Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2].[H-].[Na+].Cl.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28][Cl:29])[CH3:25]>CN(C)C=O>[ClH:29].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28])[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][CH:11]=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccccc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of 26.5 g. of 3-phenylisoindole-1-carboxylic acid ethyl ester in 600 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.40 mol. of sodium hydride (17.5 g. of a 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. Then, at -10° C. to -5° C. there are added 34.5 g. of 2-diethylaminoethyl chloride hydrochloride. The mixture is stirred for 1 hour at room temperature and subsequently heated for 3 hours at 60° C. The mixture is cooled and poured into 8 liters of ice-water. After the addition of 300 g. of sodium chloride, the oily precipitate is separated by decantation and immediately dissolved in methylene chloride. The solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is dissolved in 200 ml. of ether, treated with 280 ml. of 0.5-N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the separated hydrochloride is removed by filtration under suction, washed with water and ether and then dissolved in methylene chloride. The aqueous layer is separated and the methylene chloride solution is dried over sodium sulfate and filtered. After the addition of ether, there is obtained 2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 230°-232° C. (decomposition).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CN(Cc3ccccc3)Cc3cc(OC)ccc32)cc1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of 2-[benzyl-(3-methoxy-benzyl)-amino]-1-(4-methoxy-phenyl)-ethanol (16.23 g, 43.0 mmol, see Preparation 63) in CH2Cl2 (280 ml) was added TFA (40.0 g, 27.0 ml, 350 mmol). The mixture was refluxed overnight. The reaction mixture was allowed to cool to RT and poured onto ice-water containing sat. NaHCO3 (250 ml). The mixture was extracted with CH2Cl2 (3×150 ml) and the combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography (SiO2, gradient elution 10-40% EtOAc/Hexanes) of the residue afforded the title product (7.67 g, 21.3 mmol, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)[C@H:16]([CH2:26][O:27]CC4C=CC=CC=4)[O:15][C:14]3=[O:35])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)[C@H:16]([CH2:26][OH:27])[O:15][C:14]3=[O:35])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@H](COCc2ccccc2)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1O[C@@H](CO)[C@H](c2cc(F)cc(F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reaction time: 2 h

Procedure:
The title compound was obtained as a colorless oil from 1-((E)-3-(benzyloxy)prop-1-enyl)-3,5-difluorobenzene by the same method that is described for Example 39. (4S,5R)-3-(4-(4-chlorophenoxy)phenyl)-5-((benzyloxy)methyl)-4-(3,5-difluorophenyl)oxazolidin-2-one (Example 96) was placed into a 25 mL round bottom flask and dissolved in 7 mL ethanol:ethyl acetate (1:1) and treated with palladium on carbon (10% by weight, 73 mg). The vessel was sealed with a rubber septum and charged with hydrogen. The reaction was stirred for 2 h, then filtered on celite, evaporated to dryness and purified on silica gel (20-30% ethyl acetate/hexanes) to give the title compound as a colorless oil that solidified on standing. 1H NMR (acetone-d6) δ (ppm) 7.53 (d, J=9.1 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.21-7.16 (m, 2H), d, J=6.15 Hz, 2H), 7.02-6.93 (m, 5H), 5.58 (d, J=5.4 Hz, 1H), 4.55 (t, J=5.8 Hz, 1H), 4.45 (ddd, J=5.6, 3.7, 3.6), 3.97 (ddd, J=12.3, 5.6, 3.8 Hz, 1H), 3.90 (ddd, J=12.3, 5.6, 3.8 Hz, 1H); HPLC-MS calculated C22H16ClF2NO4 (M+H+): 432.1, found: 432.0.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[CH3:10]OC(OC)N(C)C.[N+]([O-])(O)=O.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[NH:32][C:33]([NH2:35])=[NH:34].[OH-].[Na+]>O.CO>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[NH:32][C:33]1[N:35]=[C:1]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:2]=[CH:10][N:34]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: CC(=O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Yield: 73.4 %

