Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[O:13])[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6](=[O:36])[CH2:5]1.Br[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:40]=1.O>CN(C=O)C>[C:51]([O:50][C:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([CH2:38][CH:5]2[C:4](=[O:3])[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[O:13])[C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[N:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:6]2=[O:36])=[N:40]1)=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: COc1ccccc1N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)C(C)C
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)N(c2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
45 mg of Sodium Hydride (60% in oil, 1.12 mmol) is added to a solution of 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(2-methoxy-phenyl) acetamide, prepared as in Part D, (430 mg. 0.934 mmol) in DMF (10 mL) and the resultant mixture stirred at RT for 0.5 h prior to the addition of 3-Bromomethyl-1-tert-butoxycarbonyl-1H-indazole (291 mg, 0.934 mmol) to the reaction mixture. After stirring 22 h at RT, water (10 mL) is added and the resultant mixture extracted into ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL), dried (MgSO4), and concentrated in vacuo to afford the crude product which is purified by silica gel flash column chromatography using 3% methanol in methylene chlorideas eluent to give the desired product (260 mg) as a beige solid, which exists as 3:2 mixture of rotamers (major rotamer recorded): 1H NMR (300 MHz, CDCl3) δ8.1 (t, 1H, J=8.0), 7.90 (m, 1H), 7.60-6.90 (m, 15H), 5.05 (m, 1H, J=6.9), 4.60-3.40 (m, 8H), 1.7 (s, 9H), 1.16 (m, 6H).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([I:20])=[C:14]3[C:13]([C:21]([F:24])([F:23])[F:22])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO[C:41]([CH3:43])=[CH2:42].O.C(=O)(O)[O-].[Na+]>ClC(Cl)C.C(O)(=O)C.C(OCC)(=O)C>[I:20][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[N:11]([C:9]3[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([CH:41]([CH3:43])[CH3:42])[CH:10]=3)[N:12]=[C:13]([C:21]([F:23])([F:24])[F:22])[C:14]=12
Reactant: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)cc1N
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)c1cc(-n2nc(C(F)(F)F)c3c(I)ccnc32)ccc1C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Compound (157a) (0.200 g), sodium triacetoxyborohydride (0.189 g), and isopropenyl methyl ether (0.102 mL) were dissolved in dichloroethane (2.0 mL) and acetic acid (0.50 mL), followed by stirring at 0° C. for 1 hr. The reaction solution was distributed between ethyl acetate and saturated sodium bicarbonate water, and the organic layer was washed with saturated saline and was dried over anhydrous sodium sulfate. The solvent was distilled away to obtain 4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropyl)benzamide, which was used in the subsequent reaction without being purified. According to Example 99(2), compound (160) (the second stage yield: 30%) was prepared as a white solid using 4-{4-iodo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropyl)benzamide instead of compound (99a).
Reaction SMILES: S(Cl)(Cl)=O.F[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:15])[CH:7]=1.[CH3:16][S-:17].[Na+]>CO>[CH3:15][C:8]1[CH:7]=[C:6]([S:17][CH3:16])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: C[S-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: CSc1ccc(C(=O)O)c(C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 mL, 27.4 mmol) was added dropwise to a solution of 4-fluoro-2-methyl-benzoic acid (1.25 g, 8.11 mmol) in methanol (10 mL). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and methyl 4-fluoro-2-methylbenzoate was used in the next step without further purification. Methyl 4-fluoro-2-methylbenzoate was dissolved in DMF (5 mL) and sodium thiomethoxide (1.1 g, 15.7 mmol) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was then partitioned between 1M hydrochloric acid and ethyl acetate. The layers were separated and the organic layer was washed with 1M hydrochloric acid, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 2-methyl-4-(methylthio)benzoic acid which was carried to the next step without further purification. 2-Methyl-4-(methylthio)benzoic acid was suspended in acetic acid (10 mL) and hydrogen peroxide (5 mL of 30% w/w) was added and the reaction mixture was heated to 80° C. for 2 hours. The reaction mixture was concentrated in vacuo, then partitioned between 0.2 M HCl (25 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous extracted with ethyl acetate (50 mL). The combined organics washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The resulting solid was rinsed with ether (2×10 mL) and dried in vacuo to give 2-methyl-4-methylsulfonyl-benzoic acid (0.87 g, 50%) as a white solid. ESI-MS m/z calc. 214.0. Found 215.5 (M+1)+; Retention time: 0.48 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.1 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 3.25 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16])[CH3:18]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C

