Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][Cl:21])[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.N1C=CC=CC=1.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:10][C@@H:11]1[C:34](=[O:35])[N:13]2[C:14]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][Cl:21])[CH2:16][S:17][C@H:12]12
Reactant: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: -40 °C
Yield: 50.7 %

Procedure:
2.56 g of 4-methoxybenzyl 7β-phenylacetamido-3-[(Z)-3-chloro-1-propenyl]-3-cephem-4-carboxylate [IR υ max(Nujol)cm-1 : 3265, 1759, 1719, 1661, 1612, 1250, 1221, 1175, 1101, 1036, 824. NMR δ(CDCl3)ppm: 3.20, 3.44(2 H, ABq, J=18), 3.56(2 H, s), 3.71(3 H, s), 3.72(2 H, m), 4.87(1 H, d, J=4.5), 5.03(2 H, s), 5.4-5.9(2 H, m), 6.12(1 H, d, J=11), 6.30(1 H, d, J=9), 6.73(2 H, d, J=8.5), 7.15(5 H, s), 7.17(2 H, d, J=8.5)] was dissolved in 75 ml of dry methylene chloride and the solution was cooled to -40 ° C. 0.68 ml of pyridine and 1.35 g of PCL5 were successively added thereto with stirring. The resulting solution was stirred at room temperature for 2.5 hours and cooled to -40° C. and 46.5 ml of MeOH was dropwise added thereto. The resulting solution was stirred at room temperature for 1.5 hours, and neutralized with an aqueous NaHCO3 solution. The organic layer was washed with brine and water and dried over Na2SO4. After evaporation of the solvent, the residue was purified by silica gel column chromatography (60 g) with a mixture of benzene and ethyl acetate (1/1 volume) to give 1.0 g (51% yield) of 4-methoxybenzyl 7β-amino-3-[(Z)-3-chloro-1-propenyl]-3-cephem-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:19](O)=[O:20])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(N(C(C)C)C(C)C)C>ClCCl>[OH:37][C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:19]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=2)[N:6]=1)=[O:20]
Reactant: O=C(O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 1.0 g (0.0028 mol) of 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid in 80.0 ml dichloromethane was added at room temperature 0.4 ml (0.405 g 0.0030 mol) (1-chloro-2-methyl-propenyl)-dimethyl-amine and the mixture was stirred for 0.5 hours. To the resulting dark solution was added 0.35 g (0.0030 mol) (1R,2R)-2-amino-cyclohexanol and 0.94 ml (0.712 g, 0.0060 mol) N-ethyldiisopropylamine and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic phase washed with 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of 100% heptane to heptane with 40% ethyl acetate to yield 1.107 g of the tile compound as a white waxy solid. MS (ISP) (M+H+)=360.0 and 362.0.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10](#[N:12])[CH3:11].Cl[Sn](Cl)(Cl)Cl>ClCCCl>[NH2:12][C:10](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:11]
Reactant: CC#N
Reactant: COC(=O)CC(=O)OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)C(C(=O)OC)=C(C)N

Procedure:
To a stirred solution containing 4.36 mL (38.0 mmol) of dimethyl malonate and 2.00 mL (38.0 mmol) of acetonitrile in 20 mL of 1,2-dichloroethane were added 8.90 mL (76.0 mmol) of SnCl4. The reaction mixture was stirred at reflux for 2 h. The reaction mixture was then concentrated under diminished pressure and the residue was dissolved into 100 mL of acetone. Then, 70 mL of satd. aq. sodium carbonate were added and the mixture was stirred for 20 minutes. The mixture was poured into 200 mL of satd. aq. sodium bicarbonate and extracted with two 200-mL portions of DCM. The combined organic solution was washed with a 200-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was recrystallized in ethyl acetate/hexanes to afford the expected product as colorless crystals: yield 3.96 g (60%); mp: 81-82° C.; silica gel TLC Rf 0.5 (1:1 ethyl acetate-hexanes); 1H NMR (CDCl3) δ 2.10 (s, 3H), 3.66 (s, 3H), 3.69 (s, 3H), 5.29 (br s, 1H) and 8.94 (br s, 1H); 13C NMR (CDCl3) δ 22.0, 51.0, 51.6, 92.4, 164.0, 168.7 and 168.9; mass spectrum (APCI), m/z 174.0760 (M+H)+ (C7H12NO4 requires 174.0766).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[CH:33]=[N:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[CH:33]=[N:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(Cl)cn1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3cnc(C(F)(F)F)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyrazine in dimethylsulfoxide at 100° C. in the presence of potassium carbonate. LC (method 4): tR=1.06 min; Mass spectrum (ESI+): m/z=524 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)#N.Cl.[OH-:14].[Na+].[OH2:16]>>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([OH:16])=[O:14]
Reactant: [OH-]
Reactant: N#CCc1ccc(C(=O)O)cc1
Reactant: O
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 11.7 %

