Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>>[F:1][C:2]1[C:3]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:4]([CH:12]=[C:13]([CH2:16][NH:17][O:18][CH3:19])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Product: CONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Yield: 81 %

Procedure:
The title compound was obtained by a procedure similar to that in Step C of Example 9. Namely, (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyimino-methyl)-benzamide was reduced with borane-pyridine complex in the presence of dichloroacetic acid to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(methoxyamino-methyl)-benzamide (28.14 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[NH:5][C:4](=[O:12])[CH:3]=1.Cl.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[N:14]=[O:15]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(=O)n1C1CC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CC1
Reaction time: 2 h

Procedure:
31.7 g (0.19 mol) of 6-amino-1-cyclopropyl-2,4-(1H,3H)-pyrimidinedione (II) was suspended in 250 ml water. To this was added 45 ml of 5N HCl and 15 g of NaNO2 (0.22 mol) which was dissolved in water. The reaction mixture was stirred for 2 hours and after cooling, the red crystals were filtered off and washed with water. Yield 31.9 g (86%) (III) NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[C:10]1([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH2:20][CH2:19]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([C:8](=[O:9])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:20][CH2:19]3)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1cccnc1
Reactant: c1ccc(-c2ccc3c(c2)CCN3)cc1
Product: O=C(Nc1cccnc1)N1CCc2cc(-c3ccccc3)ccc21

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridyl isocyanate and 5-phenylindoline (D30) to give (E15) (0.73 g, 52%) m.p. 241°-2° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.Cl[CH2:24][C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH3:37])[CH:31]=2)[O:28][CH:29]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([CH3:37])[CH:31]=3)[O:28][CH:29]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: Cc1cc(-c2nc(CCl)co2)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(CSc3nc(N)c(C#N)c(-c4ccc(OCCO)cc4)c3C#N)co2)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
52 mg (0.17 mmol) of the compound from Example 1A and 89 mg (0.18 mmol) of the compound from Example 28A, together with 42 mg (0.50 mmol) of sodium bicarbonate, are suspended in 1.8 ml of dry DMF. The reaction mixture is stirred at RT for 12 h. The mixture is then filtered and the filtrate is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)[N:17]=1)[C:12]([OH:14])=O.[O-:25][N+:26]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[C:28]([C@H:36]([NH2:38])[CH3:37])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)[N:17]=1)[C:12]([NH:38][C@@H:36]([C:28]1[CH:27]=[N+:26]([O-:25])[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=1)[CH3:37])=[O:14]
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reactant: Cc1ncc(-c2cc(C(=O)O)cc(-c3ccc(F)cc3F)n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(-c2cc(C(=O)N[C@H](C)c3ccc(C(F)(F)F)[n+]([O-])c3)cc(-c3ccc(F)cc3F)n2)cn1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 2-(2,4-difluorophenyl)-6-(2-methylpyrimidin-5-yl)isonicotinic acid (21.3 mg, 0.05 mmol) in DMF (0.5 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (27.0 mg, 0.07 mmol), HATU (0.5 M in DMF; 0.16 mL, 0.08 mmol) and diisopropylethylamine (65 μL, 0.37 mmol). The mixture was stirred at ambient temperature. After 25 min, the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound, which was converted to hydrochloride salt using 2.0 M HCl in ether (31 mg). HRMS 516.1453 (M+1). 1H NMR (400 MHz, CDCl3): δ 9.34 (s, 2H), 8.42 (s, 1H), 8.24-8.15 (m, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.11-7.04 (m, 1H), 6.97 (t, J=9.8 Hz, 1H), 6.85 (d, J=7.0 Hz, 1H), 5.37-5.30 (m, 1H), 2.83 (s, 3H), 1.69 (d, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][SH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:25]1[C:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:26]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][S:21][CH2:26][CH:27]([OH:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCC1=CO1
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)CSC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(=O)O

Procedure:
5.6 g of N-palmitoylcysteine, 5 g of 1,2-epoxy-octadecene and 5.35 g of potassium carbonate in 100 ml ethanol are heated in an atmosphere of nitrogen at 80° for 15 hours. After evaporation, HCl is added so as to obtain a pH of about 3 and the mixture is extracted with chloroform. The chloroform extract is washed with water and is then dried with sodium sulfate. After evaporation there is obtained a colorless residue which is recrystallized from ethyl acetate. There are obtained colorless crystals of the N-palmitoyl-S-[2(R,S)-hydroxyoctadecyl]-(L)-cysteine of melting point 96°-98° [α]D20 =+16° (c=0.78, chloroform).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22](F)[C:19]([C:20]#[N:21])=[C:18]([F:25])[CH:17]=2)[CH:9]=1)[CH3:2].[Na].[CH3:27][SH:28].O>CN(C=O)C>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([S:28][CH3:27])[C:19]([C:20]#[N:21])=[C:18]([F:25])[CH:17]=2)[CH:9]=1)[CH3:2]
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(F)c2)nc(NC)n1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(SC)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (140 mg, 0.408 mmol) in DMF (4 mL), was added methyl mercaptan sodium salt (ca. 15% in water) (252 mg, 0.543 mmol). The orange colored solution was stirred at room temperature overnight in a capped 10 mL vial. LCMS was very clean. The mixture was poured into water (15 mL). The formed solid was filtered, washed by water and dried to afford the title compound (136 mg) as a light yellow solid. LC-MS (ES) m/z=372 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[CH2:13]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (4.2 g of 60% dispersion in oil) is added to a solution of 4-hydroxybenzaldehyde (12.2 g) in dimethylformamide. The mixture is stirred for 30 min, and 1-bromooctane (18 ml) is added. The reaction mixture is stirred at 90° for five hours, cooled, and the solvent removed in vacuo. The residue is shaken with water, and extracted with three portions of hexane. The hexane extracts are dried, concentrated, and distilled in vacuo to provide 20.3 g of 4-octyloxybenzaldehyde.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4].C1(OC)C=CC=CC=1.ClC(Cl)(Cl)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([OH:27])=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Yield: 103.4 %