Procedure:
26.60 g of 3-acetylpyridine (0.219 mol; 1 eq.) and 44.0 mL of N,N-dimethylformamide dimethyl acetal (39.47 g; 0.331 mol; 1.508 eq.) were placed in a reactor flask and the mixture was refluxed for 1.5 h. Methanol, produced in the reaction was removed by distillation and the mixture was refluxed for further 2 hours. The rest of methanol and excess of the acetal were removed by distillation under slightly reduced pressure. The hot residue was treated with 100 mL DMF, and, after cooling down, with 56.3 g of 1-(2-methyl-5-nitrophenyl)guanidine nitrate (0.219 mol; 1 eq.). A solution of 8.8 g of sodium hydroxide in 17 mL of water was then added dropwise and the mixture was refluxed for 8 hours in an oil bath. Water (200 mL) was added with care to the hot solution, and the contents of the flask were poured to 700 mL of warm water. The whole mixture was cooled with stirring to room temperature. The precipitated solid was isolated by filtration and dried in the air to afford 49.41 g of crude 2-(2-methyl-5-nitroanilino)-4-(3-pyridinyl)pyrimidine (yield 73.2% calculated on 3-acetylpyridine), m.p. 186-188° C.; 1H NMR (DMSO-d6, 200 MHz): 2.43 (3H, s, CH3), 7.54 (3H, m, 3-H phenyl +5-H pyrimidine +5-H pyridyl), 7.90 (1H, dd, J=8.2, 2.2 Hz, 4-H phenyl), 8.48 (1H, dt, J1=7.9 Hz, 4-H pyridyl), 8.62 (1H, d, J=5.4 Hz, 6-H pyrimidine), 8.71 (1H, dd, 6-H pyridyl), 8.79 (1H, d, J=2.2 Hz, 6-H phenyl), 9.27 (1H, s, NH), 9.32 (1H, d, J=1.6 Hz, 2-H pyridyl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Product: COC(=O)c1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1

Procedure:
The sub-title compound was prepared by the method of intermediate 4, using intermediate 1 and 4-(bromomethyl)benzoic acid, methyl ester.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]([OH:15])=[O:14])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:25]>C(Cl)Cl>[C:24](=[O:25])([O:26][CH2:27][CH:28]([CH3:30])[CH3:29])[O:14][C:13](=[O:15])[CH:3]([O:2][CH3:1])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(NC(=O)Cc1cccs1)C(=O)O
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(NC(=O)Cc1cccs1)C(=O)OC(=O)OCC(C)C

Procedure:
One millimole of α-methoxy-N-(2-thienylacetyl)glycine in 10 ml methylene chloride at 0° is treated successively with one millimole each of triethylamine and isobutyl chloroformate, forming α-methoxy-N-(2-thienylacetyl)glycyl i-butyl carbonate. To this solution at -78° is added p-methoxybenzyl-5-N,N-di(p-methoxybenzyl)aminocarbonyloxymethyl 6H-1,3-thiazine-4-carboxylate, and then a second millimole of triethylamine. The reaction mixture is allowed to warm to room temperature over one hour, and kept at 25° one hour. The mixture is then washed successively with aqueous pH 2 buffer, water, and aqueous bicarbonate, dried with MgSO4, filtered and evaporated, affording p-methoxybenzyl 7-methoxy-7-(2-thienylacetamido)-3-N,N-di(p-methoxybenzyl)aminocarbonyloxymethyl decephalosporanate, which may be purified if desired by chromatography on silica gel, eluting with 4:1 chloroformethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][N:20]=[C:21]=[O:22])[CH:16]=[CH:17][CH:18]=1.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:21]([NH:20][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[O:22])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C=NCc1cccc(F)c1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NCc1cccc(F)c1)NNC(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
553 mg (3.24 mmol) of 4-chlorobenzoic acid hydrazide are placed in 10 ml tetrahydrofuran at room temperature. 500 mg (3.31 mmol) of 3-fluorophenylmethyl isocyanate, dissolved in 5 ml tetrahydrofuran, are rapidly added dropwise to this suspension with stirring. The mixture is further stirred overnight at room temperature. The reaction mixture is treated with 50 ml diethyl ether, and the precipitate is recovered by filtration, then washed with diethyl ether and dried in vacuo. 965 mg (92% of theory) of the target compound are thus obtained
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=2)=[C:11]([OH:24])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:36](Cl)(=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=2)=[C:11]([O:24][C:36](=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]=[CH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCC=CCCCCCCCC(=O)Cl
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)c2cccnc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCCCCCCC=CCCCCCCCC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1OC(=O)c1cccnc1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(nicotinoyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 9-octadecenoyl chloride there is obtained 3-(9-octadecenoyloxy)-4-(nicotinoyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is reduced with sodium borohydride using the procedure described above in Example 30C, there is obtained 3-(9-octadecenoyloxy)-4-(nicotinoyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CCl
Product: CCOC(=O)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
As shown in Scheme I,2-alkynyl-dihydropyridazinones of the present invention can be prepared by cyclization. For example, in step A, di-t-butyl malonate and ethyl chloroacetate can be condensed in the presence of a strong base in a polar aprotic solvent to provide 1,1-di-tert-butyl 2-ethyl ethane-1,1,2-tricarboxylate. In step B, the 1,1-di-tert-butyl 2-ethyl ethane-1,1,2-tricarboxylate can be reacted the appropriate pyridine or pyrimidine acid chloride in the presence of base to provide a tricarboxylate which can be decarboxylated in step C to provide the appropriate ethyl 4-(pyridin-2-yl or pyrimidin-2-yl)-4-oxobutanoate. In step D, the appropriate ethyl 4-(pyridin-2-yl or pyrimidin-2-yl)-4-oxobutanoate can be cyclized with hydrazine to provide the appropriate 6-(pyridin-2-yl or pyrimidin-2-yl)dihydropyridazinone which can be alkylated in step E with an alkyne having an appropriate leaving group (L represents halogen or alkyl or aryl sulfonate).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](Cl)=[O:21].[CH3:23][NH:24][CH3:25]>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11])[C:20](=[O:21])[CH2:19][N:24]([CH3:25])[CH3:23]
Reactant: CNC
Reactant: CNc1ccc(OC)cc1C
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N(C)C(=O)CN(C)C)c(C)c1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 64 %

