Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42]([Cl:44])[CH:41]=[C:40](Br)[CH:39]=1>>[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:39]=[C:40]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:21])[F:19])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH3:32])[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (3-bromo-5-chloro-phenyl)acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23](O)=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]1[C:10]([CH3:26])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@@:14]([CH2:22][C:23]([Cl:30])=[O:24])([CH3:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)O)O2
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CC(=O)Cl)O2
Yield: 105 %

Procedure:
Reaction of 11.8 g (33.3 mmol) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid with oxalyl chloride according to Cohen et al Helv. Chim. Acta, 1978 61, 837 afforded 13.0 g (105%) of (S)-(6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl)acetyl chloride as a yellow oil. This acid chloride was reacted according to Org. Synth., 1984, 63, 198 with 4.94 g (34.3 mmol) of Meldrum's acid and 6.58 g (6.73 mL, 83.2 mmol) of dry pyridine as described above for the racemic series to afford 16.5 g of crude adduct i.e.(S)-5-[2-[3,4-dihyro-2,5,7,8-tetramethyl-6-phenylmethoxy-2H-1-benzopyran-2-yl]-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione as a brownish foam. Crystallization attempts from several solvents or solvent mixtures failed.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[N:4][CH:3]=1.[NH2:18][C:19]1[O:20][C:21]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:22]=2[N:23]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[N:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([C:25]2[CH:26]=[CH:27][C:21]4[O:20][C:19]([NH2:18])=[N:23][C:22]=4[CH:24]=2)=[CH:11]3)[CH2:13][CH2:14]1
Reactant: Nc1nc2cc(B(O)O)ccc2o1
Reactant: Brc1cnc2ccc(N3CCOCC3)nc2c1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc2cc(-c3cnc4ccc(N5CCOCC5)nc4c3)ccc2o1
Yield: 67.2 %

Procedure:
A mixture of 7-bromo-2-morpholino-1,5-naphthyridine (F-32) (180 mg, 0.6 mmol, 1.0 eq), 2-aminobenzo[d]oxazol-5-ylboronic acid (131 mg, 0.73 mmol, 1.2 eq), Pd(PPh3)4 (71 mg, 0.06 mmol, 0.1 eq), and Na2CO3 (195 mg, 1.8 mmol, 3.0 eq) were dissolved in a mixture of 1,4-dioxane (10 mL) and water (10 mL). The resulting mixture was degassed and back-filled with argon three times and heated at reflux under an argon atmosphere for 2 h. The reaction was complete based on TLC analysis. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (3-5% MeOH-DCM) to afford 5-(6-morpholino-1,5-naphthyridin-3-yl)benzo[d]oxazol-2-amine (73) (140 mg, 67.2% yield). 1H NMR (400 MHz, DMSO-d6) δ: 8.93 (s, 1H), 8.10 (m, 2H), 7.66 (s, 1H), 7.53 (s, 2H), 7.45 (m, 3H), 3.74 (m, 8H); ESI-MS m/z: 348.11 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:19].[CH3:20][S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:29]=3)=[C:3]([F:19])[CH:4]=2)[N:9]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3cc2F)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloro-6-fluoroquinazolin-4-yl)morpholine (0.15 g, 0.0004 mol—Preparation 2), 3-methylsulfonylphenylboronic acid (0.078 g, 0.00039 mol), sodium carbonate (0.114 g, 0.0011 mol), DMF (6 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.015 g, 0.000022 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 90° C. for 3 hours. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in n-hexane) to yield the desired product (0.12 g, 66%). 1H NMR (300 MHz, CDCl3): δ 8.23 (d, J=1.8 Hz, 1H), 8.06-7.90 (m, 3H), 7.68 (t, J=7.8 Hz, 1H), 7.64 (d, J=11.1 Hz, 1H), 3.92 (s, 8H), 3.12 (s, 3H): LC-MS (ESI): Calculated mass: 421.0; Observed mass [M+H]+: 422.1 (RT=1.45 min).
Reaction SMILES: O.OS(O)(=O)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:23])[CH2:20][CH2:21][OH:22])[N:18]=2)[CH:11]=[CH:12][CH:13]=1.CC([OH:27])C>CC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:23])[CH2:20][C:21]([OH:27])=[O:22])[N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(CCO)n1nnc(-c2cccc(Cl)c2)n1
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(CC(=O)O)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A mixture of CrO3 (0.46 g, 4.63 mmol), H2O (2.5 mL) and concentrated H2SO4 (0.46 mL) was added to a solution of 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]butan-1-ol (0.9 g, 3.6 mmol) in acetone (30 mL) at 0° C. The reaction was stirred at r.t. for 1.5 h. 2-Propanol was added and the mixture was concentrated. Sat. NaCl (25 mL) and EtOAc (50 mL) were added to the residue and the mixture was extracted. The water phase was re-extracted with EtOAc (50 mL) and the combined organic phases were dried (MgSO4) and concentrated to give 0.95 g (100%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[OH-].[Na+].[CH2:18]=O.Cl>O>[CH2:18]1[C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3][C@H:2]([C:13]([OH:15])=[O:14])[NH:1]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Yield: 87.4 %

