Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)C[N:4]1[C:8]2=[C:9]3[N:19]=[CH:18][N:17]=[C:10]3[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[N:7]2N=N1.[H][H]>[Pt]=O.FC(F)(F)C(O)=O.Cl>[CH3:10][CH:11]([CH3:12])[CH2:16][N:17]1[C:10]2[C:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:16]=3[N:7]=[C:8]([NH2:4])[C:9]=2[N:19]=[CH:18]1
Reactant: [H][H]
Reactant: CC(C)Cn1nnn2c3ncccc3c3ncnc-3c12
Agent: O=[Pt]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cnc2c(N)nc3c(c21)CCCN3

Procedure:
Platinum oxide catalyst was added to a solution of 1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine in trifluoroacetic acid (30 mL). The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure for 5 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under vacuum. The residue was combined with water and sodium bicarbonate. The resulting precipitate was isolated by filtration. The solid was dissolved in 1N hydrochloric acid and charcoal filtered. The filtrate was treated with 10% sodium hydroxide. The resulting precipitate was isolated by filtration then recrystallized from ethyl acetate/methanol. The recrystallized material was dissolved in dichloromethane/methanol and placed on a silica gel column. The column was eluted with 10% methanol in ethyl acetate. The eluant was concentrated under vacuum and the residue was recrystallized from methanol/water to provide 0.9 g of 6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c](1,8]naphthyridin-4-amine as a solid, m.p. 231-233° C. Analysis: Calculated for C13H19N5: %C, 63.65; %H, 7.81; %N, 28.55; Found: %C, 62.99; %H, 7.74; %N, 28.33.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:12])=[N-]>CCOCC>[CH:1]1([CH2:6][C:7]([O:9][CH3:12])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CC1CCCC1
Solvent: CCOCC
Product: COC(=O)CC1CCCC1
Temperature: 0 °C
Yield: 62.5 %

Procedure:
To an ice-cooled and stirred solution of cyclopentylacetic acid (7.9 g, 0.062 mol) in 30 ml of ether was added an excess solution of diazomethane in ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent liquid of methyl cyclopentylacetate (yielded amount 5.5g, 0.039 mol, yield 62.5%, b.p. 64°-65° C./15 mmHg). Then, a solution of n-butyl lithium in hexane (1.58N, 55.7 ml, 0.088 mol) was added dropwise to a stirred solution of dimethyl methylphosphonate (10.9 g, 0.088 mol) in 100 ml of anhydrous THF under argon atmosphere at -78° C. After 30 minutes, the above-mentioned methyl cyclopentylacetate (5.0 g, 0.035 mol) in 10 ml of anhydrous THF was further added dropwise, and the mixture was stirred in situ for 30 minutes. This reaction mixture was allowed to warm to 0° C., diluted with 5.3 ml of acetic acid and 20 ml of water, and concentrated. 30 ml of water was added to the residue. The mixture was extracted with ethyl acetate (50 ml×2), and the combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 3-cyclopentyl-2-oxo-propylphosphonate (7.8 g, 0.033 mol, yield 94.7%, b.p. 110°-112° C./0.13 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39](OCC3C=CC=CC=3)=[O:40])[CH:34]=2)[CH:29]=[N:28][CH:27]=1.Cl>C1COCC1.CCOC(C)=O>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:39](=[O:40])[C:35]2[CH:34]=[C:33]([O:32][C:30]3[CH:29]=[N:28][CH:27]=[N:26][CH:31]=3)[CH:38]=[CH:37][N:36]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)c1cc(Oc2cncnc2)ccn1
Reactant: Cc1cccc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(NC(=O)c2cc(Oc3cncnc3)ccn2)n1
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
