Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Br:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Reactant: OB(O)c1ccc(F)cc1Br
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4Br)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.053 g, 0.119 mmol) was added (2-bromo-4-fluorophenyl)boronic acid (Combi-Blocks, San Diego, Calif.) (0.042 g, 0.190 mmol), potassium carbonate (0.082 g, 0.594 mmol), dioxane (0.594 ml) and water (0.198 ml). The mixture was purged with argon prior to the addition of Pd(PPh3)4 (0.014 g, 0.012 mmol). The vessel was sealed and irradiated at 100° C. for 30 mins affording fairly clean conversion to desired product. The organic phase was decanted, the aqueous rinsed with EtOAc and the EtOAc decanted. The combined organics were dried under reduced pressure and purified with a 25 g HP silicycle column ramping EtOAc in heptane (0-45%, then isocratic at 45%) to provide product as an off-white foam 1-(2-bromo-4-fluorophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate KKK) (54 mg, 0.092 mmol, 78% yield) with minor impurities according to LC/MS and NMR (˜20% impurity). m/z (ESI) 582.2/584.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1)#[C:2][CH3:3].[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)#[C:2][CH3:3]
Reactant: CC#Cc1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC#Cc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 5-(prop-1-yn-1-yl)picolinate (0.18 g, 1.05 mmol) in tetrahydrofuran (3.48 ml) was added sodium hydroxide 1.0 N solution (1.05 mL, 1.045 mmol, Sigma). The reaction was stirred for 1.5 hours at room temperature. Hydrogen chloride (4.0M solution in 1,4-dioxane; 0.26 ml, 1.05 mmol, Sigma Aldrich) was added and the reaction stirred for an additional 10 minutes. The reaction was concentrated in vacuo to provide 5-(prop-1-yn-1-yl)picolinic acid as a light yellow solid. The material was used without further purification assuming theoretical yield. MS m/z [M+H]+=162.1. Calculated from C9H7NO2: 161.157
Reaction SMILES: C(N(CCCC)CCCC)CCC.C(O)=O.I[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]=[C:30]([C:32]1[CH:41]=[CH:40][C:39]2[C:38]([CH3:43])([CH3:42])[CH2:37][CH2:36][C:35]([CH3:45])([CH3:44])[C:34]=2[CH:33]=1)[CH3:31])[C:21]([O:23][CH3:24])=[O:22]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:31][C:30]1([C:32]2[CH:41]=[CH:40][C:39]3[C:38]([CH3:42])([CH3:43])[CH2:37][CH2:36][C:35]([CH3:44])([CH3:45])[C:34]=3[CH:33]=2)[C:26]2[CH:25]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:18][C:27]=2[O:28][CH2:29]1
Reactant: COC(=O)c1ccc(OC=C(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)C(C)(c1ccc3c(c1)C(C)(C)CCC3(C)C)CO2
Temperature: 95 °C

Procedure:
A mixture of tributylamine (2.28 ml, 9.6 mmol), palladium diacetate (0.06 g, 0.3 mmol), formic acid (0.29 ml, 7.4 mmol) and methyl 3-iodo-4-[2-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl]-1-propenyloxy]benzoate (1.37 g, 2.72 mmol) in acetonitrile (25 ml) is heated at 95° C. for 4 h. The reaction medium is concentrated on a rotary evaporator under vacuum at 40° C. 40 ml of water and 40 ml of ethyl ether are added. After separation of the phases by settling, the organic phase is washed twice with 20 ml of water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[O:26]C)=[O:11])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=[CH:15][C:14]=2[OH:26])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ccccc2)cc1NC(=O)Nc1cccc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cc(Nc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.7 %

