Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:20])[CH2:5][C:6]([OH:19])([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1.N1C=CN=C1.Cl[Si:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[CH3:1][S:2][C:3]1[C:4](=[O:20])[CH2:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([O:19][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)CC1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CSC1=CC(CCCCOc2ccccc2)(O[Si](C)(C)C)CC1=O
Yield: 89 %

Procedure:
To a solution of 400 mg of 2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 52 or Example 53 dissolved in 4 ml of dimethylformamide were added 279 mg of imidazole and 260 μl of chlorotrimethylsilane, under ice-cooling and stirring, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was extracted with an addition of water and hexane. The organic layer was washed with saturated aqueous sodium chloride, and the product dried over anhydrous sodium sulfate, filtered and concentrated, followed by silica gel column chromatography, to give 445 mg (yield 89%) of 2-methylthio-4-(4-phenoxybutyl)-4-trimethylsilyloxy-2-cyclopentenone.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C@@H:5]([OH:8])[CH2:6][OH:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:9][S:10]([O:7][CH2:6][C@H:5]([O:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:4][CH2:3][S:2][CH3:1])(=[O:12])=[O:11]
Reactant: CSCC[C@@H](O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CSCC[C@H](COS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-4-(Methylthio)-1,2-butanediol (0.47 g, 3.4 mmol) was dissolved in 5 ml of pyridine and cooled to 0° C. Methanesulfonyl chloride (0.66 ml, 8.5 mmol) was added and the mixture stirred for 2 hours while warming to room temperature, by which time tlc (ethyl acetate) indicated complete conversion of starting material (Rf 0.4) to title product (Rf 0.85). The reaction mixture was diluted with 10 ml H2O and extracted 2×15 ml of ethyl acetate. The organic layers were combined, dried (MgSO4) and stripped to in vacuo to yield title product an an oil, all of which was used in the next step; tlc Rf 0.85 (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C[N:14](C=O)C>O>[Cl:1][C:2]1[C:11]([NH2:14])=[N:10][C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CN(C)C=O
Solvent: O
Product: Nc1nc2ccccc2nc1Cl
Temperature: 60 °C
Reaction time: 72 h
Yield: 53 %

Procedure:
2,3-dichloroquinoxaline (4 g, 20 mmol, commercially available from Aldrich) is dissolved in dry DMF (20 ml) and treated with solid (NH4)2CO3 (9.7 g, 101 mmol). The resulting mixture is stirred at 60° C. for 3 days (reaction showed 60% completion). The reaction mixture is diluted with water and the product is extracted with EtOAc. The organic layer is dried and the solvent was removed under reduced pressure. The crude residue obtained is purified via column chromatography by eluting with petroleum ether: EtOAc to afford 1.9 g (53%) of the title compound as a pale yellow solid. LC/MS: (ES+): 180.1.
Reaction SMILES: [C@H:1]1([NH2:8])[CH2:6][CH2:5][C@H:4]([NH2:7])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12](Cl)[N:11]=1>CCOC(C)=O>[Cl:9][C:10]1[N:11]=[C:12]([NH:7][C@H:4]2[CH2:5][CH2:6][C@H:1]([NH2:8])[CH2:2][CH2:3]2)[CH:13]=[C:14]([I:16])[CH:15]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(I)cc(Cl)n2)CC1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of trans-cyclohexane-1,4-diamine (2.085 g, 18.26 mmol) and 2,6-dichloro-4-iodopyridine (1.000 g, 3.65 mmol) was heated in a capped vial at 120° C. After 5 hours, the reaction mixture was cooled. The solids were stirred in EtOAc for 30 minutes, and the suspension was filtered. The filtrate was diluted with EtOAc and washed with 20% brine and NaHCO3. The organic layer was dried and concentrated to give 1.20 g of the title compound. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[NH:17][C:16]2=[O:25])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]3[N:17]([CH:27]([CH3:29])[CH3:28])[C:16]2=[O:25])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc2c1n(C(C)C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (360 mg), 2-iodopropane (0.217 mL) and potassium carbonate (180 mg) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 15%-20% AcOEt in hexane) to give the title compound (218 mg) as colorless oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[C:14]([Cl:16])[S:15][C:10]=2[CH:9]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:20])=O>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[S:12][C:11]2[CH:13]=[C:14]([Cl:16])[S:15][C:10]=2[CH:9]=1)[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CON=C(C(=O)O)c1cc2sc(Cl)cc2s1
Product: CON=C(C(=O)Cl)c1cc2sc(Cl)cc2s1

