Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH3:11].[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17]OCCl.[C:23](OCC)(=[O:25])C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][O:25][CH:16]([Si:15]([CH3:14])([CH3:21])[CH3:22])[CH3:17])[N:6]=[C:5]2[CH3:11]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1n[nH]c2ccc(Br)cc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(COC(C)[Si](C)(C)C)c2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-methyl-1H-indazole 104 (0.4 g, 1.89 mmol) in anhydrous DMF (4 mL) at 0° C. was added sodium hydride (0.068 g, 2.85 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (0.377 g, 2.26 mmol). The reaction mixture was stirred at 0° C. fro 1 hour. Ethyl acetate (100 mL) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 5-bromo-3-methyl-1-(trimethylsilyl)ethoxymethyl-1H-indazole 116 (0.369 g, 1.08 mmol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:12]([C:13](OCC)=[O:14])=[C:11]([Cl:18])[N:10]([CH2:19][CH3:20])[N:9]=1.C(OCC)(=O)C.O>O1CCCC1>[Cl:7][C:8]1[C:12]([CH2:13][OH:14])=[C:11]([Cl:18])[N:10]([CH2:19][CH3:20])[N:9]=1
Reactant: CCOC(=O)c1c(Cl)nn(CC)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1nc(Cl)c(CO)c1Cl
Temperature: -50 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 0.16 g (4.2 mmoles) of lithium aluminum hydride dissolved in 70 ml of tetrahydrofuran was cooled to −50° C. Thereto was gradually added dropwise a solution of 1.0 g (4.2 mmoles) of ethyl 3,5-dichloro-1-ethyl-1H-pyrazole-4-carboxylate dissolved in 30 ml of tetrahydrofuran. The mixture was stirred at −50° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The resulting mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.82 g (yield: 100%) of (3,5-dichloro-1-ethyl-1H-pyrazol-4-yl)methanol as a brown oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Br:12])=[C:7]([OH:13])[CH:6]=2.[C:15]([O-:18])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:13][C:7]1[C:8]([Br:12])=[CH:9][C:10]2[C:5](=[CH:4][C:3]([O:18][CH2:15][C:2]3[CH:3]=[CH:4][CH:5]=[CH:10][CH:11]=3)=[C:2]([Br:1])[CH:11]=2)[CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: Oc1cc2cc(O)c(Br)cc2cc1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cc2cc(Br)c(OCc3ccccc3)cc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,6-dibromonaphthalene-2,7-diol (67.64 g, 212.7 mmol) in DMF (400 mL) is added K2CO3 (64.7 g, 468.0 mmol). Benzylbromide (56.0 mL, 468 mmol) is added to the reaction (slight exotherm) and the mixture is stirred at RT for 2 days. The solid is filtered washing with 1:4 DMF/H2O and set aside for further extraction. The filtrate is extracted 3× with EtOAc and washed with brine. The EtOAc extracts are concentrated under reduced pressure, dissolved in minimum methylene chloride and triturated into hexanes to give product. The filtered solids are washed with hexanes to give additional material which is combined with the triturated solid to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[C:14]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[C:13]([Cl:33])[CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>CO.C1COCC1.O>[Cl:33][C:13]1[CH:12]=[C:11]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9][CH2:10]2)[CH:16]=[C:15]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])[C:14]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1
Reactant: CCOC(=O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentane carboxylate (0.32 g, 0.64 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.163 g, 3.88 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (0.220 g, 73%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, 2H), 7.41 (d, 2H), 7.26 (s, 1H), 6.92 (s, 1H), 4.22 (q, 2H), 3.71 (m, 2H), 1.98 (m, 2H), 1.81 (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:36])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:35])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:3][CH2:4][OH:5].[C:37](OC(=O)C)(=[O:39])[CH3:38].O>N1C=CC=CC=1>[C:37]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:36])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:35])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])(=[O:39])[CH3:38]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CCO
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 1 h

