Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[N:18]1([C:24]2[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:21]1[CH2:22][CH2:23][N:18]([C:24]2[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)[CH2:19][CH2:20]1)=[O:9])([CH3:2])[CH3:3]
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 69 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 2-piperazin-1-yl-thiazole-5-carbonitrile. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 69%). MS (m/e): 435.4 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:14])=O)=[CH:8]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:35])[NH2:14])=[CH:8]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=O)[nH]c12
Solvent: C1CCOC1
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
To a solution of 7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxamide (0.66 g) in tetrahydrofuran (150 mL) was added Lawesson's reagent (0.89 g), and the mixture was stirred at 50° C. for 1 h. Tetrahydrofuran (100 mL) and Lawesson's reagent (0.42 g) were added to the mixture. After stirring at 50° C. for 13 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80 to 100/0, volume ratio) to give the title compound (0.68 g, 99%) as a yellow amorphous solid. MS 378 (MH+).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(Cl)(Cl)(Cl)[Cl:20]>[OH-].[Na+]>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][C:8]=1[Cl:20]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Oc1ccc(C2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Product: Oc1ccc(C2CCOCC2)cc1Cl

Procedure:
10 ml of sulfuryl chloride were added with stirring to a mixture of 14.1 g of 4-(p-hydroxyphenyl)-tetrahydropyran and 40 ml of carbon tetrachloride and the mixture was heated to 45°-50° C for 16 hours. The mixture was concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with methylene chloride yielded a crystal product which was dissolved in 200 ml of N sodium hydroxide and the solution was washed with ether and acidified with 2N hydrochloric acid. The mixture was extracted with ether and the organic phase was washed with water, then an aqueous sodium bisulfite solution and then with water. The extracts were dried and evaporated to dryness to obtain 6.4 g of 4-(4-hydroxy-3-chlorophenyl)-tetrahydropyran melting at 123°-125° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.[NH2:40][O:41][CH2:42][C:43]([CH3:46])([OH:45])[CH3:44].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[OH:45][C:43]([CH3:46])([CH3:44])[CH2:42][O:41][N:40]=[C:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:6][CH2:7]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(C)(O)CON
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=NOCC(C)(C)O)CC2)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.2 g), 1-(aminooxy)-2-methylpropan-2-ol (0.4 g) and pyridine (5 mL) was stirred at 100° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)C)[C:5]([CH3:8])=[N:6][CH:7]=1.C([O-])(=O)C.[K+].C(O)(=O)C.C(OC(=O)C)(=O)C.C(O[N:35]=O)CC(C)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][N:35]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1cc(Br)cnc1C
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Brc1cnc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a solution of N-(5-bromo-2-methylpyridin-3-yl)acetamide (8.28 g, 36 mmol) in chloroform (550 mL) at ambient temperature was added potassium acetate (4.32 g, 43.6 mmol), acetic acid (2.5 mL, 43.6 mmol) and followed by acetic anhydride (6.86 mL, 72.6 mmol). The mixture was stirred at ambient temperature for 15 minutes before being heated to 40° C. Isoamylnitrite was then added dropwise. The reaction was then stirred at 60° C. for 48 hours. The reaction mixture was poured slowly into a saturated solution of sodium bicarbonate (500 mL) at 0° C. The organic phase was retained and the aqueous phase extracted with dichloromethane (500 mL). The combined organics were then concentrated to a brown oil which was dissolved in methanol (500 mL). Aqueous sodium hydroxide (2 M, 500 mL) was added at 0° C. and the mixture stirred at ambient temperature for 1 hour before the methanol was removed in vacuo. The aqueous mixture was then extracted with ethyl acetate (3×500 mL). The combined organics were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to give 6-bromo-1H-pyrazolo[4,3-b]pyridine as a light brown solid (5.5 g, 77%). 