Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:6]=[C:2]([NH:1][C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[S:3][C:4]=1[C:12]1[CH:17]=[CH:16][N:15]([CH3:18])[C:14](=[O:19])[CH:13]=1
Reactant: O=C(O)c1ccncc1
Reactant: Cn1ccc(-c2sc(N)nc2-c2ccco2)cc1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1ccc(-c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)cc1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
2-Amino-4-(2-furyl)-5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)thiazole (222 mg, 0.812 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and isonicotinic acid (199 mg, 1.62 mmol), PyBOP (926 mg, 1.78 mmol) and triethylamine (0.497 mL, 3.56 mmol) were added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was poured into water, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=17:3), followed by reslurrying with methanol to afford the entitled Compound 123 (158 mg, 52%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[OH-].[K+].[CH:14]([OH:17])([CH3:16])[CH3:15]>O>[CH:14]([O:17][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)OCc1cccc([N+](=O)[O-])c1

Procedure:
A 500-milliliter flask equipped with a reflux condenser and a magnetic stirring bar was charged with 17.1 grams (0.1 mole) of 3-nitrobenzyl chloride in 250 milliliters of isopropanol. To this stirred solution was added 6.43 grams (0.1 mole) of potassium hydroxide in 25 milliliters of water. The reaction mixture was heated to reflux and maintained at reflux for 23 hours. The reaction mixture was then cooled, filtered, and the filtrate was concentrated on a rotary evaporator at 55° C. The residue was slurried with 300 milliliters of methylene chloride and transferred to a separatory funnel wherein it was washed consecutively with 100 milliliter portions of 1 Normal hydrochloric acid, water, 1 Normal sodium hydroxide, and water, respectively. The organic phase was separated, dried over magnesium sulfate, and concentrated on a rotary evaporator at 55° C., leaving a dark brown liquid. The dark brown liquid was charged to a distillation flask and distilled at a pressure of 2.4 millimeters of mercury. A main fraction (8.2 grams) was collected, said fraction having a boiling point of 123°-125° C. at 2.4 mm Hg pressure. This main fraction was identified by NMR spectroscopy as 1-(isopropoxymethyl)-3-nitrobenzene.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:13][C:12]2[CH:14]=[C:15](/[CH:18]=[CH:19]/[C:20](=[O:34])[N:21]([CH3:33])[CH2:22][C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[C:24]=3[CH3:32])[CH:16]=[N:17][C:11]=2[NH:10][C:9]1=[O:35])C.C(OC(=O)CN1CC2C=C(/C=C/C(=O)N(C)CC3N(C)C4C(C=3)=CC=CC=4)C=NC=2NC1=O)C>>[CH3:33][N:21]([CH2:22][C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[C:24]=1[CH3:32])[C:20](/[CH:19]=[CH:18]/[C:15]1[CH:16]=[N:17][C:11]2[NH:10][C:9](=[O:35])[N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:13][C:12]=2[CH:14]=1)=[O:34]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N(C)Cc3sc4ccccc4c3C)cnc2NC1=O
Agent: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2NC1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CC(=O)O)C(=O)N3)sc2ccccc12
Yield: 89 %

Procedure:
According to the procedure of Example 124 (b), except substituting (E)-(6-{2-[methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)acetic acid ethyl ester for the (E)-(6-{2-[methyl-(1-methyl-1H-indol-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)acetic acid ethyl ester, the title compound (720 mg, 89%) was prepared as a light yellow solid and as a mixture of amide rotomers: 1H NMR (300 MHz, DMSO-d6) δ 10.78 (br s, 1H), 10.08 (s, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.56-7.16 (m, 4H), 5.11-4.88 (m, 2H), 4.52 (s, 2H), 4.04 (s, 2H), 3.14-2.93 (m, 3H), 2.42 (s, 3H); MS (ESI) m/e 451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24](O)(=[O:27])[CH2:25][OH:26]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:25](=[O:26])[CH2:24][OH:27])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Reactant: O=C(O)CO
Product: O=C(CO)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (630 mg) was reacted with glycolic acid via General Procedure B to give 1-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:19])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1>C1COCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:19])[C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1ccccc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [2-(Methoxy-methyl-carbamoyl)-phenyl]-carbamic acid tert-butyl ester (15.0 g, 1.54 mmol) dissolved in THF (200 mL) is added p-chlorophenylmagnesium bromide (1.0M, 150 mL) at −30° C. The mixture is then stirred at RT overnight. The mixture is quenched with NH4Cl, extracted with ethyl acetate, dried over NaSO4 and concentrated then purified by silica gel. This provides the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>ClCCl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(N)c2)[C@@H](C)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(S(=O)(=O)N2[C@H](C)CN(CC(=O)Nc3ccccc3C)C[C@@H]2C)c1
Reaction time: 3 h

Procedure:
A solution of the product from Example 57 (0.2 g) and N,N-diisopropylethylamine (0.3 ml) in dichloromethane (10 ml) was rapidly stirred whilst a solution of acetyl chloride (0.055 g) in dichloromethane (2.0 ml) was added. After 3 hours a further amount of acetyl chloride (0.022 g) was added, the mixture was stirred 3 hours more then evaporated to dryness. The residue was triturated with water, filtered and dried in vacuo, to give the title compound as a white solid. Yield 0.17 g.