2-Amino-6-picoline (49 mg, 0.45 mmol, 2.0 eq) was dissolved in THF (0.55 mL) in a flame-dried round bottom flask. A 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (943 μL, 0.453 mmol, 2.00 eq) was added dropwise and the reaction was stirred for 5 min. Compound 8 (69 mg, 0.22 mmol, 1.0 eq) was added as a solution in THF (0.55 mL) and the reaction was stirred for 30 min. The reaction was diluted with EtOAc, neutralized with 1N HCl and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 45 mg (65%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 9.19 (s, 1H), 8.92 (s, 2H), 8.69 (d, J=5.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.82-7.75 (m, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.42 (dd, J=5.6, 2.6 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 2.43 (s, 3H); [M+1]+: 308.2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:3]1=[O:27].Br[CH:29]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:34]([O:33][C:31]([CH:30]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C:3]1=[O:27])[CH2:29][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)CC(Br)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccc3ccccc23)SCC(N)C1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccc3ccccc23)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a solution of a mixture of 803 g of t-butyl α-[6-amino-2-(1-naphthyl)-5-oxoperhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] and 1.13 g of ethyl 3-bromo-4-phenylbutyrate in 10 ml of dimethylformamide was added 0.66 g of sodium carbonate. The reaction mixture was stirred at 80° C. for 15 hours and then dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chloride. The ethyl acetate layer was separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent was then evaporated off. The residue was subjected to silica gel column chromatography using a 1:30 by volume mixture of ethyl acetate and methylene chloride as eluent, which separated the product into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: I[C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.C(OC([N:28]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[CH:34][C:35]=2[O:37][CH3:38])[C:30](B(O)O)=[CH:29]1)=O)(C)(C)C.C(=O)([O-])O.[Na+].C1CCCCC1.C(OCC)(=O)C>CN(C)C=O.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>[CH3:40][O:39][C:33]1[CH:32]=[C:31]2[C:36](=[C:35]([O:37][CH3:38])[CH:34]=1)[NH:28][CH:29]=[C:30]2[C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3cccnc32)cc1
Reactant: COc1cc(OC)c2c(c1)c(B(O)O)cn2C(=O)OC(C)(C)C
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: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Yield: 8 %

Procedure:
But using 2.9 g of 2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 2.34 g of 1-tert-butyloxycarbonyl-5,7-dimethoxy-1H-indole-3-boronic acid and 19 ml of a saturated aqueous solution of sodium hydrogen carbonate in 63 ml of dimethylformamide, and 0.42 g of tetrakis(triphenylphosphine)palladium is added. After flash chromatography on a silica column [eluent: cyclohexane/ethyl acetate (70/30 by volume)], 0.26 g of 2-(5,7-dimethoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([O:13][C:14]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:21]2[CH:20]=[CH:19][CH:18]=[C:15]([CH:16]=[O:17])[C:14]=2[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CCOc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Yield: 82.9 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.35 g, 2.2 mmol), 2-ethoxy-3-hydroxybenzaldehyde (0.37 g, 2.2 mmol) and cesium carbonate (0.73 g, 2.2 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 19 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(2-ethoxy-3-formylphenoxy)benzonitrile (0.55 g, 82%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[S:26])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=[C:4]([Cl:16])[N:3]=1
