Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[C@@H:10]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:9]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:11]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C@@H:10]([O:19][Si:20]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:22])[CH3:23])[CH:27]([CH3:29])[CH3:28])[C:9](=[O:30])[S:38][C:35]1[CH:36]=[CH:37][C:32]([Br:31])=[CH:33][CH:34]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)[Si](O[C@H]1C(=O)N(C(=O)OC(C)(C)C)[C@H]1c1ncccc1F)(C(C)C)C(C)C
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC(C)[Si](O[C@@H](C(=O)Sc1ccc(Br)cc1)[C@@H](NC(=O)OC(C)(C)C)c1ncccc1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 101.8 %

Procedure:
A concentrated residue (70.9 mmol) of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone (compound 20) was dissolved in diisopropyl ether (240 mL), and 4-bromothiophenol (15.5 g, 82.0 mmol) and potassium carbonate (3 g) were added thereto, and stirred at room temperature for 25 minutes. The disappearance of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone was confirmed, and then water (200 mL) and diisopropyl ether (120 mL) were added thereto and subjected to liquid-liquid separation. The organic layer was separated, washed with water (150 mL) and then with saturated saline water (150 mL), dried over magnesium sulfate, and concentrated under reduced pressure to obtain a residue of S-(4-bromophenyl) (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanethioate (compound 14) (45.3 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]1([O:35][CH2:36][CH2:37][OH:38])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P(C(C)(C)C)C(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([O:38][CH2:37][CH2:36][O:35][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[C:3]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:14]=1
Reactant: OCCOc1cccc2ccccc12
Reactant: CCOC(=O)c1c(Br)c2ccccc2n1Cc1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(OCCOc2cccc3ccccc23)c2ccccc2n1Cc1ccc(OC)cc1
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 101B (388 mg) and 2-(naphthalen-1-yloxy)ethanol (188 mg) in toluene (3 ml) was added 1,1′-binaphthyl-2-yldi-tert-butylphosphine (7.5 mg), palladium(II) acetate (5 mg) and Cs2CO3 (488 mg). The mixture was purged with argon and stirred at room temperature and then heated at 80° C. overnight. After this time the mixture was diluted with ethyl acetate (200 mL) and washed with water, brine and dried over Na2SO4. After concentration of the solvent, the residue was loaded on a silica gel column and eluted with 5% ethyl acetate in hexane to give EXAMPLE 101C.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([O:41][Si](C(C)(C)C)(C)C)[CH2:35]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:31])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:49])[C@@H:15]2[CH2:32][CH2:33][C@H:34]2[O:39][C:38](=[O:40])[CH2:37][C@H:36]([OH:41])[CH2:35]2)=[CH:10]1
Reactant: CC(Oc1ccccc1Cl)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1ccccc1Cl)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 20.3 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.0 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-chlorophenoxy)propionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 118, above] and 29.4 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.14 g of the title compound as white crystals, melting at between 152° and 155° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH2:13])=[O:6])#[N:2].C1C=CC2N(O)N=NC=2C=1.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:34](O)=[O:35])[NH:31]2)=[CH:27][CH:26]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:34]([C:30]1[NH:31][C:32]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([Cl:24])[CH:33]=2)=[O:35])=[O:6])#[N:2]
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Reactant: N#CCNC(=O)C1CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of 2-amino-cyclohexanecarboxylic acid cyanomethyl-amide (6.4 g, 35.31 mmol) in DMF (70 ml), were added HOBT (5.25 g, 38.84 mmol), 6-chloro-2-indolecarboxylic acid (7.60 g, 38.84 mmol), N-methylmorpholine (19.4 ml, 176.45 mmol), and EDCI (7.45 g, 38.84 mmol) respectively at 0° C. The reaction was stirred at room temperature for 16 hours, then 1N HCl (500 ml) was added and the resulting cloudy solution was extracted with ethyl acetate (3×200 ml). The organic layer was filtered through a Celite pad, washed with 1N NaOH (200 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo yielding 6-chloro-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide, (6.25 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1.[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH:32]=O)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]>>[CH2:17]([C:21]1[N:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:24]=[C:23]([CH2:32][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12]2)[CH:22]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Reactant: NCCN1CCN(c2ccccc2F)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3F)CC2)nn1-c1ccccc1
Yield: 71.8 %