Procedure:
4-(t-Butoxycarbonyl)morpholine-2-carboxylic acid and diethylamine were dissolved in DMF, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide was added thereto at room temperature, and the whole was stirred to obtain t-butyl 2-[(diethylamino)carbonyl]morpholine-4-carboxylate.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:24](C1(C)C(O)=C(C(C)(C)C)C=C(C)C1)(C)(C)[CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([CH:24]=[CH2:25])[CH:11]=3)[C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1=CC(C(C)(C)C)=C(O)C(C)(C(C)(C)C)C1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2cc(Br)ccc2c1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(=O)c(C(=O)OCC)cn(C3CCCCC3)c2c1
Temperature: 25 °C
Yield: 9385.9 %

Procedure:
A mixture of 1 g of ethyl 7-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 13ad)), 60 mg of palladium tetrakis-triphenylphosphine, 1.55 ml of tributyl-vinyl-stannate and 5 mg of 2,6-di-tert-butyl-4-methyl-cresol in 25 ml of toluene is heated at reflux for 1 hr. The reaction mixture is cooled to room temperature, treated with 100 ml of ethyl acetate and washed with 100 ml of 10% aqueous ammonia solution. The aqueous solution is extracted with 50 ml of ethyl acetate. The combined organic phases are washed with 100 ml of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated. The residue is chromatographed on silica gel with hexane/ethyl acetate 1:1. 0.646 g (75%) of ethyl 1-cyclohexyl-4-oxo-7-vinyl-1,4-dihydro-quinoline-3-carboxylate is obtained as a colourless amorphous solid. Mass spectrum (ISP): 326.3(M++H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: [H][H]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(O)c(N)c1

Procedure:
A mixture of 7 g of 4-methoxy-2-nitrophenol, 50 ml of ethyl acetate and 1.3 g of 5% palladium on carbon was stirred under about one atmosphere of hydrogen at room temperature for 3.3 hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure to give 2-amino-4-methoxyphenol. This is used in the following reaction without purification.
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([OH:15])[C:7]3[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=3[CH:9]=[C:4]2[O:3][CH:2]=1.[O:16]([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[O:16]([CH2:23][CH2:24][CH2:25][CH2:26][O:15][C:6]1[C:7]2[CH:14]=[CH:13][C:11](=[O:12])[O:10][C:8]=2[CH:9]=[C:4]2[O:3][CH:2]=[CH:1][C:5]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCCOc1ccccc1
Reactant: O=c1ccc2c(O)c3ccoc3cc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1ccc2c(OCCCCOc3ccccc3)c3ccoc3cc2o1
Reaction time: 0.29 h

Procedure:
700 mg (3.462 mmol) of 5-hydroxypsoralen (crystallized) and 600 mg (3.462 mmol) of 4-phenoxybutyl bromide was refluxed in 30 ml of 2-butanone in the presence of an excess (2 g) of anhydrous potassium carbonate and catalytic amounts of potassium iodide for 24 hours. The progress of the reaction was monitored by thin layer chromatography. After 24 hours the reaction mixture was concentrated under reduced pressure. The oily residue was cooled and diluted with water. The aqueous solution was then acidified with concentrated hydrochloric acid to pH 1. The slurry was stirred for 15-20 min and extracted with 3×100 ml of dichloromethane. The dichloromethane layer was extracted with 25 ml of 1% sodium hydroxide to separate the un-reacted 5-hydroxypsoralen. The dichloromethane layer was washed with 30 ml of 2% hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The solid residue was dissolved in a methanol-acetone mixture, treated with charcoal and re-crystallized from a methanol-acetone (80:20) mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:15]([N:18]([CH3:20])[CH3:19])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[O:12])=[CH:8][C:9]=1[N:10]=[CH:15][N:18]([CH3:20])[CH3:19])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc(C=O)cc1N
Product: COC(=O)c1sc(C=O)cc1N=CN(C)C