Procedure:
To a cold (0° C.) suspension of N-(3-(trifluoromethyl)phenyl)-N'-(2-methoxy-5-(phenylamino)phenyl) urea (1.00 g, 2.5 mmol) in dichloromethane (50 ml), boron tribromide (0.48 ml, 5.1 mmol) was added. After the addition of boron tribromide the ice bath was removed and the reaction mixture was stirred for 3 hours at RT. The reaction was poured on ice (10 ml) and 1M sodium bicarbonate (50 ml) was added. The aqueous phase was extracted with ethyl acetate (50 ml) and the organic phase dried over magnesium sulfate. 1.05 g crude product was obtained. The crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate 1:1 as eluent. The partly purified product (0.61 g) was recrystallized from ethanol/water 1:1 (20 ml). 0.20 g (21%) of the title compound was isolated. M.p. 166°-168° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]([C:7]1[C:11](=[O:12])[C@@H:10]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C@:9]([OH:25])([C:18]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[O:19])[C:8]=1[OH:26])=[O:6])[CH3:3].[H][H].S(=O)(=O)(O)O>CO.[Pd]>[CH3:17][CH:15]([CH2:14][CH2:13][C@@H:10]1[C@@:9]([OH:25])([C:18]([CH2:20][CH2:21][CH:22]([CH3:23])[CH3:24])=[O:19])[C:8]([OH:26])=[C:7]([C:5]([CH2:4][CH:2]([CH3:3])[CH3:1])=[O:6])[C:11]1=[O:12])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)=CCC(=O)[C@]1(O)C(O)=C(C(=O)CC(C)C)C(=O)[C@H]1CC=C(C)C
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(C)CCC(=O)[C@@]1(O)C(O)=C(C(=O)CC(C)C)C(=O)[C@@H]1CCC(C)C
Reaction time: 0.08 h

Procedure:
96.3 mg of the dry Mg salt of (+)-cis isohumulone ((+)-VIII) was dissolved in 1 mL of methanol. 3.1 mg (0.3 eq) of MgO was added, and the reaction mixture was stirred for five minutes. 30 mg of 10% Pd/C was added to the solution, and stirring was resumed. A hydrogen atmosphere was introduced by bubbling hydrogen gas into the solution. After 45 minutes the reaction was judged to be complete by HPLC, the stirring was stopped, and the hydrogen atmosphere was removed by opening the vial. 1 equivalent of sulfuric acid was added to the reaction mixture (pH ˜1), and the reaction was filtered through a 0.2 mm syringe filter. The reaction vessel and filter were washed 2 times successively with ethyl acetate. The filtrate was concentrated in vacuo, redissolved in hexanes, dried over Na2SO4, filtered via a cotton pipette, and concentrated in vacuo and dried overnight at 0.070 mbar. 58.1 mg of (+)-KDT-500 was produced. Further purification was carried out via chromatography and crystallization.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][N:11]2[C:22]([O:24][CH3:25])=[O:23])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CCCCCCC.CC(O)C.CCCCCCC.CCO>C(#N)C>[CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][C@H:10]2[CH2:15][C@@H:14]([C:16]3[O:20][NH:19][C:18](=[O:21])[CH:17]=3)[CH2:13][CH2:12][N:11]2[C:22]([O:24][CH3:25])=[O:23])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1Cc1ccc(S(C)(=O)=O)cc1
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CC(C)O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(S(C)(=O)=O)cc1
Yield: 23.1 %

Procedure:
Methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1 g, 2.54 mmol) was subjected to chiral preparative HPLC in two steps (first using Column: Chiralcel OJ (250×50), 20 μm particle size, mobile phase: Heptane/IPA/FA 30/70/0.1, flow rate 120 mL/min and then using Column: Chiralpak AD (250×50), 20 μm particle size, mobile phase: Heptane/EtOH/FA 40/60/0.1, flow rate 120 mL/min) to yield (2R,4S)-Methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (231 mg, 23%), Chiral purity 99.5% ee, Optical rotation [α]D20=+10.1 (acetonitrile, c=1), 1H NMR (600 MHz, cdcl3) δ 1.87-1.97 (m, 3H), 2.02-2.11 (m, 1H), 2.68 (dd, 1H), 2.88 (dd, 1H), 2.96-3.06 (m, 4H), 3.12-3.22 (m, 1H), 3.60 (s, 3H), 3.96-4.02 (m, 1H), 4.27-4.35 (m, 1H), 5.74 (s, 1H), 7.30 (d, 2H), 7.82 (d, 2H); (2S,4R)-methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (225 mg, 22.5%), Chiral purity 98.4% ee, Optical rotation [α]D20=−11.4 (acetonitrile, c=1), 1H NMR (600 MHz, cdcl3) δ 1.86-1.97 (m, 3H), 2.02-2.10 (m, 1H), 2.67 (dd, 1H), 2.87 (dd, 1H), 2.96-3.05 (m, 4H), 3.12-3.20 (m, 1H), 3.59 (s, 3H), 3.95-4.02 (m, 1H), 4.27-4.34 (m, 1H), 5.74 (s, 1H), 7.29 (d, 2H), 7.81 (d, 2H) and trans-methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (185 mg, 18.5%)
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Cl:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH2:10]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of 4,5-dichloropyridazin-3(2H)-one (26.7 g, 160 mmol), benzyl bromide (19.3 mL, 160 mmol), tetrabutylammonium bromide (2.61 g, 8.10 mmol), and potassium carbonate (56.0 g, 405 mmol) in acetonitrile (405 mL) was heated to reflux for 2 h. The mixture was cooled to room temperature, filtered through a fitted glass, concentrated, and purified by flash chromatography to afford the title compound as a white solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.23 (s, 1H); 7.27-7.35 (m, 5H); 5.27 (s, 2H). LRMS (APCI) calc'd for (C11H9Cl2N2O) [M÷H]+, 255.0. found 255.0.
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:26])[N:11]([CH:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH2:14]2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO.C(O)(=O)C>[CH2:1]([C:8]1[NH:9][C:10](=[O:26])[N:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(Cc2ccccc2)cn1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c(Cc2ccccc2)cn1C1CCNCC1
Reaction time: 16 h