Procedure:
3.5 g of 3,7,11,15,19,23,27-heptamethyl-6,10,14, 18,22,26-octacosahexaenol was dissolved in 20 ml of pyridine, and 10 ml of acetic anhydride was added. After 20 g of iced water was added, the solution was stirred for one hour and extraction was then made using 100 ml of n-hexane. The extract was washed with 1N hydrochloric acid and then with water, dried and concentrated. The concentrate was refined by silica gel column chromatography, providing 3 g of the captioned 3,7,11,15,19,23,27-heptamethyl-6,10, 14,18,22,26-octacosahexaenyl acetate in a colorless oily form.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([NH:7][CH:8]1[C:14]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:13]2[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6].C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[N:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([NH:7][CH:8]1[C:14]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:13]2[CH2:12][CH2:11][N:10]([CH3:32])[CH2:9]1)=[O:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ncccc1C(=O)NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ncccc1C(=O)NC1CN(C)CCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.5 %

Procedure:
To a solution of 0.055 g (0.14 mmol) of (+/−)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-nicotinamide (example 3) in 3.00 mL of dichloroethane was added 0.050 mL (0.70 mmol) of formaldehyde (37% in water solution), 0.089 g (0.42 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 12 hours. A solution of sodium hydroxyl (35%) was added and the mixture was extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 90/10/1 to afford 0.014 g (24%) of pure product.
Reaction SMILES: CC1(C)CC(=O)CC(=O)C1.C([O:14][C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([C:39]([N+:42]([O-:44])=[O:43])=[CH:40][N:41]=2)[N:38]=1)[CH2:18][NH:19][C:20]1[C:25]([Cl:26])=[C:24]([CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=1)C=C.O>C1(C)C=CC=CC=1.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>[Cl:26][C:25]1[C:20]([NH:19][CH2:18][C:17]2[CH:16]=[C:15]([OH:14])[C:31]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N+:42]([O-:44])=[O:43])=[CH:40][N:41]=4)[N:38]=3)=[CH:30][CH:29]=2)=[N:21][C:22]([CH3:28])=[N:23][C:24]=1[CH3:27]
Reactant: C=CCOc1cc(CNc2nc(C)nc(C)c2Cl)ccc1Oc1ccc2ncc([N+](=O)[O-])n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(C)c(Cl)c(NCc2ccc(Oc3ccc4ncc([N+](=O)[O-])n4n3)c(O)c2)n1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
0.14 g (1.0 mmol) of dimedone and catalytic amount of tetrakis(triphenylphosphine)palladium(0) (12 mg) are added to a solution of 0.48 g (1.0 mmol) of [3-allyloxy-4-(3-nitro-imidazo[1,2-b]pyridazin-6-yloxy)-benzyl]-(5-chloro-2,6-dimethyl-pyrimidin-4-yl)-amine (from example A15) in 15 ml of dry toluene. The reaction mixture is refluxed under nitrogen for 1 h and then cooled to room temperature. The solution is poured into water (100 ml), extracted with ethyl acetate (4×100 ml) and the combined organic layers are dried with magnesium sulphate and concentrated in vacuo. The residue is crystallized from petroleum ether to give 0.44 g (50%) of the title compound as a beige powder of m.p. >114° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[O:12])CC2.BrC1C=CC(CC(O)=O)=CC=1.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:9]([CH2:8][C:7]([Cl:27])=[O:12])=[CH:10][CH:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCc2cc(Br)ccc2C1
Agent: O=C(O)Cc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc(Br)cc1

