Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[C:7]([N:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:2].[CH3:22][C@@H:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1.C(O)(C)C>CO>[CH3:14][N:12]([CH3:13])[C:7]1[C:6]([NH:5][C:4]([NH:30][C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:22])=[N:3][C:1]#[N:2])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1
Solvent: CC(C)O
Solvent: CO
Solvent: CN1CCOCC1
Product: C[C@@H](NC(=NC#N)Nc1cccnc1N(C)C)c1ccccc1

Procedure:
A stirred mixture of the crude product from Step 3, (R)-(+)-α-methylbenzylamine (1.01 ml, 0.00782 mol), N-methylmorpholine (1.69 ml, 0.0154 mol) and isopropanol (20 ml) was refluxed, under nitrogen for 5 hours and then concentrated. The residue was chromatographed on silica gel first with mixtures of MeOH--CHCl3 containing from 1-10% MeOH to give an impure product which was rechromatographed on silica gel with mixtures of EtOAc-hexane containing from 1-50% EtOAc. The product obtained in this manner was dissolved in MeOH, decolorized with activated carbon and crystallized from MeOH-EtOAc-hexane to give 0.700 g of the titled product, mp 111°-128° C. (dec.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[O:15][C:14](=S)[NH:13][C:12]1=[O:17].C([OH:20])C.OO>C(Cl)(Cl)Cl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[O:15][C:14](=[O:20])[NH:13][C:12]1=[O:17]
Reactant: CCO
Reactant: O=C1NC(=S)OC1c1ccc2ccccc2c1
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1NC(=O)C(c2ccc3ccccc3c2)O1

Procedure:
5-(2-Naphthyl)oxazolidin-4-one-2-thione (2.0 g., 8.2 mmoles) was partially dissolved in 25 ml. of aqueous ethanol at 50° C. Hydrogen peroxide (30%, 7 ml. was added) and the mixture refluxed for 4 hours. The reaction mixture was cooled, diluted with chloroform and water and the organic layer separated. The organic layer was extracted with saturated sodium bicarbonate. The bicarbonate layer was carefully acidified with dilute hydrochloric acid and the precipitated product recovered by filtration. Recrystallization from toluene gave purified 5-(2-naphthyl)oxazolidine-2,4-dione [0.2 g., m.p. 187°-188° C., pnmr/CDCl3 /delta: 6.54 (s, 1H), 7.3-8.1 (m, 7H)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Yield: 100.4 %

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyloxy)-5-Nitro-benzoic acid methyl ester (4.9 g, 16 mmol) in ethanol (100 mL) was treated with hydrogen gas (60 psi) for 48 h in the presence of palladium on carbon catalyst (0.31 g, 10% Pd). The catalyst was removed by filtration through CELITE®, and the filtrate was concentrated to a syrup and dried in vacuo to afford the intermediate 5-amino-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid methyl ester as a dark brown solid (4.52 g, 99%).
Reaction SMILES: C[O-].[Na+].O1CCNC1=O.[C:10](=O)([O:13][CH3:14])[O:11]C.[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=2)[C@H:25](C(O)=O)[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=2)[C@H:25]([C:10]([O:13][CH3:14])=[O:11])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cn1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: O=C1NCCO1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 288.8 %

Procedure:
Sodium methoxide (664 mg, 12 mmol) was added to a solution of the oxazolidinone from preparation 6 (1.17 g, 2.5 mmol) and dimethyl carbonate (1.03 mL, 12 mmol) in dichloromethane (15 mL) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (30 mL). The aqueous layer was neutralised by the addition of 2M HCl (˜6 mL) and then concentrated in vacuo. The residue was triturated with acetonitrile (25 mL) and then filtered. Concentration of the filtrate gave (3S,4S)-1-benzyl-4-(5-chloropyridin-2-yl)pyrrolidine-3-carboxylic acid (123 mg, 16%) as yellow solid (see preparation 8 for spectroscopic data). The ethyl acetate layer was dried (MgSO4) and evaporated. Purification of the residue by column chromatography (silica), eluting with ethyl acetate/pentane 2:8, increasing polarity to 2:3 gave the title compound (371 mg, 45%) as a colourless oil. 1H NMR (CDCl3, 400 MHz) δ2.71 (1H, t), 2.97 (1H, t), 3.05 (2H, m), 3.23 (1H, m), 3.63 (5H, m), 3.82 (1H, q), 7.15-7.35 (6H, m), 7.55 (1H, d), 8.46 (1H, s); LRMS (APCI+) 331 [MH+].
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[CH2:22]([C:24]1[CH:25]=[CH:26][C:27](/[CH:30]=[CH:31]\[C:32]#[N:33])=[N:28][CH:29]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:31]=[C:32]([NH2:33])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)=[N:28][CH:29]=1)[CH3:23]
Reactant: CCc1ccc(/C=C\C#N)nc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Product: CCc1ccc(-c2cc(N)n3nc(-c4ccccn4)nc3c2)nc1