Procedure:
Compound 66 was prepared using the same method as that of Example 1 except that 4-(2-fluorophenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OCCCC)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)(=[O:3])[CH3:2].C(OCC(F)(F)F)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[N:10]1([C:7]2[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:9][N:8]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CCCCOC(=O)N1CCN(c2ncc(C(C)=O)cn2)CC1
Agent: CC(=O)OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
To a solution of -butyl 4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate (4.5 g, 14.7 mmol) in dichloromethane (80 mL) was added trifluoroethyl acetate (20 mL), and the mixture was stirred at RT for 3 h. LCMS showed the reaction was completed. The reaction mixture was neutralized with sodium carbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound as a light yellow solid (2.6 g, 86%), which was directly used in the next step without further purification. MS (ES+) C10H14N4O requires: 206, found: 207 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cnn(-c4ccc(F)cc4)c3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(-n2cc(-c3ccc([C@H]4CNCCO4)cc3)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)morpholine-4-carboxylate (45 mg, 0.106 mmol) was dissolved in dioxane (0.2 ml) and a solution of HCl in dioxane (4M, 0.4 ml, 1.59 mmol) was added. The reaction mixture was stirred at 60° C. overnight. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)morpholine hydrochloride (38 mg, 99%) as a white solid. MS (ISP): 324.2 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)c(F)c1
Solvent: c1ccccc1
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2)c(F)c1
Yield: 74 %

Procedure:
Prepared analogous to Example 25 from 4-(2-fluoro-4-biphenylyl)-4-oxo-butyric acid. Yield: 74% of theory, m.p. 133°-135° C. (from benzene).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(OC)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-methoxybenzenesulfonyl chloride according to METHOD A, giving 9.83 g (55%) of pure material: MS (Ionspray, [M+H]+) m/z 356; Anal. Calcd. (found) for C14H16N2O5S2: C, 47.2 (47.1)%; H, 4.5 (4.5)%; N, 7.9 (7.8)%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH:19][C:20]3[N:28]=[CH:27][N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][N:24]4C3CCCCO3)[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:35])=[O:4]>C(Cl)Cl>[CH:14]1([N:12]2[C:13]3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([F:35])[CH:7]=[CH:8][C:9]=3[N:10]=[C:11]2[C@@H:17]([NH:19][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:18])[CH2:16][CH2:15]1
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(C3CC3)c12
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(C3CC3)c12
Yield: 24.6 %

Procedure:
A solution of 3-cyclopropyl-5-fluoro-2-{(S)-1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid methyl ester (178 mg, 0.37 mmol) in DCM was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue subjected to a second SCX-2 cartridge purification. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 386 as a white solid (36 mg, 25%). LCMS (Method K): RT 3.03 min [M+H]+ 396.04. 1H NMR (DMSO-d6, 400 MHz): δ 8.25-8.11 (2H, m), 8.03 (1H, s), 7.73 (1H, dd, J=8.81, 4.72 Hz), 7.13 (1H, t, J=9.78 Hz), 5.98 (1H, s), 3.94 (3H, s), 1.68 (3H, d, J=6.74 Hz), 1.17-0.84 (4H, m)
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH2+:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:18]([O:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27](Cl)[O:28][C:24]=2[CH:23]=1)(=[O:20])[CH3:19]>>[C:18]([O:21][C:22]1[CH:31]=[CH:30][C:25]2[N:26]=[C:27]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]3[C:10]([O:9][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[O:28][C:24]=2[CH:23]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Oc1ccc2nc(Cl)oc2c1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCC[NH2+]1
Agent: [Cl-]
Product: CC(=O)Oc1ccc2nc(N3CCCC[C@H]3C(=O)OCc3ccccc3)oc2c1