Procedure:
The synthesis of 6-bromo-2-tetralone is accomplished by dissolving 4-bromophenylacetic acid in methylene chloride and dimethyl formamide, under nitrogen. Oxalyl chloride is added and the mixture is stirred under a positive nitrogen atmosphere to produce the 4-bromo-phenylacetyl chloride, at a yield which typically is better than 99%.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.[NH2:21][C:22]1[N:27]=[C:26]2[CH2:28][C:29]3([CH2:39][C:25]2=[CH:24][CH:23]=1)[C:37]1[C:32](=[N:33][CH:34]=[CH:35][CH:36]=1)[NH:31][C:30]3=[O:38].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:21][C:22]2[N:27]=[C:26]3[CH2:28][C:29]4([CH2:39][C:25]3=[CH:24][CH:23]=2)[C:37]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[NH:31][C:30]4=[O:38])=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Reactant: Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1c(=O)n(-c2ccccn2)c2ccccc21)Nc1ccc2c(n1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (16 mg, 0.060 mmol, described in Intermediate 7), (±)-2-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1W)-one (15 mg, 0.060 mmol, described in Intermediate 5), PyClu (26 mg, 0.072 mmol), and DIEA (0.053 mL, 0.30 mmol) in THF (1 mL) was stirred at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=504 (M+1). HRMS: m/z=504.1796; calculated m/z=504.1779 for C28H22N7O3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=2)=[O:43])=[C:18]([CH3:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: CCc1nnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (42 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 68 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CN(C=O)C.[CH3:19][C:20]1([CH3:33])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24]([NH2:32])[CH:23]=[CH:22][C:21]1=2.O>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:32][C:24]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:33])([CH3:19])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]=3[CH:25]=2)=[O:10])=[CH:11][CH:12]=1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Terephthalic acid monomethyl ester (194 mg, 1.08 mmol) was dissolved in SOCl2 (5.39 mL) at 0° C. A drop of DMF was added and the mixture was stirred for 30 min. The SOCl2 was removed under vacuum and the crude acid chloride was dissolved in pyridine (12.5 mL). 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine 6 (200 g, 0.98 mmol) and DMAP (12 mg, 0.1 mmol) was added and the mixture was heated at 60° C. for 2 h with stirring. The mixture was poured into H2O and the product was extracted with EtOAc. Them organic layer was washed successively with HCl 2M, saturated NaHCO3, saturated NaCl, dried over MgSO4 and filtrated to give after evaporation N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-terephthalamic acid methyl ester 7 (316 mg, 88% yield) as a white solid.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:22])=[CH:19][C:20]=2[F:21])=[CH:13][C:12]([C:23]([OH:25])=[O:24])=[C:11]([OH:26])[CH:10]=1.FC(F)(F)C(O)=O>C(#N)C>[F:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[CH:16][C:15]=1[C:14]1[CH:13]=[C:12]([C:23]([OH:25])=[O:24])[C:11]([OH:26])=[C:10]([I:8])[CH:9]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O

Procedure:
198 mg (0.88 mmol, 1.1 eq) of NIS was added at room temperature to a solution of 200 mg (0.8 mmol) of diflunisal in 4 ml of acetonitrile and a catalytic quantity of 18 μl (0.24 mmol, 0.3 eq) of trifluoroacetic acid. It was stirred continuously. The solvent was evaporated at low pressure, it was diluted with dichloromethane and the product was then worked up as in example 1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][C:29]1([CH3:32])[CH2:31][O:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C(=O)C>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:28][C:29]([OH:30])([CH3:32])[CH3:31])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C)n(CC(C)(C)O)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 2,2-dimethyloxirane (2.5 mL), cesium carbonate (1.83 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 24 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.92 g, 76%).
Reaction SMILES: C1(S([CH2:10][CH2:11][CH2:12][CH:13]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]2=O)(=O)=O)C=CC=CC=1.CC(C)([O-])C.[K+].O.CCOCC>C1(C)C=CC=CC=1>[C:13]12[CH2:12][CH2:11][CH:10]=[C:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=2
Reactant: O=C1CCCCCCCCCCC1CCCS(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C2CCC=C2CCCCCCCCC1
Yield: 83.2 %

Procedure:
0.728 g (2 mmole) of 2-(3-phenylsulfonyl-prop-1-yl)-cyclododecanone and 0.560 g (5 mmole) of potassium tert-butoxide in 8 ml of toluene were heated to reflux for 1 hour in a reaction vessel fitted with a water separator. After cooling to 10°, addition of water (15 ml), extraction with ether (2×15 ml), washing of the organic layer with brine (15 ml), then with water, drying over Na2SO4, evaporation and final distillation (0.02 Torr--bath temperature: 140°) there were isolated 0.340 g (83% yield) of the desired compound.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[OH-].[K+].[C:14](=[O:16])=[O:15]>>[NH2:1][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C=O
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 185 °C
Yield: 30 %