Procedure:
3-Amino-5-formylthiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 308.40 (C15H20N2O3S) was obtained in this way; MS (ESI): 309 (M+H+).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[CH2:35]([N:37]=C=O)[CH3:36].O1CCOCC1.Cl>C(#N)C>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:9]2[NH:17][C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:8][C:6]([NH:37][CH2:35][CH3:36])=[O:5])[C:11]=3[N:10]=2)[CH2:21][CH2:22]1
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc2c(N)cccc21
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cccc2[nH]c(NCC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) in acetonitrile (1 ml), ethyl isocyanate (0.08 mmol) was added and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride-1,4-dioxane solution (1 ml) to the reaction mixture, it was stirred at 50° C. for 1 hour and then the reaction mixture was passed through SCX (Bond Elute SCX500MG). The SCX was washed with methanol and elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain 1-(2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-3-ethyl-urea. The compound was identified by LC-MS.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([N:25]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1
Reactant: NCc1ccccc1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(Cl)c2c1
Solvent: O
Product: CN(C)c1ccc2nc(N)c(C#N)c(N=Cc3ccccc3)c2c1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 mL of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.3 g of the title compound is obtained, m.p.: 265° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH3:23])[C:13]=3[CH:24]2SCCS2)[N:9]([CH3:29])[CH2:8]1)=[O:5])[CH3:2]>CO>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[N:14]([CH3:23])[C:13]=3[CH3:24])[N:9]([CH3:29])[CH2:8]1)=[O:5])[CH3:31]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(C3SCCS3)n4C)C[C@H]2N(C)C1
Solvent: CO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3c(c(C)n4C)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.1 %

Procedure:
7.5 ml of a Raney nickel suspension is washed four times with respectively 30 ml of methanol. Thereafter, 15 ml of methanol and then a solution of 690 mg (1.5 mmol) of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-1,6-dimethyl-8α-ergolinyl]urea in 15 ml of methanol are added thereto. The mixture is agitated for 3 hours at room temperature and then once more 7.5 ml of a Raney nickel suspension, previously washed as above four times with respectively 30 ml of methanol, is added thereto. After another 2 hours of agitation at room temperature, the catalyst is filtered off via a silica gel column and washed thoroughly with methanol. The filtrate is evaporated and the residue crystallized from methanol/ethyl acetate, thus obtaining 150 mg of 1,1-diethyl-3-(1,2,6-trimethyl8α-ergolinyl)urea (27% yield).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH3:32])=[O:30])[CH2:6][C@@H:5]1[OH:33])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[C:34]([O:33][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH3:32])=[O:30])[CH2:6]1)(=[O:36])[CH3:35]
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NCCC(C)C)C[C@]2(C)[C@@H](C(=O)OC)CC[C@@H]32)C[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NCCC(C)C)C[C@]2(C)[C@@H](C(=O)OC)CC[C@@H]32)C[C@@H]1OC(C)=O
Reaction time: 3 h

Procedure:
Methyl 2β-ethoxy-3α-hydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (464 mg) in chloroform containing dry PTSA (344 mg) was stirred for 20 min, then treated with acetic anhydride (1.0 ml) and the mixture left for 3 h. The reaction mixture was diluted with ethanol and evaporated to give an oil. This was dissolved in ethyl acetate, washed with dilute ammonia solution (2×), water (1×), dried and evaporated to give an oil. This was purified by preparative t.l.c. in CHCl3 /MeOH (20:1) to give the title compound as an oil (415 mg), [α]D +27.9°, νmax 1725 cm-1.
Reaction SMILES: [F:1][C:2](=[CH2:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=[O:5].[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12]/[CH:11]=[C:2](\[F:1])/[C:3]([CH3:10])([CH3:9])[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: C=C(F)C(C)(C)C(=O)OCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C(=O)O)/C(F)=C/Br
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
Ethyl 3-fluoro-2,2-dimethyl-3-butenoate (14 g) and bromine (11 g) were dissolved in 50 mL of CCl4, and the solution heated at reflux for one hour. The solution was then cooled and concentrated in vacuo. The dibromo ester was taken up in 100 mL of dry THF and stirred at 0° C. while DBU (13 g) was added dropwise. Stirring was continued overnight, allowing the solution to warm to ambient temperature. The dark solution was then poured onto ice and excess 10N HCl, and the product was isolated by extraction into ether, washing with a saturated brine solution, drying and removal of the solvent. The bromovinyl ester (10.4 g) was then hydrolyzed by treatment with 7.3 g of potassium hydroxide in a solution of 10 mL of ethanol and 90 mL of water, at the reflux temperature for one hour. After the solution had cooled, it was diluted with 100 mL of water, acidified, extracted with ether (2×100 mL), and the combined organic layer washed with brine, dried and concentrated to yield 7.3 g of (Z) 4-bromo-3-fluoro-2,2-dimethyl-3-butenoic acid as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:25]([CH3:27])=[CH2:26].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:14]([CH:25]([CH3:27])[CH3:26])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:22])[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CNc2ccccc2)COC1(C)C
Reactant: C=C(C)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)N(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 40 °C
Yield: 89 %