1HNMR (400 MHz, CD3OD, δ): 8.55 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[C:34](=[O:35])[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([CH3:36])[CH:32]=5)[N:27]([CH3:37])[C:26]4=[O:38])[CH2:21][CH2:20]3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:39][CH3:40])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[C:34](=[O:35])[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([CH3:36])[CH:32]=5)[N:27]([CH3:37])[C:26]4=[O:38])[CH2:21][CH2:20]3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:39][CH3:40]
Reactant: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
In 10 ml of ethanol was dissolved 150 mg (0.28 mmol) of Compound 87 obtained in Example 66, and 30 mg of 10% palladium on carbon was added thereto, followed by vigorous stirring at room temperature for 6 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered using a filter aid, and the filtrate was concentrated under reduced pressure. To the residue were added ethanol and ethyl acetate. The precipitated crystals were collected by filtration, washed, and dried to give 105.2 mg (yield: 84%) of Compound 89 as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:49])[CH2:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:49])[CH2:35][O:36][C:37](=[O:48])[C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=4)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: COc1ccc(C(=O)OC[C@H](C)NC(C)C)cc1OC
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COC(=O)c3ccc(OC)c(OC)c3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoic acid and 3,4-dimethoxy-benzoic acid (S)-2-isopropylamino-propyl ester as described for example 1.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[ClH:5].[CH3:6][C:7]1[C:13](=O)[CH:12]=[C:11]([CH3:15])[C:9](=[O:10])[CH:8]=1>C(O)C>[ClH:5].[NH2:1][C:2]1[S:3][C:12]2[C:11]([CH3:15])=[C:9]([OH:10])[CH:8]=[C:7]([CH3:6])[C:13]=2[N:4]=1
Reactant: CC1=CC(=O)C(C)=CC1=O
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: Cc1cc(O)c(C)c2sc(N)nc12

Procedure:
To 2.24 g of thiourea were added 60 ml of ethanol and 2.5 ml of concentrated hydrochloric acid, followed by stirring. Then a solution of 8.0 g of p-xyloquinone in ethanol (120 ml) was slowly added dropwise thereto. The reaction mixture was stirred at room temperature for 24 hours and then concentrated to about one-half. The crystals thus precipitated were separated by filtering and washed with a small amount of ethanol. Thus 6.80 g of the title compound was obtained in the form of white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][C:19]([F:31])=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:32][C:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[NH:35][N:34]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][C:19]([F:31])=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:38]3[CH:37]=[C:36]4[C:41]([C:33]([CH3:32])=[N:34][NH:35]4)=[CH:40][CH:39]=3)[C:3]=12
Reactant: Cc1n[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: CC(c1oc2ccc(F)cc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2cc(-c3nn(C(C)c4oc5ccc(F)cc5c(=O)c4-c4ccccc4)c4ncnc(N)c34)ccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 16.1 %

Procedure:
To a solution of Example 57e (0.400 g, 0.758 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), 3-methyl-6-indazoleboronic acid pinacol ester 97 (0.391 g, 1.517 mmoles) and sodium carbonate (0.241 g, 2.27 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.044 g, 0.037 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as yellow solid (0.065 g, 15% yield). MP: 253-255° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 12.75(s,1H), 8.08(s,1H), 7.85(d, J=8.3 Hz, 1H), 7.75(m,3H), 7.63(s,1H), 7.35(dd, J=8.4,1.2 Hz, 1H), 7.28(m,3H), 7.14(br s,2H), 6.00(q, J=7.1 Hz, 1H),2.52(s,3H), 1.91(d, J=7.1 Hz, 3H). Mass: 532.03(M++1).
