Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:61]([O:63]CC1C=CC=CC=1)=O)[CH2:56][CH2:57][C:58]([OH:60])=[O:59])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:44]([NH:54][C@H:55]([C:61]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:63])[CH2:56][CH2:57][C:58](=[O:59])[O:60][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-O-benzyl-L-glutamic acid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12].[CH3:27]I.O>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH3:27])[C:11]([C:13]1[S:26][C:16]2[C:17]3[CH:25]=[N:24][CH:23]=[CH:22][C:18]=3[O:19][CH2:20][CH2:21][C:15]=2[CH:14]=1)=[O:12]
Reactant: CI
Reactant: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cnccc1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1cnccc1OCC2)c1ccccc1Cl
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Sodium hydride, 60% dispersion in mineral oil (80 mg, 2.0 mmol) was added to a solution of N-(2-chlorophenyl)-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepin-2-carboxamide (71.4 mg, 0.2 mmol) in 10 ml of tetrahydrofuran. The mixture was stirred for 30 min and mixed with methyl iodide (0.12 mL, 2.0 mmol). The reaction mixture was stirred for 1 hour. The mixture was mixed with 50 ml of iced water and extracted with ethyl acetate twice. The combined ethyl acetate solution was washed with brine, dried over MgSO4, concentrated in vacuo, and purified on silica gel column eluting with 25% of ethylacetate in methylene chloride to give 162 (yield 50 mg, 67%). 1H NMR (400 MHz, DMSO) δ 8.57 (s, 1H), 8.25 (d, J=5.5, 1H), 7.68 (t, J=5.9, 2H), 7.60-7.50 (m, 2H), 6.98 (d, J=5.5, 1H), 6.64 (s, 1H), 4.27 (m, 2H), 3.28 (s, 3H), 2.99 (m, 2H). MS (ESI+) 371.1
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:2]([CH3:4])[CH3:3])=[C:8]([O:13][CH3:14])[CH:7]=1
Reactant: CC(C)Br
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(Br)ccc1OC(C)C
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
2-Bromopropane (3.39 mL, 36.2 mmol) was added to a suspension of 4-bromo-2-methoxy-phenol (5 g, 24.1 mmol), K2CO3 (6.67 g, 48.3 mmol) and DMSO (71 mL) at room temperature. The heterogeneous mixture was stirred at 55° C. for 2 hours, then cooled to room temperature and diluted with water. The reaction mixture was extracted with Et2O and the extract was washed successively with 10% aq. NaOH solution, water, then brine solution. The organics were separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-1-isopropoxy-2-methoxy-benzene (5.83 g, 94%) as a pale yellow oil. ESI-MS m/z calc. 244.0, found 245.0 (M+1)+; Retention time: 1.93 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.03-6.95 (m, 2H), 6.76 (dd, J=7.7, 1.1 Hz, 1H), 4.47 (dt, J=12.2, 6.1 Hz, 1H), 3.84 (s, 3H), 1.35 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](O)[CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:10][C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH3:9])=[N:6][CH:7]=1
Reactant: CC(O)c1ccc(Br)cn1
Reactant: Oc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cccnc1)c1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(5-bromopyridin-2-yl)ethanol (600 mg, 3.00 mmol), pyridin-3-ol (283 mg, 2.98 mmol) and triphenyl phosphine (1.54 g, 5.88 mmol) was stirred in anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere. After stirring for 1 hour, the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (658 mg, 3.26 mmol) was added dropwise and the reaction was stirred at room temperature for 18 hours. Then the solvent was evaporated and the residue was purified by column chromatography (silica gel, pure ether) to 5-bromo-2-(1-(pyridin-3-yloxy)ethyl)pyridine (744 mg, 89%). 1H NMR (300 MHz, CD3OD): δ 8.63-8.62 (m, 1H), 8.21-8.19 (m, 1H), 8.08-8.06 (m, 1H), 7.98-7.94 (m, 1H), 7.45 (d, J=5.1 Hz, 1H), 7.33-7.28 (m, 2H), 5.51 (q, J=6.3 Hz, 1H), 1.68 (d, J=6.3 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17]([CH:19]2CC2)=[O:18])[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([F:22])[CH:11]=2)[N:6]=1)[CH3:4].C(C1C(C)=C(OC(C2CC2)=O)C2C(=CC=C(F)C=2F)N=1)C.O>O1CCCC1>[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:17](=[O:18])[CH3:19])[C:12]2[C:7](=[CH:8][C:9]([F:23])=[C:10]([F:22])[CH:11]=2)[N:6]=1)[CH3:4]
Reactant: CCc1nc2cc(F)c(F)cc2c(OC(=O)C2CC2)c1C
Agent: CCc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2cc(F)c(F)cc2c(OC(C)=O)c1C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
2-Ethyl-3-methyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (5.5 g) prepared as described in Example 1 was dissolved in 50 ml of methanol. A solution of 2.5 g of sodium hydroxide in 50 ml of water was added to this solution, and the mixture was stirred at 50° C. for 3 hr. The reaction solution was allowed to stand for cooling and was then poured into 50 ml of water. The mixture was neutralized with 1N hydrochloric acid, and the precipitate was then collected by filtration to give 5.1 g of 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline. In 20 ml of tetrahydrofuran was suspended 96 mg of 60% sodium hydride. Separately, 446 mg of the 2-ethyl-3-methyl-4-hydroxy-6,7-difluoroquinoline (starting material 1) was suspended in 10 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The mixture was stirred for 1 hr, and 188.4 mg of acetyl chloride (starting material 2) was then added thereto. The mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 168.6 mg of 2-ethyl-3-methyl-4-acetyloxy-6,7-difluoroquinoline (compound 3). 1H-NMR data are shown in Table 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([CH2:13][NH2:14])=[CH:6]2.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7]([CH2:13][NH:14][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])=[CH:6]2
Reactant: COc1ccc2c(c1)C=C(CN)CO2
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCC1=Cc2cc(OC)ccc2OC1
Reaction time: 0.5 h