Procedure:
A mixture of 7.65 g of benzhydryl 7-[2-(2-chloroacetamidothiazol-4-yl]-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate, 25 ml of methylene chloride, 5 ml of anisole and 20 ml of trichloroacetic acid was allowed to react at room temperature for 30 minutes. At the end of this time, 300 ml of diisopropyl ether were added to the reaction mixture and the resulting precipitates were collected by filtration, giving 5.95 g of 7-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ncc2c(cc(-c3cccs3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 42.5 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.18 mmol), tributyl-thiophen-2-yl-stannane (0.070 mL, 0.22 mmol), and PdCl2(PPh3)2 (25 mg, 0.036 mmol) in DMF (4 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (40 mL) were added. 1 M HCl was added with stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (0-50% EtOAc/hexanes+2% AcOH) to give 30 mg of the title compound. MS: (+) m/z 393.24 (M+1).
Reaction SMILES: CN(C=O)C.[Br:6]N1C(=O)CCC1=O.[C:14]1([C:20]2[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[OH:30])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[Br:6][C:22]1[CH:23]=[C:24]([C:26]([CH3:27])([CH3:29])[CH3:28])[CH:25]=[C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]=1[OH:30]
Reactant: CC(C)(C)c1ccc(O)c(-c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Br)c(O)c(-c2ccccc2)c1
Reaction time: 48 h

Procedure:
A 20 mL DMF solution of N-bromosuccinimide (4.07 g, 22.9 mmol) was slowly added to a DMF solution (100 mL) of 2-phenyl-4-tert-butyl-phenol (4.93 g, 21.8 mmol), forming a dark green solution. After stirring in the dark for 48 h, the resultant dark red solution was poured into 500 mL of water, forming a cloudy solution. This was extracted with 95:5 hexane/toluene (3×200 mL), dried over MgSO4, filtered and the solvent removed to give 7 as a thick red oil. Yield: 6.32 g (95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:27][CH2:9][C:6]1[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc(C)nc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)nc1-c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 3-methoxy-6-methyl-2-(4-(trifluoromethyl)phenyl)pyridine (0.59 g, 2.2 mmol) in CCl4 (40 mL) was added NBS (440 mg, 2.5 mmol) and AIBN (33 mg, 0.20 mmol). The reaction mixture was heated to reflux for 13 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered through a pad (1.5 cm) of silica, and concentrated. The product 6-(bromomethyl)-3-methoxy-2-(4-(trifluoromethyl)phenyl)pyridine was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:12][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][OH:11]
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Br)ccc1NCCO
Temperature: 85 °C
Yield: 90.8 %

Procedure:
2-(4-Bromo-2-nitrophenylamino)ethanol (3.20 g, 12.3 mmol) was stirred in EtOH (100 mL) and water (50 mL), and iron powder (3.45 g, 61.6 mmol) and ammonium chloride (731 mg, 13.5 mmol) were added. The mixture was heated at 85° C. for 2 h, then filtered through a pad of celite and rinsed with EtOH (500 mL). The filtrate was concentrated and purified by column chromatography eluting with methylene chloride and a 9:1 methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to 85% methylene chloride, to provide the title compound (2.58 g, 91%) as a yellow oil: ESI MS m/z 231 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:25](O)[CH3:26]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:25][CH3:26])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 2-methyl-5-nitrobenzoic acid (27.6 mmol, 5 g) in ethanol (100 mL), sulfuric acid (138 mmol, 7.36 ml) was added slowly and stirred overnight at 80° C. The reaction mixture was neutralized with saturated solution of Na2CO3, extracted with diethyl ether (3×), organic layers were washed with brine, dried and concentrated under reduced pressure to yield crude product ethyl 2-methyl-5-nitrobenzoate 101 (5.4 g, 95%). NMR (400 MHz, CDCl3) 1.44 (t, J=7.0 Hz, 3H), 2.72 (s, 3H), 4.42 (q, J=7.04 Hz, 2H), 7.43 (d, J=8.6 Hz, 1H), 8.23 (dd, J=8.6 Hz and 2.7 Hz, 1H), 8.76 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([S:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].[F-].[Cs+]>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:25][CH2:24][C:23]([O:27][CH3:28])=[O:26])[C:12]([S:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(SC)[nH]c(=O)c1OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)c1nc(SC)n(CCC(=O)OC)c(=O)c1OCc1ccccc1
Yield: 82 %