Procedure:
The title compound was prepared by a similar method to Preparation 2 from (2S)-2-[(benzyloxy)carbonyl]piperidinium chloride [see EP 530167 A1 930303] and 2-chloro-1,3-benzoxazol-6-yl acetate [see Preparation 35]. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:10 changing to 40:10, by volume, hexane:ethyl acetate to afford benzyl (2S)-1-[6-(acetyloxy)-1,3-benzoxazol-2-yl]-2-piperidinecarboxylate as a gum.
Reaction SMILES: [O:1]1CCC[O:3][CH:2]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1.C(O)(C)C.ClCCl.O>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2].S(=O)(=O)(O)O>[C:2]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)([OH:3])=[O:1]
Reactant: c1ccc(-c2noc(-c3ccccc3OCCC3OCCCO3)n2)cc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CCOc1ccccc1-c1nc(-c2ccccc2)no1
Temperature: 21.5 °C
Reaction time: 20 h

Procedure:
2.5 g of 5-{2-[2-(1,3-dioxan-2-yl)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole are dissolved in 50 ml of acetone and at 0° C. a solution of chromium(VI)oxide in 30% sulphuric acid is added dropwise thereto. The mixture is then stirred for a further 20 hours at 20-23° C. and then 25 ml of isopropanol are added with cooling at 5° C. The mixture is added to a suspension of 100 ml of dichloromethane and 100 ml of water and the organic phase is separated off. The aqueous phase is extracted once more with dichloromethane and the combined organic solutions are again extracted with water. The extract is dried over sodium sulphate, evaporated down in vacuo and the residue is chromatographed on silica gel with dichloromethane/methanol (97:3). The product is recrystallised from ethyl acetate. Yield: 0.23 g (11% of theory), melting point 170-171° C.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:19][CH3:20])=[C:9]([CH3:18])[C:10]=1[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])(OCC)=O.[CH3:21]C1OC(C)OC(C)O1>>[CH2:1]([C:6]1[NH:7][C:8]([CH2:19][CH3:20])=[C:9]([CH3:18])[C:10]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH3:21]
Reactant: CC1OC(C)OC(C)O1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c(CC)c1C
Product: CCc1[nH]c(CC)c(CCC(=O)O)c1C