Procedure:
The title compound, MS m/e (%):317 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-(5-ethyl-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]([NH2:24])([C:21](=[O:23])[NH2:22])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH2:24][C:18]1([C:21]([NH2:22])=[O:23])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(N)CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoroacetic acid (6.17 mL, 83.0 mmol) was added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (2.02 g, 8.30 mmol) in dichloromethane (16.6 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in methanol (2.00 mL), repeatedly concentrated under reduced pressure twice and dried under reduced pressure to give 4-amino-piperidine-4-carboxylic amide 2TFA salt as a colorless substance (3.25 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:25])=[C:9]([CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[N:10]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>C(OCC)(=O)C>[Cl:35][CH2:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:25])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 84.7 %

Procedure:
To a mixture of methyl 2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-5-hydroxymethylbenzoate (2.50 g) and toluene (100 mL) was added thionyl chloride (0.95 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give methyl 5-chloromethyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzoate as colorless crystals (2.23 g, yield 84%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[NH:28][C:27](=O)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]3[N:28]=[C:27]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(Cc3nc4ccccc4c(=O)[nH]3)CC2)cc1
Reactant: C1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(Cc3nc(N4CCCCC4)c4ccccc4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-ylmethyl]-3H-quinazolin-4-one (83 mg, 0.2 mmol) in POCl3 (1 mL) was heated to 90° C. for 2 hours. Then the excess POCl3 was removed in vacuo. The residue was dissolved in toluene (5 mL) and then the solvent was removed in vacuo. This step was repeated twice more. The residue was then dissolved in THF (1 mL) and piperidine (197 μL, 2 mmol) was added. The reaction was stirred at room temperature for 1 day. The reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by HPLC. 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 3H), 7.67 (m, 3H), 7.03 (d, J=8.8 Hz, 2H), 4.70 (s, 2H), 4.12 (s, 4H), 3.90 (s, 3H), 3.45 (m, 8H), 1.88 (m, 6H); HPLC ret. time 2.61 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 482.0 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9]C)=[O:8])=[CH:5][N:6]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[C:17]([CH3:24])[C:16]=2[CH:25]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[S:19][C:18]([S:20]([NH:1][C:2]3[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=3)(=[O:22])=[O:21])=[C:17]([CH3:24])[C:16]=2[CH:25]=1
Reactant: COC(=O)c1cnc(N)s1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2ncc(C(=O)O)s2)sc2ccc(Cl)cc12
Yield: 35 %