Procedure:
A suspension of N,2-dimethyl-4-(methyloxy)aniline (5.10 g, 33.7 mmol) and potassium carbonate (9.32 g, 67.5 mmol) in tetrahydrofuran (150 ml) was treated with bromoacetylchloride (3.50 ml, 42.2 mmol), stirred for 45 minutes, and dimethyl amine in tetrahydrofuran (67.5 ml, 135 mmol) was added. The solution was stirred for 3 hours, additional dimethyl amine in tetrahydrofuran (67.5 ml, 135 mmol) was added, and the solution was warmed to 50° C. and maintained overnight. The solution was cooled, poured into ethyl acetate/saturated sodium bicarbonate, and the organic layer was separated, dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford N1,N2,N2-trimethyl-N1-[2-methyl-4-(methyloxy)phenyl]glycinamide (5.10 g, 21.58 mmol, 64.0% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6); two protons likely obstructed by DMSO; δ ppm 7.13 (d, J=8.6 Hz, 1 H), 6.90 (d, J=2.6 Hz, 1 H), 6.77-6.84 (m, 1 H), 3.76 (s, 3 H), 3.00 (s, 3 H), 2.13 (s, 3 H), 2.08 (s, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11](C(OCC)=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:18][Mg]Br.C([O:23][CH2:24][CH3:25])C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:24]([OH:23])([CH3:25])[CH3:18])[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)ns1
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(-c2ccc(F)cc2)ns1
Reaction time: 0.33 h

Procedure:
To a stirred and cooled (0° C.) solution of ethyl 3-(4-fluorophenyl)isothiazole-5-carboxylate (38.50 g, 153.2 mmol) in THF (400 mL) was added a solution of methylmagnesium bromide in diethyl ether (3.0 M, 128 mL, 384 mmol), dropwise over 20 minutes. After another 1.5 hours at 0° C. the reaction was quenched by the slow addition of ethyl acetate (20 mL) and concentrated. The residue was taken up in aqueous NH4Cl (400 mL) and extracted with ethyl acetate (2×150 mL). The combined extracts were dried (Na2SO4) and concentrated. The resulting amber syrup was purified by flash chromatography using a hexane/ethyl acetate gradient to afford 2-(3-(4-fluorophenyl)isothiazol-5-yl)propan-2-ol as soft, golden solid (29.02 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:16])[CH2:5]2.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:16])[CH2:5]2)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CN1C(=O)Cc2cc(N)ccc21
Solvent: c1ccncc1
Product: COC(=O)CN1C(=O)Cc2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a solution of methyl 2-(5-amino-2-oxoindolin-1-yl)acetate (0.120 g, 0.545 mmol) in pyridine (8 ml) cooled to 0° C., methanesulfonyl chloride (0.047 ml, 0.599 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The solvent was removed and the crude was portioned between DCM and 1N HCl. The organic phase was dried over sodium sulfate, and the solvent was removed. The crude was purified by filtration on silica gel cartridge (DCM:MeOH from 99:1 to 97:3) affording methyl 2-(5-(methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.133 g, 0.446 mmol, 82% yield). MS/ESI+ 298.9 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.Cl.[O:11]=[C:12]1[C@@H:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=2)[CH2:15][CH2:14][N:13]1[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([N:31]2[CH2:32][CH2:33][CH:28]([N:13]3[CH2:14][CH2:15][C@H:16]([O:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=4)[C:12]3=[O:11])[CH2:29][CH2:30]2)=[N:6][CH:7]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
5-Chloro-2,3-difluoropyridine (0.20 g, 1.3 mmol) was added to a mixture of (S)-methyl 5-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)picolinate hydrochloride (0.17 g, 0.44 mmol) and DIEA (0.38 mL, 2.2 mmol) in DMF (1.5 mL). The mixture was stirred at 100° C. overnight and then cooled to ambient temperature. The mixture was partitioned between saturated aqueous NH4Cl (20 mL) and EtOAc (50 mL). The organic phase was washed successively with water (20 mL), water (20 mL) and then brine (20 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified on silica (eluting with EtOAc) to afford (S)-methyl 5-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinate (0.17 g, 0.38 mmol, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:18])[CH:13](Cl)[C:14]([CH3:16])=O)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:20]([NH2:23])(=[S:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:13]3[S:22][C:20]([CH3:21])=[N:23][C:14]=3[CH3:16])=[O:18])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(N)=S
Reactant: CC(=O)C(Cl)C(=O)Nc1cccc2c1CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)Nc2cccc3c2CCC3(C)C)s1
Reaction time: 4 h
Yield: 42.4 %