Procedure:
p-Acetaminophenol 15 g, and potassium hydroxide 60 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 185° C., maintained for 14 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the yield is 30%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[Cl-].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](=[O:9])[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:16]([Cl:15])[CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C

Procedure:
Starting material (18(e)) was prepared as follows. A suspension of isophthalic acid monomethyl ester (18(a)), (2.65 g, 14.7 mmol) in CH2Cl2 (100 mL) and DMF (10 drops) was treated with oxallyl chloride (2.6 ml, 29.8 mmol) at 0° under argon. The reaction mixture was allowed to warm to room temperature over 18 h. The resulting solution was concentrated and azeotroped with toluene to give a crystalline yellow solid. This was then redissolved in CH2Cl2 (100 mL) and added dropwise to a stirred solution of 3,4-dichlorobenzylamine (2.6 g, 14.7 mmol) and Et3N (5 mL, 35.9 mmol) in CH2Cl2 (100 mL) at 0° under argon. The resulting solution was allowed to warm to room temperature over 4 hours, washed with 1N HCl(50 mL), saturated NaHCO3 (aq) (50 mL), dried over MgSO4, filtered and concentrated to an orange oil. This was then purified by flash chromatography on 9385 SiO2 eluting on a gradient of 25-50% EtOAc/i-Hexane to yield 3-(3,4-dichlorobenzyl-carbamoyl)-benzoic acid methyl ester (18(b)) as a pale yellow oil: 3.99 g (80%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.[OH-].[Na+:17].C(=O)([O-])O.[Na+].[CH3:23][S:24]([CH2:27][CH2:28][O:29][C:30](Cl)=[O:31])(=[O:26])=[O:25]>O.O1CCCC1>[CH3:23][S:24]([CH2:27][CH2:28][O:29][C:30]([NH:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12)=[O:31])(=[O:26])=[O:25].[Na+:17]
Reactant: CS(=O)(=O)CCOC(=O)Cl
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)CCOC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12

Procedure:
In 50 ml of water is suspended 4.60 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid and, with ice-cooling and stirring, 20 ml of 1N aqueous sodium hydroxide solution is added to the suspension for dissolving the acid. To the solution is added 1.85 g of sodium hydrogen carbonate and, then, a solution of 4.11 g of 2-methylsulfonylethoxycarbonyl chloride in 40 ml of tetrahydrofuran is added dropwise. The mixtrue is stirred with ice-cooling for 2 hours, then adjusted to pH 6.5, washed with ethyl acetate, and concentrated under reduced pressure. The residue is subjected to column chromatography on XAD-II (600 ml). Elution is performed with water and the eluate is concentrated under reduced pressure and freeze-dried to give 3.10 g of sodium 7β-(2-methylsulfonylethoxycarbonylamino)-3-hydroxymethyl-3-cephem-4-carboxylate as light yellow powders.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br)([O-:9])=[O:8].P([O-])([O-])([O-])=O>CN(C=O)C.O>[N+:7]([C:10]1[CH:11]=[C:12]([CH2:13][O:3][CH2:2][CH2:1][OH:4])[CH:15]=[CH:16][CH:17]=1)([O-:9])=[O:8]
Reactant: OCCO
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(COCCO)c1
Reaction time: 0.5 h
Yield: 358 %

Procedure:
Ethylene glycol (7.18 g) in anhydrous DMF (50 ml) was treated at 0° under nitrogen with sodium hydride (60% dispersion in mineral oil, 1.85 g) and the mixture stirred for 30 min. 3-Nitrobenzyl bromide (5.00 g) was added and the mixture was warmed to 200 over 1 h and stirred for a further 15 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product was extracted with EtOAc (2×150 ml). The combined organic layer was washed with water (2×200 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 2:1) followed by solvent evaporation in vacuo gave the title compound (16.34 g) HPLC RT=1.554 min. TSP+ve 215 (MNH4)+.