Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@:9]([CH2:14][CH:15]([CH2:17][OH:18])[OH:16])([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:19])[CH3:2].C(=O)([O-])O.[Na+].[CH2:25](Br)[C:26]1C=CC=[CH:28][CH:27]=1>CS(C)=O>[CH2:1]([O:3][C:4]1[C@@:9]([CH2:14][CH:15]([CH2:17][OH:18])[OH:16])([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[O:19][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:2]
Reactant: CCOC1=C(O)C(=O)O[C@]1(CC(O)CO)[C@@H](O)CO
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCOC1=C(OCC)[C@@](CC(O)CO)([C@@H](O)CO)OC1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 25.4 %

Procedure:
Under an argon atmosphere, 3-O-ethylglyceryl ascorbic acid (3.03 g) obtained in Example 7 was stirred in DMSO (10 mL), and further, sodium hydrogen carbonate (0.92 g) and benzyl bromide (1.79 g) were added. The mixture was heated up to 100° C. and stirred for 5 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 2.16 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:20/3/0.3), and concentration was performed under reduced pressure to obtain 3-O-ethylglyceryl-2-O-butyl ascorbic acid (0.89 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18](O)=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>O1CCCC1>[CH2:1]([N:8]1[C:17]([CH2:18][OH:19])=[C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a solution of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) in tetrahydrofuran (THF) (5 ml) were added oxalyl chloride (60 μl) and DMF (0.1 ml), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure. A solution of the residue in THF (3 ml) was added dropwise to a suspension of sodium borohydride (39 mg) in 1,2-dimethoxyethane. The mixture was stirred under ice-cooling for 1 hr. and poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound (33 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[C:2]([Br:1])=[CH:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cn(Cc2ccccc2)c2ncccc12
Reaction time: 0.83 h

Procedure:
To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg) in N,N-dimethylformamide (10 mL) was added NaH (70 mg). The mixture was stirred for 50 minutes, and (bromomethyl)benzene (0.290 mL) was added dropwise. The reaction was stirred for 48 hours and quenched by the addition of water and ethyl acetate. The layers were separated, and the organic layer was washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 2:1 hexane to ethyl acetate, to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C2C=C(C=CC=2)C=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([CH2:27][CH2:28][S:29][CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1CCCCCCCCC1C=CC=CC=1)[CH:31]([OH:36])[C:32]([O:34]C)=[O:33])([O:25]C)=[O:24]>>[C:23]([CH2:27][CH2:28][S:29][CH:30]([C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:42]=1)[CH:31]([OH:36])[C:32]([OH:34])=[O:33])([OH:25])=[O:24]
Reactant: O=Cc1cccc(CCCCCCCCc2ccccc2)c1
Reactant: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)OC
Product: O=C(O)CCSC(c1cccc(CCCCCCCCc2ccccc2)c1)C(O)C(=O)O

Procedure:
Similarly, following the procedure of Example (b), 3-bromobenzaldehyde was reacted with 1-phenylocta-1,7-diyne to yield 3-(8-phenyl-1,7-octadiynyl)benzaldehyde which was reduced to 3-(8-phenyloctyl)benzaldehyde and the latter was reacted as described in Example 35(a), (b) and (c) to give 3-(2-carboxyethylthio)-3-[3-(8-phenyloctyl)phenyl]-2-hydroxypropanoic acid, dipotassium salt, hydrate as a mixture of isomers, -log KB value 6.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(S(C)(=O)=O)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1-fluoro-4-methylsulfonyl-benzene following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].O1CCCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:8]([C:6]5[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:23]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: CCn1cc(C(=O)O)c(C)n1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2F)c(C)n1
Yield: 35.5 %

Procedure:
In the same manner as in Example 55 and using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (62.6 mg, 0.406 mmol), tetrahydrofuran (5 mL), thionyl chloride (70.0 μL, 0.807 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (60.4 mg, 36%) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si](CC)(CC)CC)[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])C1C=CC=CC=1.[NH2:31][CH2:32][CH2:33][C:34]1[CH:57]=[CH:56][C:37]([NH:38][CH:39]2[CH2:44][CH2:43][N:42]([C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:46])[CH2:41][CH2:40]2)=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:48]([NH:47][C:45]([N:42]1[CH2:41][CH2:40][CH:39]([NH:38][C:37]2[CH:36]=[CH:35][C:34]([CH2:33][CH2:32][NH:31][CH2:16][C@H:15]([OH:18])[C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:11]=3)=[CH:57][CH:56]=2)[CH2:44][CH2:43]1)=[O:46])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)CC1