Procedure:
A solution of 4-cyanomethyl-benzoic acid (0.53 g, 3.31 mmol) in a 50% aqueous hydrochloric acid solution (42.8 mL) was heated at 80° C. for 16 h. At this time, the reaction was cooled to 25° C. and adjusted to pH=3 by the dropwise addition of a 50% aqueous sodium hydroxide solution. The resulting mixture was diluted with water and extracted with butanol (2×50 mL). The combined organic layers were then extracted with water (5×50 mL, pH=6-7). The aqueous extracts were adjusted to pH=3 with a 3M aqueous hydrochloric acid solution and concentrated in vacuo to afford 4-carboxymethyl-benzoic acid (70 mg, 11.7%) as a white solid: mp 235-237° C.; EI-HRMS m/e calcd for C9H8O4 (M+) 180.0422, found 180.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:24])[C:9]([CH2:21][C:22]#N)=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=O)C.[OH-:25].[Na+].[CH2:27]([OH:30])[CH2:28]C>O>[CH2:27]([O:30][C:22]([CH2:21][C:9]1[C:8]([CH3:24])=[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[C:10]=1[CH3:20])[NH:4][CH2:5][CH2:6]2)=[O:25])[CH3:28]
Reactant: CC(=O)N1CCc2c(C)c(CC#N)c(C)c(NC(=O)C(C)(C)C)c21
Reactant: [OH-]
Reactant: CCCO
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1c(C)c2c(c(NC(=O)C(C)(C)C)c1C)NCC2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
N-(1-Acetyl-5-cyanomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (5.0 g) was suspended in n-PrOH (25 ml) and a solution of NaOH (9.6 g) in water (10 ml) was added, which was followed by stirring at 90° C. for 8 hr in an autoclave under a nitrogen atmosphere. The aqueous layer was separated, and the organic layer was neutralized with 2N-hydrochloric acid. The solvent was evaporated under reduced pressure. The residue was suspended in EtOH (200 ml), and 10N HCl-EtOH (7.2 ml) was added, which was followed by refluxing for 1 hr. EtOH was evaporated under reduced pressure, and the mixture was neutralized with saturated aqueous solution of sodium hydrogencarbonate and extracted with AcOEt (200 ml). The AcOEt layer was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=1/0-20/1) to give 3.0 g of N-(5-ethoxycarbonylmethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Br)=[CH:18][CH:17]=3)=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([O:33]S(C)(=O)=O)=[CH:29][CH:28]=3)[S:12][C:11]=2[CH:38]=1)(=O)=O.CN(C)C=O.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.[I-].[K+]>C(Cl)(Cl)Cl.CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:20][CH:21]=3)=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[S:12][C:11]=2[CH:38]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCBr)cc2)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 110 °C
Reaction time: 120 h

