide (0.054 g) in dichloromethane (3 mL) was added a sodium hydroxide aqueous solution (5 mol/L, 0.9 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: tetrahydrofuran). The obtained semi purified 5-isopropyl-4-[(4-isobutylphenyl)methyl]-3-(2,3,4,6-tetraacetyl-β-D-gluco-pyranosyloxy)-1H-pyrazole was dissolved in methanol (5 mL), and sodium methoxide (28% methanol solution, 0.29 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solvent of the reaction mixture was removed under reduced pressure, and water was added to the residue. The mixture was purified by solid phase extraction (washing solvent: water, eluent: methanol). Further purification by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-7/1) gave the title compound (0.080 g).