Procedure:
N-(2-(Benzyloxy)-5-{(1R)-2-iodo-1-[(triethylsilyl)oxy]ethyl}phenyl)methanesulfonamide (E. J. Corey and J. O. Link, J. Org. Chem., 1991, 56, 422 and WO 9737646) (1.0 g, 1.93 mmol) was refluxed in anhydrous tetrahydrofuran (30 mL) with 4-[4-(2-aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (1.48 g, 3.98 mmol) and N,N-diisopropylethylamine (0.69 mL). The reaction was stirred at reflux for 7 days. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel Merck-60 (eluant: 20:1 chloroform-methanol containing 2% triethylamine) to furnish the title compound (0.92 g, 1.14 mmol).
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[O:8])[CH:6]2[CH2:9][CH2:10][N:3]1[CH2:4][CH2:5]2.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCCCCC>[N:11]1([CH2:1][CH:2]2[C:7](=[O:8])[CH:6]3[CH2:9][CH2:10][N:3]2[CH2:4][CH2:5]3)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: C1CCNCC1
Solvent: CCCCCC
Product: O=C1C2CCN(CC2)C1CN1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
A reaction flask containing 2-methylenequinuclidin-3-one (6.86 g, 50 mmoles) and a magnetic stir bar was charged with piperidine (12 ml, 120 mmoles). The mixture was stirred at room temperature for 18 hours, and the mixture was added to hexane (300 ml). The solution was filtered through Celite® and the filtrate was concentrated in vacuo (maximum temperature 60° C.) to provide 11.03 g (99%) of the product as a pale yellow solid, mp 34°-37° C.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:14]=2)=[CH:8][C:7]=1[CH3:35].[OH-].[Na+]>CO>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]([CH3:35])[CH:8]=2)=[C:21]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH:22]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3F)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3F)c2)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.7 %

Procedure:
A solution of 3-(4-{3-[4-chloro-2-(2-fluoro-phenoxy)-phenoxy]-phenoxy}-2-methyl-phenyl)-propionic acid methyl ester (72 mg, 0.1 mmol) in MeOH (10 mL) is treated with 5N aqueous sodium hydroxide (0.3 mL). The reaction is heated to reflux and stirred for 2 hr. The reaction is cooled to room temperature and quenched with 1N aqueous HCl to pH=4. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate and filtered. The solvent is removed to afford about 60 mg (87%) of product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H22ClFO5 506, found 524 (M+NH4, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butoxycarbonylaminophenylacetic acid (4.0 mmol) in CH2Cl2 (8.0 mL) is added morpholine (4.0 mmol), EDCl—H2O (4.8 mmol) and DMAP (0.40 mmol) at room temperature. After stirring at room temperature for 24 h, the reaction is quenched by the addition of water. The mixture is extracted with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting solid is triturated with ether-n-hexane to give the title compound; 1H NMR (CDCl3) δ 1.41 (s, 9H), 3.08-3.12 (m, 1H), 3.20-3.28 (m, 1H), 3.39-3.45 (m, 1H), 3.49-3.60 (m, 3H), 3.66-3.76 (m, 2H), 5.54 (d, 1H), 6.01 (d, 1H), 7.29-7.36 (m, 5H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:14].C(N(CC)CC)C>C(O)C>[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])[NH2:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C(CCl)NCC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(N(N)CC(=O)NCC2CCCCC2)cc1
Yield: 100 %