Procedure:
20.0 g D-tryptophan is suspended in 40 ml of water and 7.83 g 50%(w/w) sodium hydroxide solution is added and this mixture is stirred to give a clear solution. 7.95 g 37% formaldehyde is added and this mixture is stirred for 2 hours at room temperature, then refluxed for 3 hours. The hot solution is poured into 200 ml water and, with vigorous stirring, the pH is adjust to 5 with 6N hydrochloric acid, giving a precipitate. The slurry is stirred for 18 hours, filtered, and the solid dried at 70° C./0.1 mm Hg overnight to give 18.5 g (3R)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid.
Reaction SMILES: [Li+].CCC[CH2-].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.CCCCCC>CCOCC>[Br:6][C:7]1[CH:8]=[C:9]([B:18]([OH:19])[OH:17])[CH:10]=[CH:11][CH:12]=1
Reactant: Brc1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-Butyllithium (2.5M; 44 mL; 0.11M) was added dropwise over 15 mins. to a vigorously stirred solution of m-dibromobenzene (25 g; 0.106M) in 500 mL of anhydrous ether at -78° under nitrogen. After stirring 10 mins. more, a solution of triisopropylborate (25.3 mL; 0.11M) in anhydrous ether (200 mL) was added over 20 mins. The cooling bath was then removed, and the stirring solution was allowed to warm to R.T. over ~2 hrs. A small amount of solid separated. After stirring 15 mins. more at R.T., 150 mL of ice cold 8% aqueous hydrochloric acid was cautiously added, and the stirring was continued for 15 mins. The organic phase was separated, washed with 2×100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent removal gave -30G of crude product as a semi-solid, which was shaken well with 150 mL of hexane. The solid was filtered and washed with 2×25 mL of hexane. The resulting silky solid (mp 178°-9° C. after softening at ~160° C.) (6.5 g) was used as 3-bromophenylboronic acid with a small amount of contamination. The hexane filtrate was concentrated and the residue was stirred well with 150 mL of petroleum ether (30°-60°). The resulting solid was filtered and washed with 2×25 mL of petroleum ether. This resulting solid (4.4 g) melting at 178.3°-179° C. was the desired 3-bromophenylboronic acid.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH3:16].OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:1])[CH3:16]
Reactant: O=C(O)CCCCCCCCCCI
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCCCCCI

Procedure:
11-Iodo-undecanoic acid ethyl ester was synthesized according to Bergbreiter, J. Org. Chem., 40/6 (1975) 779. Briefly, 246.6 g 11-Iodo undecanoic acid, 440 ml dry ethanol, 440 ml dry toluol and 5 ml H2SO4 (98%) were combined. The mixture was distilled whereby about 400 ml aceotrope was removed at 75° C. or 76° C., respectively. Then 15 g K2CO3 was added and after 5 min the mixtures was filtered and finally distilled at a bath temperature of 115° C. The resulting brown oil was purified by filtration through a frit filled with silica gel (eluent: acetic acid ethyl ester/petrol ether 1:7). The final product was characterized by 1H-NMR and thin layer chromatography.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:5]=2[CH:4]=1.[C:28]1([P:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>C(OCC)C>[C:41]1([PH+:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1.[Br:1][CH2:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH2:16][Br:17])=[CH:10][CH:11]=3)[CH:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:5]=2[CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: COCCOCCOCCC1c2cc(CBr)ccc2-c2ccc(CBr)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1