Procedure:
Following the procedure of Example 1, 827 mg of α-methoxyimino-α-(5-chlorothieno[3,2-b]thien-2-yl)-acetic acid from Preparation 2 was reacted with oxalyl chloride to provide α-methoxyimino-α-(5-chlorothieno[3,2-b]thien-2-yl)acetyl chloride which was reacted with 642 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid silylated with 2.31 g of BSTFA. The reaction afforded 1.1 g of 7-[α-methoxyimino-α-(5-chlorothieno[3,2-b]thien-2-yl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. The thienothienyl oxime was reacted with 544 mg of zinc dust in formic acid and methanol to provide 1.1 g of 7-(5-chlorothieno[3,2-b]thien-2-yl)glycylamido-3-methyl-3-cephem-4-carboxylic acid. Reverse phase high performance chromatography provided
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.Br>[CH3:12][O:11][C:9](=[O:10])[CH:8]([Br:13])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1cccc(F)c1
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(Br)c1cccc(F)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
Methyl 2-(3-fluorophenyl)acetate (1.90 g, 11.3 mmol) and N-bromo succinimide (2.01 g, 11.3 mmol) are dissolved in CCl4 (80 mL). HBr (64 ul, 0.56 mmol) is added and the mixture is stirred under reflux overnight. The mixture is cooled at RT, diluted with DCM and washed with sat. NaHCO3, water and brine. The organic layer is dried (Na2SO4), filtered and evaporated obtaining intermediate I144 as a yellow oil (2.68 g, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].S([O-])([O-])=O.[Na+].[Na+].[C:20](=O)(O)[O-].[Na+].BrCC(O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([CH3:20])(=[O:12])=[O:11]
Reactant: O=C([O-])O
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1Cl
Agent: O=C(O)CBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1cc(F)c(F)cc1Cl
Temperature: 150 °C
Yield: 48 %

Procedure:
2-Chloro-4,5-difluorobenzenesulfonyl chloride (300 mg) was added to a solution of sodium sulfite (306 mg) and sodium bicarbonate (153 mg) in water (4 mL). The mixture was heated to 150° C. in a sealed microwave vial for 400 seconds and allowed to cool. The mixture was treated with bromoacetic acid (253 mg) in water (1 mL), and heated to 150° C. for 300 seconds then allowed to cool, following which the precipitate was removed by filtration and dried in vacuo to give the desired compound (132 mg). The material was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:28]1[O:29][C:30]2[C:31]([N:36]=1)=[N:32][CH:33]=[CH:34][CH:35]=2.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[CH2:19]([N:18]([C:28]1[O:29][C:30]2[C:31]([N:36]=1)=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: Clc1nc2ncccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1nc2ncccc2o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloro[1,3]oxazolo[4,5-b]pyridine as starting materials and by an operation similar to that of Example 303-3 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: CCCS(=O)(=O)Nc1cc2nc(-c3ccccc3)n(-c3ccccc3)c2cc1OCCCCCC(=O)OC(C)C

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with propanesulfonic acid chloride.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].ClC1C=CC=C(C(OO)=[O:23])C=1.C1C=CC=CC=1>CCCCCC>[O:23]1[CH:2]([CH:3]([OH:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1]1
Reactant: C=CC(O)CCCCCCCCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCC(O)C1CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
A 500-ml flask equipped with a stirrer was charged with 23.8 g (0.12 mol) of 1-tridecen-3-ol, 25.0 g (0.145 mol) of m-chloroperbenzoic acid and 250 ml of benzene, and the contents were stirred at room temperature for 48 hours. After completion of the reaction, 200 ml of hexane. Solids deposited were separated by filtration, and the solvent was distilled off under reduced pressure. The resultant residue was purified by column chromatography on silica gel, thereby obtaining 19.0 g (yield: 74%) of 1,2-epoxy-3-tridecanol.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27]I)=[CH:21][C:20]=2[F:29])=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][O:8][CH2:9][CH2:10][O:11]C=C)=[O:6].[CH3:30][NH2:31]>>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH:31][CH3:30])=[CH:21][C:20]=2[F:29])=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CN
Reactant: C=COCCONC(=O)c1ccc(F)c(F)c1Nc1ccc(CCCI)cc1F
Product: CNCCCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 32 %