Reaction SMILES: Cl.C(O[C:5](=[NH:7])[CH3:6])C.[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13]>>[NH:7]=[C:5]([N:14]([C:12](=[O:13])[C:11]1[CH:10]=[C:9]([F:8])[CH:18]=[C:17]([F:19])[CH:16]=1)[NH2:15])[CH3:6]
Reactant: CCOC(C)=N
Reactant: NNC(=O)c1cc(F)cc(F)c1
Agent: Cl
Product: CC(=N)N(N)C(=O)c1cc(F)cc(F)c1

Procedure:
The compound is obtained analogously to the method described for intermediate product 1a) from 4.91 g (40 mmol) ethylacetimidate hydrochloride and 3.80 g (22 mmol) 3,5 difluoro-benzoic acid hydrazide.
Reaction SMILES: O=[C:2]1[NH:8][C:7]2[S:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]2[CH:12]=[CH:13][CH:14]=[C:3]12.[B].CSC.CO>O1CCCC1>[S:9]1[C:7]2[NH:8][CH2:2][C:3]3[N:4]([CH:12]=[CH:13][CH:14]=3)[CH2:5][C:6]=2[CH:11]=[CH:10]1
Reactant: O=C1Nc2sccc2Cn2cccc21
Agent: [B]
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: c1cc2n(c1)Cc1ccsc1NC2
Temperature: 25 °C

Procedure:
To a mixture of 7.0 g of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10 molar boron-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2N NaOH. The mixture is refluxed 5 hours and filtered. The solid is extracted with dichloromethane and the extract is washed with 2N citric acid, water and dried (Na2SO4). The solvent is removed in vacuo to give the desired product as a solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:19]1[CH2:21][NH:20]1)#[N:18].C(N(CC)CC)C>C(OCC)C>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:20]2[CH2:21][CH:19]2[C:17]#[N:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1CN1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#CC1CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
The same compound is also obtained when a solution of 1.15 g. diphenylacetyl chloride in 5 ml. anhydrous diethyl ether is added dropwise at 0° C. to a solution of 0.35 g. 2-cyanoaziridine and 0.6 g. triethylamine in 15 ml. diethyl ether and the reaction mixture then stirred for 1 hour at 0° C. and for 2 hours at ambient temperature. The precipitated hydrochloride is filtered off with suction (0.7 g.) and the ethereal filtrate is concentrated to a volume of about 10 ml. and shaken out twice with 5 ml. amounts of water. After evaporation of the ethereal phase, there is obtained 1.13 g. of the desired compound.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Br:21]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:21][CH2:19][CH2:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC(O)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCCCBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Part A. Pyridine (0.66 mL, 8.21 mmol) was added slowly to an ice cooled solution of 4-nitrophenyl butanol (1.0 gm,5.13 mmol) and dibromotriphenylphosphorane (2.8 gm, 6.66 mmol) in 20 mL acetonitrile under a nitrogen atmosphere. The reaction solution was stirred for 1/2 hr and allowed to warm to ambient temperature and stir overnight. The reaction was concentrated invacuo to give a residue. The residue was filtered through a short plug of silica gel and then the product was purifed by flash chromatography on silica gel eluting methylene chloride:hexane (v:v, 50:50), to give 1-bromo-4-(4-nitrophenyl)butane as an oil 1.3 gm (98%) MS 275(M+NH4)+ 1 H NMR (CDCl3): 8.2(d, 2H), 7.4(d, 2H), 3.4(t, 2H), 2.8(t, 2H), 1.8-2.0(m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[S:24][C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:36][CH2:37]O.COC(=O)CC(=O)C(Br)C.FC(F)(F)OC1C=CC(C(N)=S)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:37][CH2:36][C:21]2[N:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)[S:24][C:20]=2[CH3:19])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Reactant: Cc1sc(-c2ccc(OC(F)(F)F)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: COC(=O)CC(=O)C(C)Br
Agent: NC(=S)c1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(OC(F)(F)F)cc3)sc2C)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 4 c]) was reacted with 2-[5-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl]-ethanol (prepared from [rac]-4-bromo-3-oxo-pentanoic acid methyl ester [PCT Int. Appl. (2001), WO 01/79202] and 4-trifluoromethoxy-thiobenzamide in analogy to the procedures described in examples 12 a] and 12 b]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-methyl-4-{2-[5-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-methyl-4-{2-[5-methyl-2-(4-trifluoromethoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as light yellow solid.