Reaction SMILES: Cl.C(OC(=O)[C@H](CCCC(C(OCC1C=CC=CC=1)=O)N)N)C.[CH2:24]([O:26][C:27]([C@@H:29]([NH:45][CH:46]([C:48]([N:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52]([OH:54])=[O:53])=[O:49])[CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34]C(OCC1C=CC=CC=1)=O)=[O:28])[CH3:25]>O>[CH2:24]([O:26][C:27]([C@@H:29]([NH:45][CH:46]([C:48]([N:50]1[CH2:57][CH2:56][CH2:55][C@H:51]1[C:52]([OH:54])=[O:53])=[O:49])[CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])=[O:28])[CH3:25]
Reactant: CCOC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)[C@@H](N)CCCC(N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O
Product: CCOC(=O)[C@H](CCCCN)NC(C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ε-benzyloxycarbonyl-L-lysine ethyl ester hydrochloride (2.94 g.) in water (10 ml.) is made basic with 15 ml. of saturated aqueous potassium bicarbonate and extracted with CH2Cl2. The extract is dried over MgSO4 and concentrated to dryness. The residue, ε-Benzyl oxycarbonyl-L-lysine ethyl ester, is dissolved in THF (20 ml.) and pyruvoylproline (555 mg.) and powdered No. 4A molecular sieves (1.0 g.) are added. The mixture is stirred at room temperature for 4 hours. Sodium cyanoborohydride (630 mg.) in 1 ml. of CH3OH is added over 2 hours and the mixture is stirred overnight. It is then filtered, concentrated to dryness, and the residue partitioned between water (10 ml.) and CH2Cl2 (15 ml.). The aqueous phase is absorbed on strong acid ion-exchange resin and eluted with 4% pyridine in water to yield 470 mg. of N-(1(S)-ethoxycarbonyl-5-benzyloxycarbonylaminopentyl)-D,L-alanyl-L-proline. The protecting group is removed by hydrogenation in ethanol-water 1:1 over 10 % Pd/c catalyst at 40 ps.i. The mixture is filtered and the filtrate taken to dryness. The residue in methanol is chromatographed on an LH-20 column to give the desired N-(1(S)-ethoxycarbonyl-5-aminopentyl)-D,L-alanyl-L-proline. The mass spectrum of silylated material gave a peak at 559 m/e for the trisilylated derivative and a peak at 487 m/e for the disilylated derivative. The nmr (D2O) confirmed the structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:42]1[S:46][C:45]([C:47]([O:49]C)=[O:48])=[CH:44][C:43]=1[CH3:51].C(=O)([O-])[O-].[K+].[K+].O.C(O)C>CN(C)C=O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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>[CH3:51][C:43]1[CH:44]=[C:45]([C:47]([OH:49])=[O:48])[S:46][C:42]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Reactant: COC(=O)c1cc(C)c(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)sc1-c1ccc2c(N3CCOCC3)nncc2c1
Reaction time: 0.17 h

Procedure:
6-Bromo-1-morpholinophthalazine (405 mg, 1377 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (524 mg, 2065 μmol), potassium acetate (541 mg, 5507 μmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (101 mg, 138 μmol) were dissolved in N,N-dimethylformamide (4.6 mL) and placed in the microwave for 10 min at 160° C. The reaction mixture was added to a vial containing methyl 5-bromo-4-methylthiophene-2-carboxylate (388 mg, 1652 μmol), tetrakis(triphenylphosphine)palladium (159 mg, 138 μmol), potassium carbonate-2 M in water (2754 μl, 5507 μmol), and ethanol (4590 μl, 1377 μmol). The vial was placed in the microwave for 10 min at 160° C., cooled, diluted with 75 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous), and separated. The aqueous layer was acidified to pH 4 with conc. HCl and extracted 3× with 50 mL of chloroform. The combined organic layers were dried over sodium sulfate, and concentrated via rotovap to give a crude product, which was purified by chromatography to obtain the title compound, as the TFA salt. Found MS (ES+): 356(M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:24]=1
Reactant: OCc1cccnc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.30 g, 1.00 mmol), 3-pyridinemethanol (0.15 mL, 1.50 mmol) and triphenylphosphine (0.36 g, 1.36 mmol) in tetrahydrofuran (7 mL) under nitrogen was slowly added a solution of diethyl azodicarboxylate (0.29 g, 1.67 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred at ambient temperature for 21 h. The solvents were removed under reduced pressure, and the residue was taken up into 2 M sodium carbonate (50 mL) and extracted with dichloromethane (2×30 mL). The combined organic solution was dried with sodium sulfate, filtered and concentrated under reduced pressure. The filterate was purified by flash column chromatography with dichloromethane/isopropanol (49:1, increased to 29:1) to give a mixture of the desired product and triphenylphosphine oxide. This material was acidified with 1 M hydrochloric acid (30 mL) and extracted with diethyl ether (3×30 mL). The aqueous solution was made basic with 5 M sodium hydroxide and extracted with dichloromethane (3×30 mL). Once dried with sodium sulfate, the organic solution was concentrated under reduced pressure to afford 1′-(pyridin-3-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.22 g, 57%) as a colorless solid: mp 142-143° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.93-8.47 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 7.45-7.36 (m, 1H), 7.23 (ddd, J=7.8, 7.8, 0.9 Hz, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.19 (s, 1H), 5.09 (d, J=15.8 Hz, 1H), 4.924 (d, J=9.0 Hz, 1H), 4.919 (d, J=15.8 Hz, 1H), 4.66 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 2H), 4.14-4.09 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.4, 148.0, 147.5, 144.9, 141.5, 138.5, 137.0, 132.2, 129.1, 124.3, 124.0, 120.8, 111.5, 109.0, 99.6, 80.2, 64.6, 64.0, 58.1, 41.7; MS (ES+) m/z 386.7 (M+1).