Procedure:
A solution of 0.49 g (2.57 mmol) of the amine obtained in Step B of Example 40 in 10 ml of dichloromethane is cooled to 0° C.; 1 ml (7.7 mmol) of triethylamine and also 0.41 g (3.85 mmol) of butyryl chloride are then added in succession to the medium. After 30 minutes of stirring under an inert atmosphere, the reaction mixture is acidified with a hydrochloric acid solution (1N); the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on a silica column (eluant:PE/AcOEt:40/60) yields the title amide in the form of a white solid.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-phenylpiperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-10.45 (c=0.61, methanol).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH:8]([N:11]([CH:23]([CH3:25])[CH3:24])[C:12](=[O:22])[CH:13](Cl)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([CH3:10])[CH3:9]>CN(C)C=O>[CH:23]([N:11]([CH:8]([CH3:10])[CH3:9])[C:12](=[O:22])[CH:13]([C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([CH3:24])[CH3:25]
Reactant: c1c[nH]cn1
Reactant: CC(C)N(C(=O)C(Cl)c1ccc(Cl)cc1)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)C(c1ccc(Cl)cc1)n1ccnc1)C(C)C

Procedure:
While stirring, a solution of 4.5 g of imidazole in 30 ml of dimethylformamide is dripped into a suspension of 1.3 g of sodium hydride in 30 ml of dimethylformamide. When no more gas evolves, a solution of 13.6 g of α-chloro-α-(4-chlorophenyl)-acetic acid-diisopropyl amide (see d)) in 100 ml of dimethylformamide is dripped in and the mixture is stirred overnight at room temperature. The oil which remains after the solvent has been evaporated off is taken up in 100 ml of dichloromethane and shaken 5 times, each time with 100 ml of 5% strength sodium chloride solution. The organic phase is then concentrated and chromatographed on silica gel (25×6 cm) using dichloromethane/acetone (9:1). After 2 l of first runnings have been separated off, the product fractions are obtained from which, after concentration and trituration with 10 ml of diisopropyl ether, 8.9 g of colorless crystals (m.p.: 112° C.) are isolated.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[C:12](Cl)(=O)[C:13](Cl)=O>ClCCl.CN(C)C=O>[CH:1]1([C:4]2[CH:8]=[CH:7][NH:6][C:5]=2[C:9]([NH:6][C:5]2[CH:4]=[CH:1][CH:2]=[CH:3][C:12]=2[CH3:13])=[O:11])[CH2:2][CH2:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1[nH]ccc1C1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)c1[nH]ccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 186.6 %