Reaction SMILES: [CH3:1][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1)=O)(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1)=[CH2:1])(=[O:33])[CH3:32]
Reactant: COC(=O)c1ccc(C(=O)CCCOC(C)=O)cc1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(CCCOC(C)=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl triphenylphosphonium (1.5 g, 1.1 eq) was suspended in 50 ml of anhydrous tetrahydrofuran and 4.0 ml of 1.0M solution of sodium hexamethyldisilazide (1.05 eq) in tetrahydrofuran were added via syringe. The mixture was stirred at room temperature for one hour and a solution of 1.0 g (1.0 eq) of methyl 4-(4-acetoxy-1-oxobutyl)benzoate in anhydrous tetrahydrofuran, was added dropwise. The resulting reaction mixture was stirred for 2 hours at room temperature. Sodium bromide/triphenylphosphineoxide precipitate was removed by filtration, and the filtrate washed with water. After extraction of the aqueous layer with diethyl ether, the organic layers were dried over magnesium sulfate and evaporated to dryness to yield the product which was further purified by flash chromatography eluting with 1:5 ethyl acetate:hexanes. M.S.:m/z=262 (M+,CI), 231.1020 (M+ --CH3O, calc. for C14H15O3 : 231.1021), 202 (M+ - AcOH), 176, 143 (100%). 1H-N.M.R. (CDCl3, 300 MHz): δ=1.80(quin, 2H, CH2 --CH2 --CH2, J=7.5 Hz); 2:04(s, 3H, CH3 --CO); 2.62 (t, 2H, CH2 --C=, J=7.5 Hz); 3.94(s, 3H, CH3O); 4.10(t, 2H, CH2O, J=7.5 Hz); 5.20 (s, 1Holef.); 5.41(s, 1Holef.); 7.48(d, 2Harom., J=9 Hz); 8.01(d, 2Harom., J=9 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:28]([O:30][C:31](=[O:36])[CH2:32]C([O-])=O)[CH3:29].[K+].[Cl-].[Mg+2].[Cl-]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13](=[O:15])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)CNC(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
In a 1 liter four-necked flask were charged 50 g (0.24 mol) of N-benzyloxycarbonylglycine and 300 ml of acetonitrile in a nitrogen stream, and 39.5 g (0.24 mol) of 1,1′-carbonyldiimidazole was added thereto over 30 minutes, followed by stirring at room temperature (22 to 24° C.) for 2 hours. After cooling to 7° C., 61.0 g (0.36 mol) of potassium malonate ethyl ester was added over 5 minutes, and 23.0 g (0.24 mol) of magnesium chloride was added over 30 minutes, followed by stirring at room temperature for 30 minutes and then at 50° C. for 2 hours to complete the reaction. Acetonitrile was removed by evaporation under reduced pressure, and 550 ml of a 5% hydrochloric acid aqueous solution was added to the reaction. The mixture was extracted and washed with 180 ml of butyl acetate. The organic layer was further washed with 100 ml of a 5% hydrochloric acid aqueous solution, neutralized with 100 ml of a 8% sodium carbonate aqueous solution, and washed with 100 ml of water. The solvent was removed by evaporation under reduced pressure to yield 67.1 g (90% as purified by column chromatography) of ethyl 4-benzyloxycarbonylamino-3-oxobutyrate as liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reaction mixture stirred overnight at room temperature. The mixture was poured into vigorously stirring 6M HCl, and the solids were collected by vacuum filtration, washed well with H2O, and dried in vacuo to yield the title compound. 1H NMR (CDCl3) δ 7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d, J=8.8 Hz, 2H) 1.32 (s, 9H) MS (ES) m/z=212.1
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
To 25 ml of a solution of 0.68 g of Boc-Ala-OH in methylene chloride the H-Pro-resin described above was added and 5 ml of a solution of 0.74 g of DCC in methylene chloride was then added to the resulting mixture. The mixture was reacted at room temperature for 2 hours. After washing the resin 6 times with 30 ml of methylene chloride, the resin was added to 25 ml of a methylene chloride solution of 0.68 g of Boc-Ala-OH and 0.55 g of 1-hydroxybenzotriazole. Then, 5 ml of a methylene chloride solution of 0.74 g of DCC was added thereto and the resulting mixture was again reacted in a similar manner (double coupling). The resin was thoroughly washed with methylene chloride to obtain Boc-Ala-Pro-resin.