Procedure:
To a stirred solution of (S)-2,2-dimethyl-4-phenylaminomethyl-oxazolidine-3-carboxylic acid tert-butyl ester (650 mg) at r.t. in 1,2-dichloroethane (15 ml) under an argon atmosphere were added 2-methoxypropene (0.30 ml), trifluoroacetic acid (0.16 ml) and sodium triacetoxyborohydride (674 mg). The mixture was heated to 40° C. overnight. The mixture was cooled to r.t., directly adsorbed on silica gel and purified by chromatography (SiO2; gradient:cyclohexane->cyclohexane/EtOAc 7:3) to give (S)-4-[(isopropyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (659 mg, 89%) as light yellow viscous oil. MS (ISP): 349.5 ([M+H]+)
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:11]2=[CH:17][CH:18]=1)=[O:7]>CC(C)=O>[N:1]([C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[O:16])[O:14][C:12](=[O:13])[C:11]2=[CH:17][CH:18]=1)=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)OC2=O
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1ccc2c(c1)C(=O)OC2=O
Reaction time: 17 h

Procedure:
A total of 3.25 g of sodium azide was added in portions to a solution of 10.5 g of 4-chlorocarbonylphthalic anhydride in 100 ml of acetone. The mixture was allowed to stand for 17 hours at room temperature (circa 25°C) after which the yellow solution so obtained was evaporated to dryness under reduced pressure. There was thus obtained a substantially quantitative yield of 4-azidocarbonylphthalic anhydride in the form of a crystalline solid having a melting point of 100° to 103°C with decomposition.
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[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=[C:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[C:14]3[C:13]([O:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])=[CH:7][CH:8]=4)=[N:18][CH:17]=[N:16][C:15]=3[O:19][C:20]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)CCc1ccc(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4ccc(CCC(=O)O)cc4)c23)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Initially charge 137 mg (0.285 mmol) of 3-(4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]-pyrimidin-4-yl]oxy}phenyl)propanoic acid methyl ester in 4.5 ml of THF, and add 0.855 ml of 1N sodium hydroxide solution at RT. Stir the mixture at 50° C. for 1 h. After cooling, acidify with 1N hydrochloric acid and filter off the precipitated solid with suction, wash with water and dry under high vacuum. 125.9 mg (94.7% of theory) of the target compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=[O:13])=[C:7]2[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[C:7]2[NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1NCc1ccc(OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2c(C(=O)O)cnc3c(Br)cccc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To a solution of ethyl 8-bromo-4-((4-methoxybenzyl)amino)quinoline-3-carboxylate (1.2 g, 2.89 mmol) in THF-MeOH—H2O (10:7:3, 20 mL) was added LiOH—H2O (452 mg, 10.77 mmol) and the reaction mixture was stirred at rt for 12 h. Then the reaction mixture was acidified with citric acid and the organic volatiles were removed. The residue was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated to afford 1.0 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.96 (s, 1H), 8.42-8.39 (d, J=8.7 Hz, 1H), 8.11-8.09 (d, J=7.2 Hz, 1H), 7.35-7.30 (m, 3H), 6.95-6.92 (d, J=8.7 Hz, 2H), 4.91 (s, 2H), 3.74 (s, 3H).
Reaction SMILES: C(O)C.[NH2:4][C:5]1C=[C:12]([F:14])[C:11]([CH3:15])=[CH:10][C:6]=1C(O)=O.C[Si](C=[N+]=[N-])(C)C.[CH2:23]([O:25][C:26](=[O:28])[CH3:27])C>>[CH3:23][O:25][C:26](=[O:28])[C:27]1[C:5]([NH2:4])=[CH:6][CH:10]=[C:11]([CH3:15])[C:12]=1[F:14]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(=O)O)c(N)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCO
Product: COC(=O)c1c(N)ccc(C)c1F
Reaction time: 16 h

Procedure:
Dissolve in ethylacetate (1 mL) and ethanol (1 mL) 6-Amino-2-fluoro-3-methyl-benzoic acid and 2-Amino-4-fluoro-5-methyl-benzoic acid (240 mg, 1.42 mmol) and add (trimethylsilyl) diazomethane (0.7 mL, 1.4 mmol, 2M in hexane) at room temperature and stir the solution for 16 h. Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (10:1), to afford the titled compound (50 mg). 1H NMR (CDCl3, 300 MHz) δ 2.13 (d, J=2.4 Hz, 3H), 3.9 (s, 3H), 6.39 (dd, J=0.8, 8.5 Hz, 1H), 7.04 (t, J=8.1 Hz, 1H). MS (ES+): 184 (M+H).