Reactant: CCOC(=O)C(=O)Nc1ccc(Cl)nc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=S)Nc1ccc(Cl)nc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-(2,6-dichloropyridin-3-ylamino)-2-oxoacetate (48.92 g, 186.0 mmol) in toluene (380 mL) was added Lawesson's Reagent (75.21 g, 186.0 mmol), and the resulting suspension was stirred at 90° C. for 4 h. The reaction mixture was then cooled to room temperature and filtered through Celite™, washing with 300 mL toluene. The combined filtrates were concentrated in vacuo at 40° C., and the residue was taken up in CH2Cl2 (200 mL) and filtered through a 200 g pad of silica gel, washing with additional CH2Cl2 (4×150 mL). The filtrate was concentrated in vacuo to afford ethyl 2-(2,6-dichloropyridin-3-ylamino)-2-thioxoacetate as an orange solid.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[Cl:38])=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=3[Cl:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1cccc(Cl)c1Cl
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2cccc(Cl)c2Cl)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(2,3-dichlorophenyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(2,3-dichlorophenyl)-6-oxohexyl)piperidine-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[SH:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Cl)s1
Reactant: Sc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncc(Sc2ncccn2)s1
Temperature: 150 °C
Yield: 60.2 %

Procedure:
A mixture of 2-acetamido-5-chlorothiazole (14.3 g), 2-mercaptopyrimidine (10 g) and potassium carbonate anhydrous (22.4 g) in N,N-dimethylformamide (280 ml) was stirred at 150° C. an hour. The reaction mixture was poured into water with stirring under ice cooling. The mixture was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give solid. The solid was triturated with water, and the precipitates were collected by filtration, washed with water and dried in vacuo no give 2-acetamido-5-(2-pyrimidinylthio)thiazole (12.30 g, yield: 60.2%). mp: 225° C. (dec.) IR (Nujol): 3170, 1645, 1555, 1310 cm-1NMR (DMSO-d6, 60 MHZ, ppm): 2.20 (3H, s), 7.33 (1H, t, j=4 Hz), 7.70 (1H, s), 8.68 (2H, d, J=4 Hz), 12.33 (1H, br s) Mass: M+2 254, M+1 253, M 252, m/e 210, 168
Reaction SMILES: [ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH:39]1([CH2:42]Br)[CH2:41][CH2:40]1>O>[ClH:1].[CH:39]1([CH2:42][N:19]2[CH2:18][CH2:17][C@:15]34[C:16]5[C:3]6[O:2][C@H:14]3[C:13](=[O:20])[CH2:12][CH2:11][C@@:10]4([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:9]2[CH2:8][C:7]=5[CH:6]=[CH:5][C:4]=6[O:31][CH3:32])[CH2:41][CH2:40]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)NCC[C@]314
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)N(CC2CC2)CC[C@]314
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (1.5 g, 3.57 mmol), potassium carbonate (3.00 g, 21.7 mmol) and cyclopropylmethylbromide (1.0 ml, 6.62 mmol) in water-free N,N-dimethylformamide (10 ml) was stirred for 4 h under exclusion of moisture and under nitrogen at 80° C. (bath temperature). After filtration from the inorganic residue, which was washed three times each time with 10 ml dichloromethane, the filtrate was evaporated down under reduced pressure. The oily residue was dissolved in 50 ml dichloromethane, washed with water (3×50 ml) and saturated sodium chloride solution (4×50 ml), dried over sodium sulphate and evaporated down. The evaporation residue (1.42 g of yellow oil) was purified by column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH 250:2:0.5), the oily evaporation residue dissolved in 50 ml ether and precipitated by the addition of etherial HCl up to the acidic reaction. Yield: 0.60 g (53%) of the compound 3.HCl as colourless crystals. Fp. 130-133° C.; MS (EI): 473 (M+); IR (KBr): 1725 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): δ 8.30 (s, wide, HN+), 7.31-7.18 (m, 5 arom. H), 6.88 (d, 1 arom. H, J=8.4 Hz), 6.78 (d, 1 arom. H, J=8.4 Hz), 4.96 (s, CH-5), 3.81 (s, CH3O), 0.80-0.40 (m, 5 cyclopropyl H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:44]=[CH:43][C:21]([CH2:22][O:23]/[N:24]=[C:25](\[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)/[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:20][CH:19]=1.O.Cl>O1CCCC1.CO>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23]/[N:24]=[C:25](\[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)/[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:43][CH:44]=1