Procedure:
In a 1 L three-hole flask equipped with a stirrer, a thermometer and a reflux condenser, 24.9 g (0.05 mol) of 2,7-bis(bromomethyl)-9-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}fluorene, 39.3 g (0.15 mol) of triphenylphosphine, and 300 ml of dimethylformamide were introduced and reacted for 12 hours at reflux temperature. After reaction, the temperature was decreased to room temperature, and the reactant was dropped down slowly in 1.5 L of ethylether solvent under agitation, to obtain a white solid. After filtering, such extracted solid was washed several times with ethylether, and then dried sufficiently in a vacuum oven at 40° C. As a result, 48.5 g (yield: 95%) of a white solid was obtained. [1H=NMR (CDCl3), δ 1.22-1.41(m, 2H, CH2), 2.16-2.42(br, s, 3H, OCH3), 3.41-3.71(m, 10H, OCH2 CH2), 4.18(t, 1H, CH), 5.58-5.81(d, 4H, CH2Br), 6.81-7.22(m, 6H, fluoreyl aromatic), 7.27-7.84(m, 30H, aromatic)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 92.8 %

Procedure:
A mixture of 30.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 18.7 g of 2-(dimethylamino)ethyl chloride hydrochloride, 33.0 g of potassium carbonate and 240 ml of ethyl acetate is refluxed for 30 minutes under stirring. Then, 5 ml of water are added to the mixture, and the aqueous mixture is further refluxed for 6 hours under stirring. After cooling the reaction mixture, said mixture is washed with water. The ethyl acetate layer is separated and washed with water. The ethyl acetate layer is then evaporated under reduced pressure to remove ethyl acetate. The residue is dissolved in ethanol. After cooling the solution, said solution is acidified with 10% HCl/ethanol and then stirred at a temperature below 10° C. for 5 hours. The crystalline precipitates are collected by filtration, washed with ethanol and then dried. 37.9 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride are thereby obtained. Yield: 92.7%
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][N:14]=[C:6]3[C:5]3([O:21][CH2:20][CH2:19][CH2:18][O:17]3)[C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>O1CCOCC1>[CH3:15][C:12]1([CH3:16])[CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH:22]=[CH2:23])=[CH:3][C:4]=3[C:5]3([O:17][CH2:18][CH2:19][CH2:20][O:21]3)[C:6]2=[N:14][CH2:13]1
Reactant: CC1(C)CN=C2N(C1)c1ccc(Br)cc1C21OCCCO1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)C1(OCCCO1)C1=NCC(C)(C)CN12
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.6 %

Procedure:
To the stirred solution of 8′-bromo-3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2- a]indole](2.576 g, 7.330 mmol) in dioxane (70 mL) was added tributyl (vinyl) tin (3.490 g, 10.995 mmol) and the solution was degassed with N2 for 15 min. Pd(PPh3) 4 was added and the mixture was stirred at 100° C. for 6 hr. The reaction was diluted with EtOAc, washed with brine and concentrated. The resulting residue was dissolved in EtOAc and stirred with 1M KF solution (20 mL) overnight. The reaction was filtered and the filtrate was washed with brine. The organics were dried over Na2SO4 and concentrated to give the title compound as white solid (1.720 g, 79%). NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1)[CH3:24]>C1(C)C=CC=CC=1>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 56 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 4-ethylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 90 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 42 mg of the title compound (yield: 56%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[NH:6][CH:5]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+]>[C:21]1([CH2:20][O:19][C:17]([NH:1][CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=3)[NH:6][CH:5]=2)=[O:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1c[nH]c2ccc(C(=O)O)cc12
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCc1c[nH]c2ccc(C(=O)O)cc12)OCc1ccccc1
Reaction time: 1.25 h