Procedure:
To a suspension of the 3-cyclopropyl-1H-pyrrole-2-carboxylic acid (50 mg, 0,33 mmol) in dry dichloromethane (0.4 mL) was added a solution of oxalyl chloride (0.04 mL, 0,37 mmol) in 0.3 mL of dichloromethane atroom temperatureand 3 drops of N,N-dimethylformamide. After 1.5 h at this temperature, the mixture was concentrated under vacuum and the residue was redissolved in dichloromethane (1 mL). To this solution was added a solution of o-toluidine in dichloromethane (0,2 mL) and the mixture was stirred at room temperature overnight. The reaction was worked-up diluting with dichloromethane and washing with sodium bicarbonate (2×) and brine. The organic phase was dried and concentrated to give 74 mg of the title compound (88% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:29])([C:24]1[O:25][CH:26]=[CH:27][N:28]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[O:25][CH:26]=[CH:27][N:28]=1)[CH3:29]
Reactant: CC(C)(N)c1ncco1
Reactant: O=C(O)c1ccc(N2CCCC2=O)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(N2CCCC2=O)c(OCC2CC2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(2-oxo-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=358.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]=2[NH:5][CH:4]=1.Br[CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27]>CN(C=O)C>[C:18]1(=[O:27])[N:17]([CH2:16]/[CH:15]=[CH:14]/[CH2:13][N:5]2[C:6]3=[N:11][CH:10]=[CH:9][CH:8]=[C:7]3[N:3]=[CH:4]2)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Reactant: c1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/Cn1cnc2cccnc21
Reaction time: 0.17 h
Yield: 32.2 %

Procedure:
A slurry of NaH (1.02 g, 25.4 mmol) in DMF (50 mL) at room temperature was treated with 4-azabenzimidazole (2.90 g, 24.4 mmol). After 10 min., the reaction mixture was treated with a solution of (E)-N-(4-bromo-2-butenyl)phthalimide (5.7 g, 20.3 mmol) in DMF (5 mL) over 30 min. The reaction mixture was allowed to stir for 1 h, then quenched by careful addition of water (5 mL) and the reaction mixture was concentrated in vacuo. The resulting residue was diluted with CH2Cl2 (50 mL), washed with brine (2×25 mL), dried (MgSO4), and concentrated in vacuo to afford an off-white solid. Purification by flash chromatography (ethyl acetate containing 3% NH4OH) afforded 2.08 g of 3-[(E)-4-phthalimido-2-butenyl]-3H-imidazo[4,5-b]pyridine. Changing the chromatography solvent to 5% methanol/ethyl acetate containing 5% NH4OH afforded 1.66 g of 1-[(E)-4-phthalimido-2-butenyl]-1H-imidazo[4,5-b]pyridine; mass (CI) m/z=319 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[S:23][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][C:24]2[S:23][C:22]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[N:21][C:20]=2[CH3:19])=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-{3-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{3-fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-propionic acid as light yellow solid,
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13]([OH:15])=O)=[O:5])[CH3:2].[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[Na+]>ClCCl.O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][C:13](=[O:15])[NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[O:5])[CH3:2]
Reactant: CC(=O)NCCN
Reactant: CCOC(=O)c1c(C)c[nH]c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(C)c[nH]c1CC(=O)NCCNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A stirred solution of 2-carboxymethyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (2.78 g, 13.17 mmol) in dichloromethane (100 ml) was added with N-(2-amino-ethyl)-acetamide (1.478 g, 14.5 mmol), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (6.65 g, 34.25 mmol) and 1-hydroxybenzotriazol (4.6 g, 34.25 mmol) in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred under an argon atmosphere at room temperature overnight. The resulting mixture was added with cold water (100 ml), adjusted to pH 14 with 1M aqueous sodium hydroxide solution and extracted with ethyl acetate (200 ml). The combined organic extracts were washed with brine (200 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-[(2-acetylamino-ethylcarbamoyl)-methyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (3.5 g, 95.7%) as an orange solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:16][C:15]2[CH:17]=[C:18]([CH:21]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])[CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc2c(c1)CN(c1nc3ccccc3o1)CCO2
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)CN(c2nc4ccccc4o2)CCO3)S1

Procedure:
To 4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-7-carbaldehyde [compound of Step VI] (0.176 g, 0.6 mmol) taken in toluene (25 mL) were added 2,4-thiazolidine dione (0.105 g, 0.9 mmol) and catalytic amount of piperidinium acetate (0.025 g). The resulting mixture was refluxed under Dean Stark conditions for 1.5 hours and then cooled in an ice-bath. The precipitate was filtered and washed with toluene and petroleum ether to give 5-(4-benzooxazol-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione.
Reaction SMILES: ClCC([C:5]1[C:15]2[CH2:14][CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(#N)C.C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[F:20][C:21]1[CH:35]=[CH:34][C:24]2[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([CH2:44][C:45]([N:10]4[C:11]5[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=5[CH2:13][CH2:14][C:15]5[CH:5]=[CH:6][CH:7]=[CH:8][C:9]4=5)=[O:46])[CH2:32][CH2:33]3)=[N:26][O:27][C:23]=2[CH:22]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C(CCl)c1cccc2c1CCc1ccccc1N2
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1c2ccccc2CCc2ccccc21