Reactant: CCOC(=O)CCCCCC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCCCCCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Lithium hydroxide monohydrate (159 mg) was added to a solution of ethyl Z-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoate (340 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (3.8 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-8-phenyloctanoic acid (293 mg, yield 91%) as colorless crystals. m.p. 88-89° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[SH:10][CH:11]([CH3:15])[C:12]([OH:14])=O.S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:10][CH:11]([CH3:15])[C:12]([O:1][CH2:2][C:3]([CH2:8][O:9][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])([CH2:6][O:7][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])[CH2:4][O:5][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])=[O:14]
Reactant: CC(S)C(=O)O
Reactant: OCC(CO)(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(S)C(=O)OCC(COC(=O)C(C)S)(COC(=O)C(C)S)COC(=O)C(C)S
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
To a 500-milliliter round-bottom flask equipped with a magnetic stirring bar, a water separator, and a condenser were added 27.23 grams (0.200 mol) of pentaerythritol, 90.22 grams (0.850 mol) of 2-mercaptopropionic acid, 100 milliliters of toluene, and 0.5 milliliter of concentrated sulfuric acid. The mixture was heated under reflux with stirring. After about 2 days, the solid material had disappeared, and about 17 milliliters (0.94 mol) of water had been collected by the water separator. Upon cooling to room temperature, the mixture was extracted with 30 milliliters of saturated NaHCO3 solution and washed with two 50-milliliter portions of water. The organic layer was dried over anhydrous MgSO4, and most of the toluene and residual 2-mercaptopropionic acid were removed by distillation under vacuum. Recrystallization of the residue from ethanol gave 86.0 grams (88.4%, calcd. 97.3 grams) of pentaerythritol tetrakis(2-mercaptopropionate) as a white solid, mp 93-96° C.; 1H NMR (in CDCl3 w/TMS, ppm): 4.17-4.30 (AB m, 8H, CH2O), 3.50 (pentuplet, 4H, CHSH), 2.17 (d of d, 4H, SH), 1.51 (d, 12H, CH3); {1H}13C NMR (in CDCl3 w/TMS, ppm): 172.79 (C═O), 62.47 (CH2O), 43.05 [C(CH2)4], 35.43 (CHSH), 20.94 (CH3).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Se](=O)=[O:14]>O1CCOCC1.O>[C:4]([C:3]1[C:2]([CH:1]=[O:14])=[N:12][CH:11]=[CH:10][CH:9]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cccnc1C
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1C=O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a stirred solution of ethyl 2-methylnicotinate (1.657 g, 10.0 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added selenium dioxide (1.568 g, 14.1 mmol) and the resultant mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3:1 hexanes/ethyl acetate) and provided the title compound (0.90 g, 50%) as a yellow oil. 1H NMR (CDCl3) δ 1.41 (t, 3H, J=7.5 Hz), 4.45 (q, 2 H; J=7.5 Hz), 7.56 (dd, 1H, J=6.0, 6.0 Hz), 8.11 (dd, 1H, J=6.0, 1.0 Hz), 8.87 (dd, 1H, J=6.0, 1.0 Hz), 10.34 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[N:8](C(OC1C=CC=CC=1)=O)[C:7](=[O:22])[C:6]2([C:33]1[C:34]([O:39][CH2:40][CH3:41])=[N:35][CH:36]=[CH:37][CH:38]=1)[O:23][C:24](OC1C=CC=CC=1)=[O:25])#[N:2].[CH3:42][N:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:45][CH2:44]1>O1CCCC1>[CH3:42][N:43]1[CH2:44][CH2:45][CH:46]([N:49]2[CH2:54][CH2:53][N:52]([C:24]([O:23][C:6]3([C:33]4[C:34]([O:39][CH2:40][CH3:41])=[N:35][CH:36]=[CH:37][CH:38]=4)[C:5]4[C:9](=[CH:10][C:11]([F:12])=[C:3]([C:1]#[N:2])[CH:4]=4)[NH:8][C:7]3=[O:22])=[O:25])[CH2:51][CH2:50]2)[CH2:47][CH2:48]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2cc(F)c(C#N)cc21