Procedure:
1.14 g (4.08 mmol) of N-(1,1-dimethyl-4-indanyl)-2-chloroacetoacetamide and 0.30 g (4.08 mmol) of thioacetamide were dissolved in 10 ml of tetrahydrofuran and was refluxed for 3 hours. To the reaction mixture was added 0.56 g (4.08 mmol) of anhydrous potassium carbonate and reaction was effected for 4 hours under reflux. The resulting solution was added to water and extracted with ethyl acetate. The organic layer was concentrated and then purified by column chromatography (eluent; n-hexane:ethyl acetate=50:50 V/V) to obtain 0.52 g of N-(1,1-dimethyl-4-indanyl)-2,4-dimethylthiazole-5-carboxamide (yield 43%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[Br-:1].[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:8])=[O:7]
Reactant: O=C(O)CCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 86.7 %

Procedure:
A mixture of 5-bromopentanoic acid (6.9 g, 38 mmol) and triphenylphosphine (10 g, 38 mmol) in dry acetonitrile (30 ml) was heated under reflux overnight. Evaporation of solvent yielded crystals. The resultant crystals were washed with a small amount of acetonitrile and dried at room temperature under reduced pressure to afford a target product, (4-carboxybutyl)-triphenylphosphonium bromide (14.6 g, 87%), which was used in the next step without any further treatment.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[C:28](O)[CH:27]=[CH:26]3)=[CH:19][CH:18]=1>ClCCl.N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=3)[CH:24]=2)[CH:29]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Trifluoromethanesulfonic anhydride (1.3 mL, 7.74 mmol) was added over 5 minutes to a stirred solution of 6-(4-fluorophenyl)-2-naphthol (Step 1, 1.75 g, 7.35 mmol) in dichloromethane (25 mL) and pyridine (15 mL) at 0° C. under nitrogen. The reaction was stirred at 0° C. for 1 hour then allowed to warm to room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo to give 6-(4-fluorophenyl)-2-naphthyl trifluoromethanesulfonate (2.34 g, 86%). 1H NMR (500 MHz, CDCl3) δ 8.03 (1H, s), 7.96 (2H, dd, J=9.1, 13.1 Hz), 7.81-7.77 (2H, m), 7.67-7.65 (2H, m), 7.41 (1H, dd, J=2.4, 9.0 Hz), 7.21-7.17 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]2[O:7][CH2:13][C:9](=[O:10])[N:8]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C=NC(=O)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Product: O=C1COC(c2ccc(F)cc2)=N1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.4 %

Procedure:
To a solution of 4-fluorobenzoyl isocyanate (1.2 g, 7.2 mmol) in DCM (25 mL) was added (trimethylsilyl)diazomethane (2.0 M in hexane, 4.3 mL, 8.6 mmol) at 0° C. The reaction mixture was stirred for 45 min at rt. The mixture was diluted with water and the separated aqueous phase was extracted with DCM (3×). The combined organic layers were dried over (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 100:0-80:20 DCM-methanol) to afford 870 mg of 2-(4-fluorophenyl)oxazol-4(5H)-one: LCMS (m/z): 180.0 (MH+), tR=0.39 min