Reaction SMILES: [C:1]([N:4]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:5]1([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([N:26]([S:30]([CH3:33])(=[O:32])=[O:31])C(=O)C)=[CH:25][C:19]=3[S:18](=[O:35])(=[O:34])[N:17]=2)[C:6]1=[O:36])(=[O:3])[CH3:2]>CO.C([O-])(O)=O.[Na+]>[CH2:43]([O:42][N:4]([C:5]1([CH2:37][CH2:38][CH:39]([CH3:41])[CH3:40])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:25][C:19]=3[S:18](=[O:34])(=[O:35])[N:17]=2)[C:6]1=[O:36])[C:1](=[O:3])[CH3:2])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(=O)N(OCc1ccccc1)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(N(C(C)=O)S(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)N(OCc1ccccc1)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 78.2 %

Procedure:
A solution of Example 24A (16 mg, 0.023 mmol) in methanol (0.4 mL) and 1N NaHCO3 (0.12 mL) was stirred at 25° C. for 1 h. The solution was concentrated in vacuo. Column chromatography on silica (5% methanol/dichloromethane) afforded the title compound (12 mg, 80%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.31-0.55 (m, 1H), 0.64 (dd, J=15.07, 6.62 Hz, 6H), 0.93-1.10 (m, 1H), 1.22-1.37 (m, 1H), 2.08 (s, 3H) 2.18-2.42 (m, 2H), 3.04 (s, 3H), 5.16-5.41 (m, 2H), 7.26-7.65 (m, 11H), 8.06 (d, 1H), 10.11 (s, 1H), 14.24 (br. s, 1H); MS m/z 666.4 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11]CC)=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH2:8][CH2:9][OH:10])[CH:7]=1
Reactant: CCOc1ccc(Br)cc1CCO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(5-bromo-2-ethoxyphenyl)-1-ethanol (18.86 g, 81.65 mmol) in 400 mL CH2Cl2 at −78° is added boron tribromide (16.98 mL, 179.6 mmol) dropwise, via syringe. After stirring at −78° for 15 minutes, the solution is warmed to room temperature and stirred for 1 hour. The reaction niuture is then poured into ice water (500 mL), shaken, and separated. The organic phase is wshed with water (1×250 mL) and brine (1×100 mL), dried over MgSO4, and concentrated in vacuo. Chromatography (silica, 2:1 hexane/EtOAc) yields 2-(5-bromo-2-hydroxyphenyl)-1-ethanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([O:20]CC)=[O:19])=[CH:6]2)[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[O:9][CH:8]([C:14]([F:15])([F:16])[F:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(CC)cc(C)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C)c2c(c1)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 6-ethyl-8-methyl-2- (trifluoromethyl)-2H-chromene-3-carboxylate (2.6 g, 8.3 mmol) in EtOH (90 mL), was added IN NaOH (24.8 mL, 24.8 mmol). The reaction was stirred at 25° C. for 18 h. The ethanol was removed from the reaction under reduced pressure. The residue was acidified with 2N HCl. The product was extracted into EtOAc (300 mL) then washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. The crude product was dissolved in 20 mL EtOAc and then diluted with 150 mL hexane. The resulting solution was chilled at 0° C. for 30 min. The product, which precipitated from the solution, was collected by filtration. The desired product was isolated as an off-white solid in quantities of 1.6 g (68%). 1H NMR (DMSO-d6) 1.15 (t, 3H, J=7.56 Hz), 2.16 (s, 3H), 2.51 (q, 2H, J=7.6 Hz), 5.89 (q, 1H, J=7.4 Hz), 7.11 (d, 1H, J=2.1 Hz), 7.14 (d, 1H, J=2.1 Hz), 7.79 (s, 1H).