Solvent: C1CCOC1
Product: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 291 mg (0.53 mmol) of phenyl 5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate, 289 mg (1.58 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 6 ml of dried tetrahydrofuran (THF) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and stirred with methanol. The precipitated solid was filtered off and dried in a vacuum drying oven. 158 mg of the title compound were obtained as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[N:8][OH:9])[CH2:2][CH:3]=[CH2:4].C(OC[C@@H]1OCC2=NOC[C@@H]2C1)C1C=CC=CC=1>>[N:8]1[O:9][CH2:4][CH:3]2[CH2:2][CH2:1][O:5][CH2:6][C:7]=12
Reactant: C=CCCOCC=NO
Agent: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Product: C1CC2CON=C2CO1
Yield: 85 %

Procedure:
Compound C8 was prepared from 2-(but-3-en-1-yloxy)-N-hydroxyethanimine (C7) according to the general procedure for the synthesis of (3aR,5R)-5-[(benzyloxy)methyl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (P1) in Preparation 1. The product was obtained as a yellow oil. Yield: 4.1 g, 32 mmol, 77%; 85% yield based on recovered starting material. 1H NMR (400 MHz, CDCl3) δ 1.73-1.84 (m, 1H), 2.13-2.20 (m, 1H), 3.34-3.45 (m, 1H), 3.50 (ddd, J=12.3, 12.1, 2.0 Hz, 1H), 3.79 (dd, J=11.6, 8.1 Hz, 1H), 4.03-4.09 (m, 1H), 4.12 (dd, J=13.5, 1.2 Hz, 1H), 4.62 (dd, J=10.2, 8.0 Hz, 1H), 4.70 (br d, J=13 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[S:9])[NH2:8])=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][CH:15](Br)[CH:16]=O)[CH3:11]>C(O)C>[CH2:10]([O:12][C:13](=[O:19])[CH2:14][C:15]1[S:9][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:8][CH:16]=1)[CH3:11]
Reactant: NC(=S)c1ccncc1
Reactant: CCOC(=O)CC(Br)C=O
Solvent: CCO
Product: CCOC(=O)Cc1cnc(-c2ccncc2)s1

Procedure:
Pyridine-4-thioamide (1.38 g, 0.01 mole) and 3-bromo-4-oxobutyric acid ethyl ester (3.1 g., 0.015 mole) in ethanol (50 ml) are heated at reflux for six hours. After cooling the solvent is evaporated and the residue is neutralized with sodium bicarbonate solution and then extracted with chloroform (300 ml.). The chloroform solution is washed with water, dried with (MgSO4) and evaporated to yield crude 2-(4-pyridyl)-thiazole-5-acetic acid ethyl ester. Purification is carried out by dissolving in acetone and adding petroleum ether to induce crystallization. When this ester intermediate is treated with methanol solution saturated with ammonia gas (25 ml./g. of ester) for 3 days at room temperature 2-(4-pyridyl)thiazol-5-ylacetamide is obtained after partial evaporation of the methanol. Purification is carried out by recrystallization from ethanol. When the amide is treated according to the procedure in Example 1, there is obtained 3-hydroxy-4-[2-(4-pyridyl)thiazol-5-yl]-3-pyrroline-2,5-dione.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([I:16])[CH:15]=1)[N:12]=[CH:11][C:10]([C:17]([O:19]CC)=O)=[C:9]2[OH:22])(=O)C.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CCOCC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:17]([C:10]2[CH:11]=[N:12][C:13]3[C:8]([C:9]=2[OH:22])=[CH:7][C:6]([CH2:5][OH:4])=[CH:15][C:14]=3[I:16])=[O:19])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(I)cc(COC(C)=O)cc2c1O
Solvent: CCOCC
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CO)cc2c1O
Temperature: 180 °C
Yield: 73 %

Procedure:
A suspension of ethyl 6-[(acetyloxy)methyl]-4-hydroxy-8-iodo-3-quinolinecarboxylate (0.90 g) and 4-chlorobenzylamine (2.6 mL) is heated at 180° C. for 1 h. The reaction is cooled to room temperature and diluted with Et2O. The resulting solid is filtered and triturated with acetone to yield 0.74 g (73%) of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-8-iodo-3-quinolinecarboxamide.