Procedure:
10% Palladium on carbon (50 mg) was added to a solution of 4-benzyl-1-(1-benzylpiperidin-4-yl)-1,3-dihydro-2H-imidazol-2-one (100 mg, 0.287 mmol) in methanol (7.5 mL) and acetic acid (7.5 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 16 h, the mixture was filtered and concentrated to give the title compound. MS 258.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of t-butyl 3-methoxy-4-nitrophenylacetate (0.144 g, 0.539 mmol) and 10% Pd on carbon (0.155 g) in ethyl acetate (8 mL) and methanol (2 mL) was stirred under H2 (40-60 psi) for 2 h. The mixture was filtered through Celite and the filtrate concentrated to afford t-butyl 4-amino-3-methoxyphenylacetate (0.123 g, 96%) as a light yellow oil: 1H NMR (CDCl3, 300 MHz, ppm) 6.70 (m, 3H), 4.04 (bs, 2H), 3.84 (s, 3H), 3.42 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccccc1F)CCCC3
Temperature: 60 °C

Procedure:
To a solution of methyl [2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.266 g; 0.647 mmol) in methanol (6.5 mL) was added a solution of sodium hydroxide 5 N (1.3 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 58.6 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (3.5 g, 24.81 mmol), methyl piperidine-4-carboxylate (4.26 g, 29.77 mmol) and K2CO3 in 40 mL of ACN, was stirred at reflux overnight. The mixture was added to 150 mL of water, extracted with EA, dried over Na2SO4. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (10:1˜2:1) to give 3.84 g of methyl 1-(4-nitrophenyl)piperidine-4-carboxylate.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[C@H:13](O)[CH2:12][N:11]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:27]([O:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO[Si](C(C)(C)C)(C)C)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:27]([O:30][N:31]([C@H:13]1[CH2:12][N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH:15]=[C:14]1[CH:16]1[CH2:17][CH2:18]1)[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N+:41]([O-:43])=[O:42])(=[O:34])=[O:33])[CH:28]=[CH2:29]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(C2CC2)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-cyclopropyl-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 264, 3 g, 7.82 mmol) and N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9, 2.020 g, 7.82 mmol) following the procedure described for Intermediate 10. The desired product was obtained as a yellow oil (3.62 g, 74%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Li+].[Cl-].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:24](OCC)=[O:25]>C1COCC1>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[CH2:24][OH:25]
Reactant: CCOC(=O)c1cnc2ccccc2c1-c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnc2ccccc2c1-c1cccs1
Reaction time: 0.5 h
Yield: 11.8 %

Procedure:
A suspension of LiAlH4 (1.0 g, 29.4 mmol) and anhydrous LiCl (1.2 g, 29.4 mmol) in anhydrous THF (30 ml) was stirred for 0.5 h under an atmosphere of nitrogen at 00° C. The solution of E1 (3.2 g, 9.8 mmol) in anhydrous THF (10 ml) was added into the resulting suspension at 0° C. and stirred for 2 h before adding Na2SO4.10H2O slowly. The insolubable material was filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether-EtOAc, 2:1) to provide the title compound (0.28 g, 10%).
Reaction SMILES: [CH2:1]([O:7][N:8]=[C:9]([C:15](=O)[CH2:16]Cl)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:19][C:20]([NH2:22])=[S:21].C(O)C>O>[NH2:22][C:20]1[S:21][CH:16]=[C:15]([C:9](=[N:8][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:19]=1
Reactant: NC(N)=S
Reactant: CCCCCCON=C(C(=O)CCl)C(=O)OCC
Solvent: O
Solvent: CCO
Product: CCCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 49 %