Procedure:
A 1.5 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-(4-bromoethoxybenzoyl)-benzo[b]thiophene, hydrochloride, was combined with 25 ml. of dimethylformamide, 5 ml. of piperidine and 150 mg. of potassium iodide, and was stirred for two hours at ambient temperature. The reaction was then heated to 110° C. in an oil bath, under a nitrogen atmosphere, and stirred for 5 days. The course of the reaction was followed by thin layer chromatography on silica gel plates, using a 9/1 mixture of chloroform/methanol as the eluting solvent. As the reaction went on, the spot indicating the protected comopund gradually disappeared, and was replaced, first by spots indicating the two possible mono-protected compounds, and then by a spot indicative of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[Cl:42])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=5[Cl:42])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Fc1cccc(-c2cncc(Br)c2)c1Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5cccc(F)c5Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(2-chloro-3-fluoro-phenyl)-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:39]([C:43]1[CH:51]=[CH:50][C:46]([CH:47]=[N:48][OH:49])=[CH:45][CH:44]=1)([CH3:42])([CH3:41])[CH3:40]>CC(C)=O>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19](/[CH:18]=[CH:17]/[C:16]([NH:15][C:5]2[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:49]/[N:48]=[CH:47]/[C:46]3[CH:45]=[CH:44][C:43]([C:39]([CH3:42])([CH3:40])[CH3:41])=[CH:51][CH:50]=3)[CH:8]=[CH:9][C:4]=2[C:3]([OH:32])=[O:2])=[O:31])=[CH:24][CH:23]=1.[CH3:1][O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:49]/[N:48]=[CH:47]/[C:46]2[CH:50]=[CH:51][C:43]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:44][CH:45]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:31])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)/C=C/c3ccc(-c4ccccc4)cc3)c2)cc1
Product: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)/C=C/c1ccc(-c2ccccc2)cc1
Yield: 83 %

Procedure:
The desired product was prepared using a procedure similar to Step 6 of example 34. Thus, 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-(3-bromopropoxy)benzoic acid methyl ester (0.299 g, 0.605 mmol) was reacted with cesium carbonate (0.414 g, 1.271 mmol) and 4-tert-butyl-benzaldehyde oxime (0.118 g, 0.665 mmol) in acetone (30 ml) to give 2-{[(2E)-3-(1,1′-biphenyl-4-yl)prop-2-enoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.148 g, 0.251 mmol, 41%) as a pale yellow solid, mp 120-122° C. 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 2.10-2.22 (m, 2H), 3.85 (s, 3H), 4.18 (t, 2H), 4.26 (t, 2H), 6.80 (dd, 1H), 6.95 (d, 1H), 7.37-7.54 (m, 7H), 7.62-7.78 (m, 5H), 7.83 (d, 2H), 7.97 (d, 1H), 8.22 (s, 1H), 8.30 (dd, 1H), 11.16 (s, 1H); mass spectrum [ES(−)], m/z 589 (M−H)−.
Reaction SMILES: [O:1]=[C:2]([C:8]([O-:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]=[CH:12][C:13](=[CH2:15])[CH3:14].[C:16]1(C=CC(O)=C[CH:18]=1)O>C(#N)C>[CH3:15][C:13]1[CH2:14][C:2]([C:8]([O:10][CH2:16][CH3:18])=[O:9])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:1][CH2:11][CH:12]=1
Reactant: CCOC(=O)C(=O)C(=O)[O-]
Reactant: Oc1ccc(O)cc1
Reactant: C=CC(=C)C
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CC(C)=CCO1

Procedure:
A mixture of 25.0 g of ethyl oxomalonate, 50 ml of isoprene, 80 mg of hydroquinone and 140 ml of acetonitrile were heated for 6 hours under nitrogen in a stainless steel bomb using an oil bath at 135° C. The reaction mixture was cooled overnight and the solvent evaporated. The resulting product was distilled at 120°-130° C. (0.7 mm Hg) to give 29.6 g of an oil, which was flash chromatographed on silica gel using 20% ethyl acetate in hexane as solvent. The resulting fractions 18-40 were evaporated and Kugelrohr distilled to give 26.45 g of the desired product as a mixture of regioisomers.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[C:4]([C:9]([CH2:12][S:13](C2C=CC=CC=2O)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:25]12[CH:31](SCC3C(C(OC)=O)=C(OC)C(Br)=CC=3)[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>>[CH:25]12[CH:31]([S:13]([CH2:12][C:9]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:23][CH3:24])[C:2]([Br:1])=[CH:11][CH:10]=3)(=[O:14])=[O:15])[CH:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2O)ccc(Br)c1OC
Reactant: COC(=O)c1c(CSC2C3CCC2CC3)ccc(Br)c1OC
Product: COC(=O)c1c(CS(=O)(=O)C2C3CCC2CC3)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 138, starting from methyl 6-(bicyclo[2.2.1]heptan-7-ylthiomethyl)-3-bromo-2-methoxybenzoate (Intermediate 182).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=O)[CH3:16])=[CH:10][CH:9]=1)=[O:4].[CH3:18][O-:19].[Na+]>CO>[CH3:1][O:2][C:3]([NH:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[O:19][CH2:18]2)=[CH:10][CH:9]=1)=[O:4]
Reactant: C[O-]
Reactant: COC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: [Na+]
Solvent: CO
Product: COC(=O)NC=Cc1ccc(OCC2CO2)cc1
Temperature: 50 °C