Procedure:
The product of Example 15, Step E, 3,4-Difluoro-2-[2-fluoro-4-(3-iodopropyl)anilino]-N-[2-(vinyloxy)ethoxy]benzamide was reacted with methylamine and then deprotected according to the general procedure of Example 15, Step F, to afford 3,4-difluoro-2-{2-fluoro-4-[3-(methylamino)propyl]anilino}-N-(2-hydroxyethoxy)benzamide as a pale brown solid (32%); m.p. (Et2O) 112-116° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.61 (v br s, 1 H), 7.57-7.50 (m, 1 H), 7.02-6.94 (m, 1 H), 6.93 (dd, J=12.4, 1.5 Hz, 1 H), 6.79 (dd, J=8.3, 1.5 Hz, 1 H), 6.65 (ddd, J=8.8, 8.8, 5.9 Hz, 1 H), 3.80 (t, J=4.9 Hz, 2 H), 3.54 (t, J=4.9 Hz, 2 H), 2.66 (t, J=7.3 Hz, 2 H), 2.52 (t, J=7.6 Hz, 2 H), 2.41 (s, 3 H), 1.73 (q, J=7.5 Hz, 2 H). Not all exchangeable protons were observed. Anal. calcd. for C19H22F3N3O3.0.5H2O: C, 56.2; H, 5.7; N, 10.3. Found C, 56.2; H, 5.6; N, 10.2.
Reaction SMILES: C([O:8]C1C=C(O)C=CC=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([OH:34])(=[O:8])=[O:33]
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(O)c1ccccc1Cl
Yield: 185.2 %

Procedure:
3-Benzyloxyphenol (2.97 g, 15 mmol), as prepared in the preceding step, in methylene chloride (50 mL) was treated with diisopropylethylamine (2 mL) and 2-chlorobenzenesulfonyl chloride (3.27 g, 15.5 mmol) at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with 200 mL of methylene chloride, washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (5.35 g, 95%). 1H-NMR (300 MHz, CDCl3) δ 4.97 (s, 2H), 6.71 (dd, 1H, J=1.1, 4.1 Hz), 6.78 (t, 1H, J=2.3 Hz), 6.85 (dd, 1H, J=1.1,4.1 Hz), 7.17 (t, 1H, J=8.3 Hz), 7.37 (m, 5H), 7.58 (m, 2H), and 7.91 (dd, 1H, J=1.1, 4.1 Hz).
Reaction SMILES: [OH-:1].[Na+:2].[CH3:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:15][C:13](=[O:14])[CH2:12][CH2:11]1>CO>[Na+:2].[OH:15][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])[CH2:11][CH2:12][C:13]([O-:14])=[O:1]
Reactant: [OH-]
Reactant: CCCCCCCC1CCC(=O)O1
Agent: [Na+]
Solvent: CO
Product: CCCCCCCC(O)CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 43.6 g sodium hydroxide in 150 ml of methanol heated to reflux, 200 g gamma-undecalactone were added. After stirring for 2 hours at reflux, the mixture was cooled to room temperature and evaporated to dryness. The resulting crystals were washed with hexane to yield 240 g of colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:24][CH2:25][O:26][CH3:27]>>[CH3:27][O:26][CH2:25][CH2:24][N:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: COCCBr
Product: COCCn1cc(C2CCNCC2)c2cccnc21

Procedure:
This compound was prepared following the procedure described in example 7, parts E and F, starting with 0.2 g (0.66 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester and 0.081 ml (0.864 mmol) of 1-bromo-2-methoxyethane. After standard work-up, 0.15 g (100% of yield) of the expected product were isolated.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:22](Cl)(=[O:24])[CH3:23]>CC(N(C)C)=O>[C:22]([NH:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:19])([CH3:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:24])[CH3:23]
Reactant: CC(C)(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NC(C)(C)CO)c1I

Procedure:
Analogously to Example 3, 63.0 g. (100 mmol) of 5-amino-N-(2-hydroxy-1,1-dimethylethyl)-2,4,6-triiodoisophthalamic acid is reacted in 120 ml. of dimethylacetamide with 17 ml. of acetyl chloride and worked up. Yield: 64.0 g. (95%), m.p. 279°-281° C., with decomposition.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:18]=23)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)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>[F:8][C:4]1[N:3]=[C:2]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:27])=[O:28])[CH:24]=[CH:25][C:18]=23)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
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: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(F)n4)ccnc32)cc1