Procedure:
Reaction of intermediate 1, ethyl 5-benzyloxy-2-methylthio-6-oxo-1,6-dihydro-pyrimidine-4-carboxylate, (1.500 g, 4.68 mmol) with methyl acrylate (25 ml) and cesium fluoride (0.19 g) for 18 h as described for the preparation of intermediate 6 gave 1.560 g (82% yield) of the title ester as a white solid; mp 62–63° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.31 (3H, t, J=7.1 Hz, CH3), 2.59 (3H, s, SCH3), 2.78 (2H, m, CH2), 3.72 (3H, s, OCH3), 4.34 (4H, m, OCH2 and NCH2), 5.19 (2H, s, OCH2), 7.34 (3H, m, aromatics), 7.46 (2H, m, aromatics). MS (ESI+) m/z 407 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[NH:4][C:3]1=[O:14].[NH:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:15]1([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3](=[O:14])[NH:4][C:5]=3[CH:10]=2)=[O:13])[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:27][C@H:16]12
Reactant: Cn1c(=O)[nH]c2cc(C(=O)O)ccc21
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1c(=O)[nH]c2cc(C(=O)N3CCC[C@@H]4c5ccccc5C[C@@H]43)ccc21
Yield: 27 %

Procedure:
The title compound is prepared from 1-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 27% of theory; LC (method 4): tR=1.89 min; Mass spectrum (ESI+): m/z=348 [M+H]+.
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:2]([C:25]([OH:27])=[O:26])[C@@H:3]([CH3:24])[O:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:46]>CO.C1C=CC=CC=1>[NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:2]([C:25]([O:27][CH3:46])=[O:26])[C@@H:3]([CH3:24])[O:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C[C@@H](OC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of Fmoc-L-Thr(Trt)-OH (2.33 g, 4.00 mmol) in methanol (4.0 mL) and benzene (16 mL) was added TMS-diazomethane (2.40 mL, 4.80 mmol). After 1 hour, the mixture was concentrated in vacuo to afford Fmoc-L-Thr(Trt)-OMe which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH:27]([CH3:29])[CH3:28].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: O=S(=O)(Nc1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 100 °C
Yield: 87.2 %

Procedure:
To a mixture of 4-fluoro-N-(4-fluoro-phenyl)-benzenesulfonamide (1.0 g, 3.7 mmol) and K2CO3 (1.03 g, 7.4 mmol) in dimethylformamide (5 mL) was added 1-bromo-2-methylpropane (1.21 mL, 11.2 mmol). The mixture was heated at 100° C. in a microwave reactor for 3 hours. Water was added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated. The crude product was re-dissolved in cyclohexane then concentrated to give 4-fluoro-N-(4-fluoro-phenyl)-N-isobutyl-benzenesulfonamide (1.05 g, 86%). 1H NMR (300 MHz, CDCl3): δ 7.56-7.57 (m, 2H), 7.12-7.13 (m, 2H), 7.00 (d, 4H), 3.28 (d, 2H), 1.54 (m, 1H), 0.91 (d, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]=[O:14])=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[AlH4-].[Li+].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH2:13][OH:14])=[N:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: O=Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2c(CO)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-nitro-1H-indazole-3-carbaldehyde (500 mg, 0.003 mol) was dissolved in 50 mL THF. Lithium tetrahydroaluminate (400 mg, 0.01 mol) was added in 3 portions and the reaction mixture was stirred at room temperature overnight. Water (400 μL), 15% NaOH solution (400 μL), then water (1.2 mL) was added, and then the crystalline brown-yellow precipitate was filtered off. The filtrate was concentrate to an oil which was used directly in the next step without further purification. m/z=164.0. 1H NMR (d4-MeOH) δ 7.2 (1H, d), 7.05 (1H, d), 6.85 (1H, dd), 4.74 (2H, s).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[Cl:28][C:21]1[N:22]=[C:18]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:19][C:20]=1[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ncc(C(=O)C3CC3)[nH]2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2nc(Cl)c(C(=O)C3CC3)[nH]2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 9 %

Procedure:
To a solution (12 mL) of (2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)(cyclopropyl)methanone in 1,2-dichloroethane was added N-chlorosuccinimide (0.091 g) and the mixture was stirred at 100° C. for 6 hr. To the reaction mixture were successively added saturated aqueous sodium hydrogen carbonate solution and 1 mol/L aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was successively purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio) and thin layer chromatography (ethyl acetate:hexane=50:50), and recrystallized from diisopropyl ether-hexane to give the title compound (0.016 g, yield 9%) as colorless crystals. melting point 95-97° C.