Procedure:
6.8 g (0.035 mol) of p-(2-methoxycarbonylaminovinyl)-acetoxybenzene are suspended in 100 ml of absolute methanol, a solution of 1.9 g (0.035 mol) of sodium methoxide in 15 ml of absolute methanol is added and thereafter the mixture is warmed to 50° C. for 15 minutes. It is then evaporated to dryness in vacuo. The resulting, crude phenolate of p-(2-methoxycarbonylaminovinyl)-phenol is heated with 35 ml of epichlorohydrin to the boil for 24 hours under a reflux condenser, whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. After crystallisation of the crude product thus obtained, from acetone-ether, 1-[p-(2-methoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 125°-126° C. is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[OH-].[Na+]>C(O)C>[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:2][C:1]([C:4]2[CH:13]=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)=[O:3])=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(C=CC(=O)c2ccc3c(c2)CCCC3)cc1

Procedure:
A solution of 2.61 g of 6-acetyl-1,2,3,4-tetrahydronaphthalene (15 mmoles) (1), 2.23 g of p-dimethylaminobenzaldehyde (15 mmoles), and 0.66 g of sodium hydroxide in 50 ml of ethanol was stirred under nitrogen at about 60° for 90 hr. The reaction mixture was cooled in an ice bath, and the precipitated solid 3-[4-(dimethylamino)phenyl]-1-(5,6,7,8-tetrahydroaphthalen-2-yl)-2-propen-1-one was collected by filtration and washed with cold ethanol. Yield: 3.0 g (61%); m.p. 134° to 135°. λmax (CHCl3); 410 nm (ε=17,200); 266 nm (17,600). Calcd for C21C23NO: C, 82.59; H, 7.59; N, 4.59. Found: C, 80.38, 80.41; H, 7.30, 7.30; N, 3.59, 3.97.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26].Cl[CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>CC(O)C.[OH-].[Na+].O>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH2:24][CH3:25])=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:26]
Reactant: OC[C@H](O)CCl
Reactant: CCc1sc(C(=O)CCc2cc(C)c(O)c(C)c2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1sc(C(=O)CCc2cc(C)c(OC[C@@H](O)CO)c(C)c2)cc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 22.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (52 mg, 0.143 mmol) in 2-propanol (1 mL) and 3 N aq. NaOH (0.3 mL) is treated with (S)-3-chloro-propane-1,2-diol (79 mg, 0.71 mmol) and the mixture is stirred at 70° C. for 15 h. The reaction mixture is diluted with water and extracted with DCM. The solvent of the organic extract is evaporated and the crude product is purified on prep. TLC plates with heptane:EA 1:3 to give 3-[4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-phenyl]-1-(5-ethyl-4-phenyl-thiophen-2-yl)-propan-1-one (14 mg) as a colourless resin; LC-MS: tR=1.03 min, [M+1]+=439.25; 1H NMR (CDCl3): δ 7.58 (s, 1H), 7.45-7.30 (m, 5H), 6.88 (s, 2H), 4.11-4.04 (m, 1H), 3.87-3.80 (m, 4H), 3.67-3.60 (m, 2H), 3.60-3.56 (m, 1H), 3.48-3.40 (m, 1H), 3.20-3.10 (m, 2H), 2.98-2.87 (m, 4H), 2.25 (s, 6H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:27]1[C:28]2[CH:29]=[CH:30][NH:31][C:32]=2[CH:33]=[CH:34][CH:35]=1)O)([CH3:13])[CH3:12]>C(OCC)(=O)C>[C:1]([O:9][CH:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][CH2:15][NH:14][C:11]([CH3:13])([CH3:12])[CH3:10])[C:27]1[C:28]2[CH:29]=[CH:30][NH:31][C:32]=2[CH:33]=[CH:34][CH:35]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)NCCCOc1ccccc1C(O)c1cccc2[nH]ccc12
Solvent: CCOC(C)=O
Product: CC(C)(C)NCCCOc1ccccc1C(OC(=O)c1ccccc1)c1cccc2[nH]ccc12
Yield: 94.1 %