Procedure:
In a 20 mL microwave tube, 2-Bromo-6-fluoropyridine (L) (682 mg, 3.3 mmol, 1.2 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (B)(1.1 g, 2.8 mmol, 1 equiv.) and Pd(PPh3)4 (323 mg, 0.28 mmol), 0.1 equiv.) were suspended in a mixture of DME (10 mL) and aqueous Na2CO3 2M (3 mL). The container was sealed and the reaction mixture was exposed to microwave irradiation for 30 min at 160° C. The resulting mixture was diluted in ethyl acetate, washed with water and dried over anhydrous Na2SO4. The crude material was purified by flash chromatography on silica gel, eluting with hexanes/ethyl acetate mixtures (90:10 to 60:40). The title compound J was isolated as a pale yellow solid (2.1 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].CO.[BH4-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(C(O)c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
(a-1) To a stirred and cooled (water-bath) mixture of 48.5 parts of (4-amino-3-nitrophenyl)phenylmethanone and 320 parts of methanol were added portionwise 11.4 parts of sodium tetrahydroborate. Upon completion, stirring was continued for 15 minutes at room temperature. 100 Parts of water were added and the methanol was evaporated. The precipitated product was filtered off, washed with water, dried, filtered and crystallized twice from a moisture of methanol and water, yielding 19.6 parts of 4-amino-3-nitro-α-phenylbenzenemethanol; mp. 125° C. (int. 124).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:33])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:28]([F:31])([F:30])[F:29])[C:8]=1[CH3:32]>C1COCC1.CO>[Cl:16][C:12]1[N:11]=[C:10]2[N:9]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][C:19]=3[C:28]([F:29])([F:31])[F:30])[C:8]([CH3:32])=[C:7]([CH2:6][C:5]([OH:33])=[O:4])[C:15]2=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2nc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1M Aqueous NaOH (0.25 ml) is added to a stirring suspension of [6-chloro-1-(4-methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: (0.01 g, 0.021 mmol) in 1:1 THF/MeOH (0.5 ml). The resulting suspension is sonicated and allowed to stir at room temperature overnight. The solvent is removed in vacuo and the crude solid is dissolved in water (0.5 ml) and acidified to pH 2-3 using 1 N HCl. The suspension which forms is filtered, washed with water (0.5 ml) and dried under high vacuum to yield the titled compound. (MH+461)
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.NS(O)(=O)=O.[C:24]([O:30][CH3:31])(=[O:29])[CH2:25][C:26]([CH3:28])=O>CCOC(C)=O>[CH3:28][C:26]1[C:25]([C:24]([O:30][CH3:31])=[O:29])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:1]=1
Reactant: COC(=O)CC(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Agent: NS(=O)(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A mixture of 2-amino-5-nitrobenzophenone (1 g, 4.1 mmol), H2NSO3H (0.04 g, 041 mmol) and methyl acetoacetate (1.11 ml, 10.3 mmol) was stirred overnight at 120° C. under N2, than cooled to room temperature, diluted to 100 ml with EtOAc and washed with H2O. The organic phase was dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from EtOH to give pure product as a creamy solid (1.05 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=2.5 Hz, 1H), 8.48 (dd, J=2.5, 9.2 Hz, 1H), 7.53(m, 3H), 7.34(m, 2H), 3.59(s, 3H), 2.8(s, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36])(OCC)=O>C(#N)C.O>[C:27]1(=[O:36])[N:1]([CH:2]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[CH2:3][C:4]([OH:6])=[O:5])[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a stirred mixture of 3-amino-3-(4-methoxyphenyl)propionic acid (1.95 g, 10.0 mmol) and sodium carbonate (1.11 g, 10.5 mmol) in 200 mL of acetonitrile-water 1:1 is added N-carboethoxyphthalimide (2.26 g, 10.0 mmol). After 1 hour, the reaction slurry is filtered. The filtrate is concentrated to remove the acetonitrile and the pH adjusted to 1-2 with 4 N hydrochloric acid and stirred over night. The resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60 C, <1 mm) to afford 2.82 g (87%) of 3-phthalimido-3-(4-methoxyphenyl)propionic acid as a white powder: mp 160-164° C.; 1H NMR (DMSO-d6, 250 MHz) δ12.5 (br s, 1H), 7.95-7.80 (m, 4H), 7.36 (d 2H, J=8.7), 6.92 (d, 2H, J=8.4 Hz), 5.18-5.10 (m, 1H), 3.70-3.15 (m, 2H); 13C NMR (DMSO-d6) δ171.7, 167.6, 158.6, 134.6, 131.0, 130.8, 128.3, 123.1, 113.9, 55.0, 49.6, 35.9. Anal. Calculated for C18H15NO5. Theoretical: C, 66.46; H, 4.63; N, 4.31. Found: C, 66.25; H, 4.65; N, 4.28.