Procedure:
p-Tolylhydrazine hydrochloride (500 mg, 3.16 mmol), 2-chloro-N-(cyclohexylmethyl)acetamide (600 mg, 3.16 mmol), triethylamine (1.31 ml, 9.4 mmol) and ethanol (20 ml) were stirred together to obtain 870 mg of 2-(1-p-tolylhydrazinyl)-N-(cyclohexylmethyl)acetamide. The intermediate (870 mg, 3.15 mmol) and N-methyl-4-piperidone hydrochloride (471 mg, 3.16 mmol) were taken in ethanolic HCl (20 ml) and stirred at RT for 15 min, after which the solvent was removed in vacuo. The reaction mixture obtained was taken in ethanol and heated at 90 deg C. for 14 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness and basified with aqueous saturated sodium bicarbonate, extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to obtain the crude product which was purified by silica gel chromatography (Eluent: 10% MeOH in dichloromethane) to yield 70 mg (yield: 6.27%) of N-(cyclohexylmethyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide. The freebase obtained (70 mg, 0.19 mmol) was dissolve d in THF (10.0 ml), oxalic acid (24 mg, 0.19 mmol) in THF (10.0 ml) was added slowly, the mixture was stirred at RT for 20 min and the solid obtained was filtered, washed with ether and dried to get 70 mg (yield: 80.4%) of N-(cyclohexylmethyl)-2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide as oxalate salt. 1H NMR (DMSO-D2O) OXALATE SALT 8.3-8.2 (t, 1H), 7.30 (d, 1H), 7.2 (s, 1H), 7.0-6.9 (d, 1H), 4.70 (s, 2H), 4.3 (bs, 2H), 3.80-3.2 (m, 4H), 3.1 (bs, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.70-1.50 (m, 5H), 1.40-1.30 (m, 1H), 1.20-1.0 (m, 4H), 0.90-0.70 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[S:19]C.C(OC(=O)C)(=O)C.Cl.[N:30]1C=CC=CC=1>CO.O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[S:19][N:30]=1
Reactant: COc1ccccc1C(=O)c1cc([N+](=O)[O-])ccc1SC
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Product: COc1ccccc1-c1nsc2ccc([N+](=O)[O-])cc12

Procedure:
A solution of the oxime of 2'-methoxy-2-(methylthio)-5-nitrobenzophenone (8.3 g, 26.1 mmol) and acetic anhydride (20 mL) in pyridine (150 mL) is refluxed for 5 days, cooled and concentrated in vacuo to obtain a dark solid. A mixture of the solid in methanol is acidified with concentrated hydrochloric acid (pH5), diluted with water and filtered to obtain a solid. A solution of the solid in methylene chloride is passed through a silica gel pad and concentrated in vacuo to give the title product as a solid, mp 193°-198° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]1[O:4][CH2:3]1.S(=O)(=O)(O)[OH:12]>CC(C)=O>[CH3:9][CH:8]([CH3:10])[CH2:7][CH2:6][O:5][CH:1]([OH:12])[CH:2]([OH:4])[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CC(C)CCOCC1CO1
Solvent: CC(C)=O
Product: CC(C)CCOC(O)C(C)O

Procedure:
The thus obtained 3-methylbutyl glycidyl ether (100 g), acetone (200 ml) and a 3% sulfuric acid aqueous solution (100 ml) were refluxed for 2 hours. Then, after concentration at 50° C./26 hPa, toluene (200 ml) was added to the residue and the resulting mixture was washed with a 3% sodium hydroxide aqueous solution (170 g). The mixture was further washed with saturated brine (150 g) three times and concentrated, and the concentrate was purified by distillation to give 3-methylbutoxypropane-1,2-diol (63 g) (bp: 115–116° C./2.6 hPa).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9]2)=[N:5][N:6]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([C:38](=O)[CH2:39][CH2:40][CH3:41])[C:33](OCC)=[O:34])=[C:27]([F:43])[CH:26]=1)#[N:18].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:34])[N:7]([C@H:8]3[CH2:9][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11]3)[C:4]3[N:5]([N:6]=[C:2]([CH3:1])[N:3]=3)[C:38]=2[CH2:39][CH2:40][CH3:41])=[C:27]([F:43])[CH:26]=1)#[N:18]
Reactant: CCOC(=O)C1CC(Nc2nnc(C)[nH]2)C1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(=O)OCC)C2)c2nc(C)nn12