Procedure:
Ethyl 2-n-hexyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 55.6 g.), thiourea (15.2 g.), sodium acetate 3-hydrate (27.2 g.), ethanol (280 ml.) and water (140 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetate (syn isomer, 29.3 g.), mp 77° to 78° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15]O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37].O>C(Cl)Cl>[Br:37][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:9]=1
Reactant: OCCCOCCc1ccc2sccc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: BrCCCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
In 40 mL of methylene chloride was dissolved 2.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-propanol, and 5.55 g of triphenylphosphine was added to the solution, after which a solution of 8.42 g of carbon tetrabromide in 10 mL of methylene chloride was added dropwise thereto under ice-cooling and the resulting mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 20 mL of water, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diethyl ether was added to the residue and the insoluble materials were filtered off, after which the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography (eluent; hexane:ethyl acetate=20:1 to 10:1) to obtain 1.93 g of 5-[2-(3-bromopropoxy)ethyl]-1-benzothiophene as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.[C:20](OC)(=[O:23])[CH:21]=[CH2:22].N1C=CC=CC=1>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[C:3]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:2]3[NH:1][C:20](=[O:23])[CH2:21][CH2:22][N:6]3[N:5]=2)=[CH:8][CH:9]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: C=CC(=O)OC
Solvent: O
Solvent: c1ccncc1
Product: O=C1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1

Procedure:
A mixture of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1.016 g), methyl acrylate (10 ml), pyridine (20 ml) and water (5 ml) was refluxed for 8 hours. The mixture was cooled and concentrated in vacuo. The residue was dissolved in a mixture of acetic acid (10 ml) and concentrated hydrochloric acid (1.5 ml). The solution was refluxed for 2 hours, cooled and neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and dried to give 2-(4-fluorophenyl)-5-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (750 mg).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][O:22][CH2:21]1>ClCCl>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([C:24](=[O:25])[CH2:23][O:22][CH2:21][C:20]([OH:27])=[O:26])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(=O)O1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Solvent: ClCCl
Product: O=C(O)COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
In a similar operation, 5.0 grams (20 millimoles) of 4-benzhydrylpiperidine in 140 milliliters of dichloromethane was reacted with 2.3 grams (20 millimoles) of diglycolic anhydride in 200 milliliters of dichloromethan to obtain the desired [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetic acid product as white solid which after purifying with ethyl acetate-hexane mixture had a m.p. of 139.5°-141° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]4[C:19]([CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:20][N:21]=[C:15]4[C:14]=3N)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N([O-])=O.[Na+].[NH4+].[OH-].O.[ClH:35]>Cl[Cu]>[Cl:35][C:14]1[C:15]2[N:16]([C:19]([CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:20][N:21]=2)[CH:17]=[CH:18][C:13]=1[N:10]1[CH2:11][CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: Cl
Reactant: Nc1c(N2CCC(c3ccccc3)CC2)ccn2c(CC(F)(F)F)cnc12
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [NH4+]
Solvent: O
Product: FC(F)(F)Cc1cnc2c(Cl)c(N3CCC(c4ccccc4)CC3)ccn12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of intermediate D50 (0.05 g, 0.134 mmol) in chlorhydric acid 12N was stirred at room temperature for 10 min. Then after cooling to 0° C., NaNO2 (0.184 mg, 2.671 mmol) was slowly added, followed by CuCl (104.024 mg, 0.14 mmol). The reaction mixture was then stirred at room temperature for 16 h. The reaction was further heated at 80° C. for 90 min., cooled, poured into a mixture of NH4OH:H2O 1:1 and then extracted with DCM. The combined organic phase was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica gel; starting from DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated in vacuo. The residue thus obtained was triturated with diisopropylether to yield E51 (19 mg, 36%) as a brown solid
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:1]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:18]1[S:12][C:13](=[S:14])[NH:15][C:16]1=[O:17])([OH:11])=[O:10]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccccc1C(=O)O

Procedure:
To a hot stirred solution of 20.5 g. (134 mM) of phthalaldehydic acid and 17.95 g. (135 mM) of rhodanine in 90 ml. of glacial acetic acid is added 36.0 g. (438 mM) of sodium acetate. While heating the resulting solution to reflux, a precipitate forms and an additional 30 ml. of acetic acid is added. After refluxing the mixture for 0.5 hour, it is cooled, poured into water, and filtered to separate a yellow solid. The solid is washed with water and boiled with 500 ml. of isopropanol. The resulting mixture is cooled and filtered to separate 31.14 g. (87.5%) of the 5-o-carboxybenzylidenerhodanine as yellow needles, m.p. 276°-278°.