Procedure:
2-Carbethoxy-3-carbethoxyethyl-4-methyl-5-ethyl-pyrrole was reductively alkylated with paraldehyde to yield 2,5-diethyl-3-carboxyethyl-4-methyl-pyrrole. ##STR114##
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[C:5]=2[N:6]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Cl:1][C:2]1[S:3][C:4]2[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([F:11])[CH:8]=[C:7]([Cl:12])[C:5]=2[N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1cc(Cl)c2nc(Cl)sc2c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
23.7 g 2,4-Dichloro-6-fluorobenzothiazole was dissolved in 100 ml concentrated sulfuric acid and the solution cooled to 0° C. To this was added very slowly, dropwise, a cooled solution of 14 ml concentrated sulfuric acid and 14 ml 100% nitric acid. The mixture was stirred for 3 hours, poured into 500 ml ice water, the resulting crystals filtered off, washed with water until neutral and dried in vacuo. Yield: 22.7 g=79% of theory m.p.: 110°-112° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:24]1([CH2:36][CH2:37][C:38](O)=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl.CN(C)CCCN=C=NCC.[K+].[Br-]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH:24]1([CH2:36][CH2:37][C:38]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:39])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1COC(=O)C1
Reactant: O=C(O)CCC1CCCCCCCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CCC1CCCCCCCCCCC1)C1=C(O)COC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 0.70 g (7 mmol) of tetronic acid in 20 ml of dry dimethylformamide at 0° C. is added 1.1 ml (836 mg, 8.3 mmol) of triethylamine and 0.31 g (2.5 mmol) of dimethylaminopyridine. After stirring for 5 minutes, 2.0 g (8.3 mmol) of 3-cyclododecylpropanoic acid is added followed by 1.6 g (8.3 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After 10 minutes the ice bath is removed and the reaction mixture is allowed to stir overnight at room temperature. The reaction mixture is then poured into 1.0N hydrochloric acid and extracted 3 times with ethyl acetate. The organic layers are combined, washed with brine, dried over magnesuim sulfate, filtered and concentrated to give a yellow oil. The oil is subjected to flash chromatography using acidic silica gel and hexane/ethyl acetate (3:2) as the mobile phase to give an off white solid: m.p. 99°-102° C.; IR (KBr) 2940, 1710, 1600 and 1470 cm-1 ; NMR (CDCl3) (mixture of tautomeric forms) δ1.34 (mc, 22H), 1.50 (bs, 1H), 1.61 (m, 2H), 2.92 (m, 2H), 4.55 and 4.70 (s, 2H); MS (EI) Anal. Calc'd. for C19H30O4 : C, 67.87; H, 5.70; Found: C, 67.62; H, 5.98.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:39](=[O:56])[C:40]2[C:41]([O:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[C:42]([O:46][CH3:47])[N:43]=[CH:44][CH:45]=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:39](=[O:56])[C:40]4[C:41]([O:48][C:49]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[C:42]([O:46][CH3:47])[N:43]=[CH:44][CH:45]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nccc2c(=O)c(I)c(-c3ccccc3)oc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1nccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 71 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-8-methoxy-2-phenyl-pyrano[2,3-c]pyridin-4-one was reacted to give the title compound (53.4 mg, 71%) as a white solid. LCMS (Method A): RT=4.91 min, [M+H]+=499.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14](Br)[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.[CH2:41]1[CH2:45]OC[CH2:42]1>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>[CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([C:41]([CH3:45])=[CH2:42])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C1CCOC1
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: [Cs+]
Solvent: O
Product: C=C(C)c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
To a mixture of 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester (42.9 g, 85.7 mmol), potassium isopropenyl trifluoroborate (14.0 g, 95.2 mmol) and caesium carbonate (83.8 g, 257.1 mmol) in THF (800 mL) was added Pd(PPh3)4 (2.0 g) followed by water (150 mL). The mixture was heated at reflux for 72 h then allowed to cool to ambient. The mixture was reduced in vacuo to remove THF and then partitioned between water (500 mL) and EtOAc (300 mL). The organic portion was washed with brine, dried (MgSO4), filtered and reduced in vacuo to give the title compound (40.9 g) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[CH3:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Reactant: Cc1ccc(CBr)cc1
Product: CNC(=O)C=Cc1ccc(OCc2ccc(C)cc2)cc1
Yield: 44 %

Procedure:
The title compound is prepared in analogy to example 11 b) from 3-(4-hydroxy-phenyl)-N-methyl-acrylamide and 1-bromomethyl-4-methyl-benzene. Yield=44%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.B(Cl)(Cl)Cl.[C:14](Cl)([CH3:16])=[O:15].[Al+3].[Cl-].[Cl-].[Cl-].[OH-].[Na+]>C(Cl)Cl>[NH2:9][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:14](=[O:15])[CH3:16]
Reactant: COc1cccc(N)c1
Reactant: CC(=O)Cl
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(N)c1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
m-Anisidine (10.0 g, 82 mmol) was dissolved in CH2Cl2 (50 mL), and the solution was cooled to −50° C. BCl3 (1 M in CH2Cl2, 82 mL, 82 mmol) was added slowly during 20 min, after which the mixture was stirred at −50° C. for 30 min, followed by sequential addition of AcCl (6.0 mL, 84 mmol) and AlCl3 (11 g, 82 mmol). The mixture was stirred at −50° C. for 1 h and was then allowed to assume rt. After stirring at rt overnight, the solution was heated at 40° C. for 4 h, after which the mixture was poured over ice. The aqueous mixture was made alkaline with 10% NaOH (w/v) and extracted with EtOAc (4×200 mL). The combined organic phases were washed with brine, dried (MgSO4), and evaporated to give a black solid, which was purified by flash column chromatography (ether/CH2Cl2 20:80). The resulting solid was recrystallized from ether/hexane to give the title compound as shiny tan leaflets (5.6 g, 42%).