Procedure:
A solution of 0.745 g of benzoic acid in 11 ml of ethyl acetate was added 70° C. to a mixture of 2.15 g of product of Step A and 400 ml of ethyl acetate. The solution obtained was filtered hot and cooled to obtain 2.62 g of the desired product melting at 185° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[N:4][CH:5]=[C:6]([C:18]=1[OH:19])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:8].[CH3:21][O-:22].[Na+].CO>CN(C)C=O.[Cu]I>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[C:18]([OH:19])=[C:2]([O:22][CH3:21])[C:3]([CH3:20])=[N:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1Br
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(C)ncc(C(=O)NCc2ccc(F)cc2)c1O
Temperature: 105 °C
Reaction time: 1.67 h
Yield: 86.9 %

Procedure:
The compound 21 (75.2 g, 222 mmol) and copper (I) iodide (21.1 g, 111 mmol) were dissolved in dimethylformamide (750 ml), a 28% sodium methoxide-methanol solution (216 ml, 888 mmol) was added, and the mixture was stirred at 105° C. for 100 minutes. After cooling, ice-water (800 ml) was added, and unnecessary matters were filtered. To the solution was added 2 M hydrochloric acid (443 ml), and crystals were collected by filtration. N-(4-fluorobenzyl)-4-hydroxy-5-methoxy-6-methylnicotinamide 22 (56.0 g, 87%) was obtained as a colorless crystal.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:38])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([O:33][CH2:34][CH2:35][OH:36])=[C:19]([Br:37])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:58][C:59]1[CH:68]=[C:67](O)[CH:66]=[CH:65][C:60]=1[C:61]([O:63][CH3:64])=[O:62].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:64][O:63][C:61](=[O:62])[C:60]1[CH:65]=[CH:66][C:67]([O:36][CH2:35][CH2:34][O:33][C:20]2[C:19]([Br:37])=[CH:18][C:17]([C:16](=[O:38])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:22][C:21]=2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:68][C:59]=1[OH:58]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCOc2c(Br)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of N-(8-phenyl-octyl)-3-bromo-5-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)-benzamide (0.687 g, 1.16 mmol, 1 eq) in THF (10 mL) was added triphenylphosphine (0.680 g, 2.59 mmol, 2.23 eq) and methyl 2,4 dihydroxybenzoate (0.388 g, 2.30 mmol, 2.0 eq). The reaction was cooled to 0° C. and diethyl azodicarboxylate (0.220 mL, 1.40 mmol, 1.2 eq) was added. The cold bath was removed and the reaction was stirred overnight at rt. The reaction mixture was then poured into 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc:hexane) to afford 4-{2-[3-Bromo-5-(8-phenyl-octylcarbamoyl)-3′-trifluoromethyl-biphenyl-2-yloxy]-ethoxy}-2-hydroxy-benzoic acid methyl ester 1H NMR (CDCl3) δ 11.90 (s, 1H); 7.97 (d, 1H); 7.84–7.50 (m, 6H); 7.28–7.12 (m, 5H); 6.40 (m, 1H); 6.24 (m, 1H); 6.10 (bt, 1H); 4.12 (dd, 2H); 4.00 (m, 2H); 3.92 (s, 3H); 3.45 (dd, 2H); 2.59 (t, 2H); 1.60 (m, 4H); 1.33 (m, 8H).