Procedure:
A vigorously stirred solution of 3-(2-amino-ethyl)-1H-indole-5-carboxylic acid (50 g) in aqueous sodium hydroxide (1 M, 450 ml) was cooled in an icebath and benzyl chloroformate (60 ml) and aqueous sodium hydroxide (1 M, 430 ml) were added simultaneously dropwise over a period of 1 hour so as to maintain the pH >10. The reaction mixture was stirred at ca 5° C. for 1.25 hour then a further portion of aqueous sodium hydroxide (1 M, 130 ml) was added. After a further 2 hour. the reaction mixture was extracted with ether (2×500 l ml) and the aqueous layer treated with sodium chloride (200 g), acidified to pH 1 with concentrated hydrochloric acid (80 ml) and extracted with ethyl acetate (3×500 ml). The combined extracts were washed with aqueous sodium chloride (10%, 2×500 ml) dried (MgSO4) and evaporated to dryness to give the title compound as a white solid (61.8 g) mp 186.5°-188°.
Reaction SMILES: CO[CH2:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1.B(Br)(Br)[Br:33].COC>ClCCl>[Br:33][CH2:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: COCc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Reactant: BrB(Br)Br
Agent: COC
Solvent: ClCCl
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(CBr)c1)C(F)(F)F
Temperature: -50 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
EX-514D) The 3-[[3-(methoxymethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol from EX-514C (1 g, 2.2 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to −50° C. and a 1 M solution of BBr3 in dichloromethane (2.3 mL, 2.3 mmol) was added. The solution was stirred at −50° C. for 1 hour and warmed to room temperature over 1 hour, at which time HPLC analysis indicated that no methyl ether starting material remained. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted in dichloromethane. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 0.65 g (59%) of the desired 3-[[3-(bromomethyl)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a brown oil. HRMS calcd. for C19H18BrF7NO2: 504.0409 [M+H]+, found: 504.0361. 1H NMR (CDCl3) δ 3.3 (s, 1H), 3.6 (dd, 1H), 3.9 (dd, 1H), 4.3 (m, 1H), 4.4 (s, 2H), 4.8 (m, 2H), 5.9 (tt, 1H), 6.7 (d, 1H), 6.8-6.9 (m, 2H), 7.1-7.3 (m, 4H), 7.4 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:23])[O:12][C:11](=[O:13])[C:10]([O:14]CC3C=CC=CC=3)=[C:9]2[OH:22])=[CH:4][CH:3]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:23])[O:12][C:11](=[O:13])[C:10]([OH:14])=[C:9]2[OH:22])=[CH:6][CH:7]=1
Reactant: CC1(c2ccc(Cl)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC1(c2ccc(Cl)cc2)OC(=O)C(O)=C1O
Yield: 45.8 %

Procedure:
Hydrogenolysis of 330 mg of 5-(4-chlorophenyl)-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 110 mg (46% yield) of 5-(4-chlorophenyl)-3,4-dihydroxy-5-methyl-2(5H)-furanone a light tan solid: mp 154-155° C. dec.(benzene/hexanes) 1H NMR (acetone-d6) δ 7.52-7.34 (m, 4H), 1.82 (s, 3H). 13C NMR (acetone-d6) δ 169.0, 156.6, 139.8, 134.3, 129.2, 127.8, 117.9, 80.8, 24.6. Anal Calcd for C11H9ClO4 : C, 54.90; H, 3.77. Found: C, 54.74; H, 4.08.
Reaction SMILES: [C:1]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:12]2[C:11](=[O:26])[NH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].[CH:28]1([S:31](Cl)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[CH:28]1([S:31]([O:26][C:11]2[N:10]=[CH:9][CH:8]=[C:7]3[C:12]=2[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]4=[O:25])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:27])[NH:6]3)(=[O:33])=[O:32])[CH2:30][CH2:29]1
Reactant: CC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccc2c(=O)cc(C)oc12
Reactant: O=S(=O)(Cl)C1CC1
Product: CC(=O)C1=C(C)Nc2ccnc(OS(=O)(=O)C3CC3)c2C1c1cccc2c(=O)cc(C)oc12

Procedure:
The title compound is prepared in analogy to example 10 from 50 mg (0.13 mmol) of 3-acetyl-2-methyl-4-(2-methyl-4-oxo-4H-chromen-8-yl)-4,6-dihydro-1,6-naphthyridin-5(1H)-one and 22 mg (0.15 mmol) of cyclopropanesulfonyl chloride. 54 mg (84% of theory) of the product are obtained as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][N:15](/[CH:17]=[N:11]/[C:9]([C:7]1[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:10])[CH3:16]
Reactant: NC(=O)c1ccc([N+](=O)[O-])s1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=N/C(=O)c1ccc([N+](=O)[O-])s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
5-Nitrothiophene-2-carboxamide (5.80 g, 33.7 mmol) was combined with N,N-dimethylformamide dimethyl acetal (75 mL, 560 mmol) and stirred at 120° C. overnight (added 10 mL DMF to help dissolve the starting material). The red-brown solution was cooled to room temperature, at which point a solid precipitated from solution. The solid was isolated by filtration, washed with Et2O, and dried to provide the title compound as tan crystals.