Procedure:
The product was prepared from methyl 2-amino-1,3-thiazole-5-carboxylate (7.9 mg, 0.050 mmol) and 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (14 mg, 0.050 mmol) according to the General Procedure 10, described in Example 128. The title compound was obtained in 35% yield (6.8 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.65 (s, 3 H) 7.47 (dd, J=8.67, 2.08 Hz, 1 H) 7.80 (s, 1 H) 7.88 (dd, J=8.67, 0.57 Hz, 1 H) 7.90 (dd, J=2.08, 0.57 Hz, 1 H). MS (ESI+) m/z 389 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Product: CCCCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.125 g, 0.449 mmol) was reacted with N-(2-azidoethyl)-4-heptylbenzamide (0.129 g, 0.449 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-heptylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), δ 7.65 (d, 2H), δ 7.27 (s, 1H), δ 7.09 (d, 2H), δ 6.39 (s, 1H), δ 6.22 (s, 2H), δ 4.47 (s, 2H), δ 3.81 (s, 2H), δ 3.96 (s, 4H), δ 2.20 (s, 2H), δ 2.05 (s, 2H), 1.48 (m, 12H), δ 1.17 (m, 8H), δ 0.77 (t, 3H); 13C NMR (100 MHz, CDCl3) δ 168.3, 149.6, 148.2, 147.1, 138.6, 131.5, 128.6, 127.4, 122.1, 106.4, 84.8, 67.1, 49.4, 40.2, 37.9, 36.9, 31.9, 31.3, 31.1, 29.8, 28.4, 29.3, 28.9, 28.3, 28.1, 28.0, 25.5, 22.8, 14.3 ppm; HRMS (ESI) calcd for C31H47N7O3(M+) 565.3704. Found 656.3737, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-heptylbenzamide hydrochloride (0.194 g, 86% yield). 1H NMR (300 MHz, CD3OD) δ 8.25 (s, 1H), δ 7.71 (d, 2H), δ 7.24 (d, 2H), δ 6.45 (s, 1H), δ 4.74 (s, 2H), 3.90 (s, 2H), δ 2.63 (s, 2H), δ 2.61 (t, 2H), δ 2.41 (S, 2H), δ 1.58 (m, 6H), δ 1.26 (m, 10H), δ 0.85 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 169.2, 150.2, 147.4, 131.2, 128.5, 127.6, 127.3, 108.4, 51.4, 39.6, 36.5, 35.6, 31.8, 331.3, 29.1, 29.1, 28.3, 28.0, 27.7, 24.1, 22.6, 13.4, 13.3 ppm; HRMS (ESI) calcd for C26H39N7O (M+) 465.3216. found 465.3207.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:30])=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH3:30])=[CH:25][CH:26]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Product: COC(=O)C(Oc1ccc(Oc2ccccc2)cc1)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 35, 4.66 g of p-phenoxyphenol is reacted with methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.02 mole) in refluxing methanol-benzene for 24 hrs to give the product as a viscous oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH3:32])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 22.9 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl) isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.745 mmol) and ethyl iodide (156 mg, 0.987 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 23%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[OH:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C@@H:6]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][C:44]([O:46][CH3:47])=[O:45]>CC(C)=O>[CH3:1][O:2][C:3]([C@H:5]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[O:22][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][CH2:25][CH3:26])[CH:11]=2)[C@@H:6]1[C:27]1[CH:32]=[CH:31][C:30]2[O:33][CH2:34][O:35][C:29]=2[CH:28]=1)=[O:4]
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1O)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCC(=O)OC)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A 1 L 3 necked round-bottom flask equipped with an air driven stirrer, and a nitrogen inlet/outlet was charged with 49.0 g (102.8. mmol) of methyl-(1S,2R,3S)-1-(3,4-methylenedioxyphenyl)-3-(4-methoxy-2-hydroxyphenyl)-5-propoxyindane-2-carboxylate, 490 mL of acetone, 71.0 g of potassium carbonate and 17.3 g (110 mmol) of methyl bromoacetate. The resulting slurry was stirred at ambient temperature under an atmosphere of nitrogen while the progress of the reaction was monitored by HPLC. The reaction was deemed to be complete when all the starting material had been converted to the title compound. The slurry was filtered through 50 g of Aluminium oxide rinsing with 1250 mL of acetone. The resulting filtrate was concentrated under reduced pressure to a volume of approximately 100 mL. The concentrate was diluted with 500 mL of t-butyl methyl ether then washed with 2×300 mL portions of 5% aqueous citric acid followed by drying over anhydrous magnesium sulphate. The resulting solution was concentrated under reduced pressure to afford 49.2 g of the title compound as an oil. HPLC analysis indicated 97.8% PAR.
Reaction SMILES: C([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([OH:14])[CH:8]=1)C>Cl.C(O)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:15])=[O:3])=[CH:8][C:9]=1[OH:14]
Reactant: CCOC(=O)/C=C/c1ccc(Cl)c(O)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc(Cl)c(O)c1
Temperature: 85 °C
Yield: 96.8 %