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:26]1([N:13]2[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]3[NH:8][CH2:12][CH2:11][CH:10]23)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2c(C3CN(C4CCCC4)C4CCNC34)c[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution containing 36 (2.0 g, 4.8 mmol) in DCM (20 mL) was cooled to 0° C. TFA (6 mL) was added and the pink reaction mixture was stirred at 0° C. After 1 h, the reaction mixture was warmed to ambient temperature then concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.4 g of 37 which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ8.50 (br s, 1H), 7.58 (dd, J=5.4, 8.4 Hz, 1H), 7.05-7.01 (m, 2H), 6.92-6.85 (m, 1H), 4.17-4.11 (m, 1H), 3.92 (app q, J=6.0 Hz, 1H), 3.74 (app q, J=6.6 Hz, 1H), 3.21-3.15 (m, 1H), 3.08-2.88 (m, 3H), 2.75-2.67 (m, 2H), 1.96-1.78 (m, 5H), 1.61 (m, 4H) ppm. Mass spectrum, m/z [314.2] (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:22])[CH:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])[CH3:2].C(O)C.[OH-].[Na+]>O>[CH2:1]([O:3][C:4](=[S:22])[CH:5]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:2]
Reactant: CCOC(=O)CCCCCC(C(=S)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=S)C(CCCCCC(=O)O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cold solution of 20.4 g. of diethyl-2-phenylthio-1,8-octanedioate in 100 ml. of ethanol is added dropwise a solution of 2.41 g. of sodium hydroxide in 12 ml. of water during 5 minutes. The resulting solution is maintained at 0° C. for 3.5 days and then at ambient temperature for 2 hours. The bulk of the ethanol is removed in vacuo and the residue is partitioned with ether and water. The aqueous layer is acidified with dilute hydrochloric acid and the acidic materials are extracted with ether. This extract is washed with water and brine, dried and concentrated. The residue is subjected to dry column chromatography on silica gel with 30:20:1 ethyl acetate-heptane-acetic acid providing the product as a light yellow oil. Its infra-red spectrum has peaks at 1735 and 1700 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][OH:15])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:16]([CH3:19])(=[O:18])=[O:17])[CH3:2]>ClCCl.[O-2].[Mn+2]>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=[O:15])[CH:12]=2)[N:7]=[CH:6][C:5]=1[S:16]([CH3:19])(=[O:18])=[O:17])[CH3:2]
Reactant: CCOc1c(S(C)(=O)=O)cnc2ccc(CO)cc12
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: CCOc1c(S(C)(=O)=O)cnc2ccc(C=O)cc12
Reaction time: 6 h
Yield: 55 %

Procedure:
To a solution of (4-ethoxy-3-methanesulfonyl-quinolin-6-yl)-methanol (example 74b, 25.4 m mol) in anhydrous dichloromethane (500 mL), manganese oxide (13.3 g, 152.4 mmol) was added. The reaction mixture was stirred at 25 degrees for 6 hours. After the reaction, the solid was filtered out; the filtrate was concentrated in vacuo. Column chromatography gave 4-ethoxy-3-methanesulfonyl-quinoline-6-carbaldehyde (3.92 g, 55%). LC-MS m/e 280 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][O:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].C[O-].[Na+]>CO>[OH:21][C:7]1[C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])=[N:11][CH:10]=[C:9]2[O:12][N:13]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=12
Reactant: CCOC(=O)c1ncc2onc(-c3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2onc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A mixture of 4-hydroxy-3-phenyl-isoxazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (61 mg, 0.21 mmol), glycine (322 mg, 4.29 mmol), and a 0.5 M solution of sodium methoxide in methanol (8.1 ml) was refluxed for 20 h before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (15 ml) and the solution was extracted with methyl t-butyl ether (2×20 ml). The remaining aqueous layer was acidified to pH=3 with 1N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (26 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.47 (br s, 1H), 8.82 (s, 1H), 8.04 (m, 2H), 7.59 (m, 3H), 4.01 (d, J=6.4 Hz, 2H); MS: (+) m/z 314.07 (M+1), (−) m/z 312.20 (M−1).