Procedure:
A solution of ethyl 3-[(5-methyl-4H-1,2,4-triazol-3-yl)amino]cyclobutanecarboxylate (7.85 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (23.15 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.62 mL) in N,N-diethylaniline (70 mL) was stirred at 180° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=85/15→65/35 (volume ratio)] to give the title compound as a pale-yellow amorphous compound (1.89 g, 10%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[OH:27][CH:28]1[CH:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:30][CH:29]1[N:50]1[CH:55]=[C:54](I)[C:53](=[O:57])[NH:52][C:51]1=[O:58].[C:59]([O:63][CH3:64])(=[O:62])[CH:60]=[CH2:61]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:27][CH:28]1[CH:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:30][CH:29]1[N:50]1[CH:55]=[C:54]([CH:61]=[CH:60][C:59]([O:63][CH3:64])=[O:62])[C:53](=[O:57])[NH:52][C:51]1=[O:58]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c(=O)n(C2CC(OCc3ccccc3)C(COCc3ccccc3)C2O)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C=Cc1cn(C2CC(OCc3ccccc3)C(COCc3ccccc3)C2O)c(=O)[nH]c1=O
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
A mixture of palladium(II) acetate (0.195 g, 0.871 mmol), triphenylphosphine (0.456 g, 1.74 mmol) and triethylamine (2.56 ml, 0.0183 mol) in dioxane (200 ml, purified on basic alumina and degassed in vacuo) was heated for 10 minutes at 90° under nitrogen. A solution of [1S-(1α,2β,3α,4β)]-1-[2-hydroxy-4-(phenylmethoxy)-3-[(phenylmethoxy)-methyl]cyclopentyl-5-iodo-2,4(1H,3H)-pyrimidine-dione (6.70 g, 0.0122 mol, dried by concentration in vacuo from dry toluene) and methyl acrylate (3.23 ml, 0.0366 mol) in degassed dioxane (20 ml) was added, and the reaction was heated at 90° for 4.5 hours. Celite (5 g) was added, and after stirring at 90° for 15 minutes, the hot slurry was filtered through Celite and washed with chloroform (80 ml). The filtrate and the wash were combined and concentrated in vacuo to a residue, which was dissolved in chloroform (400 ml). The chloroform was washed with water (100 ml), dried (sodium sulfate) and concentrated in vacuo to a residue. Chromatography of the residue on a column of Merck silica gel (800 ml, packed in dichloromethane) by eluting with a gradient of chloroform to 5% ethanol in chloroform gave 2.21 g of desired product as a residue.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[CH2:15][CH2:16][N:17](CC3C=CC=CC=3)[CH2:18][CH2:19][O:20][C:10]=2[CH:9]=1.Cl>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:33]=[CH:32][C:11]2[O:12][C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=3[CH2:15][CH2:16][N:17]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:18][CH2:19][O:20][C:10]=2[CH:9]=1
Reactant: Clc1ccc2c(c1)OCCN(Cc1ccccc1)CCc1ccccc1O2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCOc2cc(Cl)ccc2Oc2ccccc2CC1
Yield: 95 %

Procedure:
4.47 ml of chloroformic acid ethyl ester were added at room temperature to a solution of 4.17 g of 3-chloro-7,8,9,10-tetrahydro-8-phenylmethyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine in 390 ml of toluene. The mixture was heated to reflux overnight, and after cooling shaken with excess of 1N hydrochloric acid. The toluene layer was separated and the acid aqueous layer extracted with diethyl ether. The combined organic extracts were shaken with 1N hydrochloric acid and water, after which the organic layer was concentrated in vacuo and dried azeotropically to yield 3.78 g (95%) of ethyl 3-chloro-7,8,9,10-tetrahydro-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine-8-carboxylate. Rf 0.6 (silica; hexane-acetone 8:2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24]C)=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:3]=1.O.[OH-].[Li+].C(O)=O>O.O1CCOCC1.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([C:16]4[CH:28]=[CH:27][O:26][C:17]=4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])=[C:4](/[CH:29]=[CH:30]\[CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH:3]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCOCC2)ccc2c1OCc1occc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCOCC2)ccc2c1OCc1occc1-2
Yield: 39 %

Procedure:
A mixture of methyl 7-{4-fluoro-2-[(Z)-3-(morpholin-4-yl)prop-1-enyl]-benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 51, 0.408 g) and lithium hydroxide monohydrate (0.526 g) in water (2.5 mL) and dioxane (10 mL), was sealed in a microwave vial and irradiated in the microwave at 135° C. for 45 minutes. After cooling, the mixture was diluted with ethanol, acidified with formic acid and evaporated to dryness. The residue was triturated with 10% methanol in DCM and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with DMAW 350. The resultant product was azeotroped with toluene and ethanol to give a solid which was triturated with methanol. The solid was collected by filtration and purified by chromatography on silica, eluting with methanol and DCM, with a gradient of 0-10%. The resultant product was triturated with acetone the solid was collected by filtration to give 7-{4-fluoro-2-[(Z)-3-(morpholin-4-yl)prop-1-enyl]benzenesulfonylamino}-4H-furo[2,3-c]chromene-6-carboxylic acid (0.155 g) as a white solid.