Procedure:
(E)-3-(4-Chloro-3-hydroxy-phenyl)-acrylic acid ethyl ester (1.45 g, 6.4 mmol) was dissolved in a mixture of 6N HCl (8 ml) and acetic acid (8 ml) and heated at 85° C. for 3.5 hrs. Solvents were evaporated, giving 1.23 g of (E)-3-(4-chloro-3-hydroxy-phenyl)-acrylic acid as a light yellow solid.
Reaction SMILES: C([O:4][C:5](=[O:55])[CH2:6][C@H:7]([OH:54])[C@H:8]([NH:12][C:13](=[O:53])[C@H:14]([NH:16][C:17](=[O:52])[C@H:18]([NH:22][C:23](=[O:51])[CH2:24][C@H:25]([OH:50])/[CH:26]=[CH:27]/[CH2:28][CH2:29][S:30][C:31]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:19]([CH3:21])[CH3:20])[CH3:15])[CH:9]([CH3:11])[CH3:10])C=C.N1CCOCC1>CO.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>[OH:54][C@H:7]([C@H:8]([NH:12][C:13](=[O:53])[C@H:14]([NH:16][C:17](=[O:52])[C@H:18]([NH:22][C:23](=[O:51])[CH2:24][C@H:25]([OH:50])/[CH:26]=[CH:27]/[CH2:28][CH2:29][S:30][C:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:19]([CH3:20])[CH3:21])[CH3:15])[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]([OH:55])=[O:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@H](NC(=O)[C@@H](C)NC(=O)[C@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CO
Product: CC(C)[C@@H](NC(=O)[C@@H](C)NC(=O)[C@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)C)[C@@H](O)CC(=O)O
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 7 (152.2 mg, 0.2 mmol), Pd(PPh3)4 (23.2 mg, 0.02 mmol) in dry methanol (6 mL) under argon was added morpholine (35 μL, 0.40 mmol) which was allowed to stir for 2 h. The reaction mixture was concentrated in vacuo, purification by column chromatography on silica (eluent 0:1-5:95-10:90-10:90+0.5% AcOH MeOH/CH2Cl2) to give a yellow solid 8 (137 mg, 0.18 mmol, 100%): Rf 0.19 MeOH/CH2Cl2 (1:9+0.5% AcOH); IR (thin film) 3271 (b), 2962 (m), 2926 (m), 1624 (s), 1536 (m) cm−1.
Reaction SMILES: C1(N[NH:8][C:9]2[CH2:14][CH2:13][NH:12][C:11](=[O:15])[CH:10]=2)C=CC=CC=1.S(=O)(=O)(O)O.[OH-].[Na+].[C:23](O)(=O)[CH3:24]>>[C:11]1(=[O:15])[C:10]2[C:24]3[CH:23]=[CH:11][CH:10]=[CH:9][C:14]=3[NH:8][C:9]=2[CH2:14][CH2:13][NH:12]1
Reactant: O=C1C=C(NNc2ccccc2)CCN1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1NCCc2[nH]c3ccccc3c21
Reaction time: 2 h

Procedure:
A solution of 5,6-dihydro-4-(2-phenylhydrazino)-2(1H)-pyridinone (8.0 g) in acetic acid (16 ml) was added over 30 min to concentrated sulphuric acid (16 ml) at 10°-20°. The reaction mixture was stirred for 2 h, then added over 10 min to 2N sodium hydroxide (150 ml) at 15°-25°. The solid product was filtered off, triturated with water (50 ml), then recrystallised from ethanol (20 ml) and dried in vacuo to give the title compound (3.79 g), m.p. 255°, t.l.c. (System B, 100:8:1) Rf 0.2.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH:8]=[CH:7][C:6](=[O:9])[CH:5]=[CH:4]1.C(O[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C)CCC.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:24]([N:18]1[CH2:19][CH:7]2[CH:8]([C:3]([O:2][CH3:1])([O:10][CH3:11])[CH:4]=[CH:5][C:6]2=[O:9])[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC1(OC)C=CC(=O)C=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(OC)C=CC(=O)C2CN(Cc3ccccc3)CC21
Reaction time: 1 h

Procedure:
To a solution of 22.9 g of 4,4-dimethoxy-2,5-cyclohexadien-1-one [J. Org. Chem., 52, 2763 (1987)] and 46 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 150 cm3 of dry dichloromethane are added dropwise 3 cm3 of trifluoroacetic acid. Once the reaction mixture has reached reflux it is allowed to return to room temperature and is then stirred for for one hour. After addition of 5 g of potassium carbonate, the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a column of silica gel (particle size 0.06-0.20 mm), eluting with a mixture of cyclohexane and ethyl acetate (90/10 then 80/20 by volume). 19 g of (3aRS,7aSR)-2-benzyl-7,7-dimethoxy-2,3,3a, 4,7,7a -hexahydro-1H-4-isoindolone are obtained in oil form.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)(=[S:14])[NH2:13]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(N)=S)C1
Reactant: O=C(CBr)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCCC(c2nc(-c3ccc(F)cc3)cs2)C1
Yield: 9 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-fluorophenyl)ethanone and tert-butyl 3-carbamothioylpiperidine-1-carboxylate as described for example 59 step 5 (95 mg, yield 9%). 1H NMR (400 MHz, CDCl3) δ 7.90-7.87 (dd, J=8.8 Hz, 5.3 Hz, 2H), 7.31 (s, 1H), 7.13-7.09 (t, J=8.8 Hz, 2H), 4.05-4.02 (m, 1H), 3.24-3.18 (m, 2H), 2.96-2.89 (m, 1H), 2.30-2.25 (m, 2H), 1.85-1.80 (m, 2H), 1.64 (m, 1H), 1.49 (s, 9H). MS (ESI) m/z: Calculated for C19H23FN2O2S: 362.15. found: 363.2 (M+H)+