Procedure:
A stirred mixture of 2-chloroacetyl-10,11-dihydro-5H-dibenz[b,f]azepine (6.6 g, 24.3 mmol), 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5 g, 22.7 mmol) and K2CO3 (3.5 g, 40 mmol) in acetonitrile (300 ml) was heated at reflux for 4 hours. The insolubles were filtered, and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography over a silica gel column (100 g of SiO2 ; eluted with dichloromethane (DCM) and 1-2% CH3OH in DCM). The product thus obtained weighed 8.7 g as a yellow oil. A sample (1.5 g) of this material was dissolved in ethanol and was treated with a solution of fumaric acid in ethanol (360 mg/3 ml). The solids collected were recrystallized from acetonitrile to yield 890 mg of white crystals, m.p. 182°-183° C.
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].[CH:21](OC)(OC)OC>>[CH3:21][O:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[C:3]([C:4]#[N:5])[C:6]#[N:7]
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: COC(OC)OC
Product: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Yield: 47.5 %

Procedure:
A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe)3 (500 mL) was heated to 75° C. for 16 hr. Then the mixture was concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid. 1H NMR (DMSO-d6) δ 7.70 (d, J=8.4 Hz, 2H), 7.52-7.45 (m, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.22-7.06 (m, 4H), 3.93 (s, 3H). MS (ESI) m/e [M+1]+ 276.9.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C1C=CC=CC=1)C.C(=O)([O-])O.[Na+]>>[Cl:14][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2cccccc-2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Product: Clc1nc2cccccc-2n1
Temperature: 70 °C
Yield: 24 %

Procedure:
In accordance with the method described in Chemical and Pharmaceutical Bulletin, Vol. 16, No. 7, pages 1300 to 1307 (1968), 10 g of 2-hydroxycycloheptimidazole, 150 g of phosphorus oxychloride and 12 g of N,N-diethylaniline were stirred under heating at an internal temperature of 70° C. for 6 hours and 30 minutes. After the reaction, the phosphorus oxychloride was evaporated off under reduced pressure, and the resulting reaction mixture was poured into 500 ml of ice-water. Sodium hydrogencarbonate was added to the resulting solution until the pH thereof became neutral, and this was extracted with chloroform (250 ml×2). The chloroform layer was dried with anhydrous sodium sulfate and the solvent was evaporated off, and then the reaction product was purified by silica gel column chromatography with a developer solvent of ethyl acetate. 2.7 g of colorless crystals were obtained.
Reaction SMILES: Br.[CH2:2]([N:5]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:12]2[C:7](=[C:8]([Cl:24])[C:9]([OH:23])=[C:10]([OH:22])[CH:11]=2)[CH2:6]1)[CH:3]=[CH2:4].[C:25]([Br:28])(=[O:27])[CH3:26]>FC(F)(F)C(O)=O>[BrH:28].[CH2:2]([N:5]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:25](=[O:27])[CH3:26])=[CH:17][CH:16]=2)[C:12]2[C:7](=[C:8]([Cl:24])[C:9]([O:23][C:10](=[O:22])[CH3:9])=[C:10]([O:22][C:18](=[O:21])[CH3:17])[CH:11]=2)[CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCN1Cc2c(cc(O)c(O)c2Cl)C(c2ccc(O)cc2)C1
Reactant: CC(=O)Br
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1Cc2c(cc(OC(C)=O)c(OC(C)=O)c2Cl)C(c2ccc(OC(C)=O)cc2)C1
Reaction time: 2 h

Procedure:
A mixture of 1 g of 2-allyl-8-chloro-6,7-dihydroxy-4-(p-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide, 1.3 ml of acetyl bromide and 200 ml of trifluoroacetic acid is stirred at 10° for 2 hours. After evaporation to dryness, the residue is purified, if necessary, by recrystallization to give 2-allyl-8-chloro-6,7-diacetoxy-4-(p-acetoxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide. Similarly tri-isobutyryloxy, -propionyloxy, -isovaleryloxy, -n-butyryloxy and -n-heptanoyloxy ester derivatives are prepared.