Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=1)[N:8]=[CH:7]2)([O-:3])=[O:2].[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=3)[N:9]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: O=[N+]([O-])c1ccc2nn(Cc3cccc(F)c3)cc2c1
Temperature: 70 °C
Reaction time: 12 h
Yield: 37 %
Yield: 32 %

Procedure:
5-nitroindazole (15 g, 92 mmol, 1 eq), 3-fluorobenzylbromide (14.7 mL, 119.5 mmol, 1.3 eq) and potassium carbonate 25.4 g (184 mmol, 2 equiv) were suspended in 150 mL acetonitrile. The reaction mixture was stirred at 70° C. for 12 h, and then allowed to cool to rt. The resultant solid was filtered and washed with CH2Cl2, and the filtrate concentrated in vacuo. The crude mixture of regioisomeric products was purified by column chromatography (5:1 to 4:1 Hex/EtOAc), yielding 5-nitro-1-N-(3-fluorobenzyl)indazole (7.9 g, 32%) and 5-nitro-2-N-(3-fluorobenzyl) indazole (9.2 g, 37%) as yellow solids.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([F:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([F:19])=[C:4]([F:20])[C:3]([F:21])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([O:24][C:23]([F:22])([F:34])[F:35])[CH:26]=3)[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(F)c(F)c1F
Product: Nc1nccc(Oc2cc(NC(=O)c3cccc(OC(F)(F)F)c3)c(F)c(F)c2F)c1[N+](=O)[O-]
Yield: 57 %

Procedure:
Method H was used with 4-(5-amino-2,3,4-trifluorophenoxy)-3-nitropyridin-2-amine and 3-(trifluoromethoxy)benzoyl chloride to afford the title compound (140 mg, 57%). 1H NMR δ (DMSO): 6.26 (d, 1H, Hpy,5, J=5.5 Hz), 7.35 (s, 2H, NH2), 7.55 (t, 1H, Harom,6′, J=6.5 Hz), 7.66 (d, 1H, Harom), 7.71 (t, 1H, Harom,5″, J=8.0 Hz), 7.91 (s, 1H, Harom,2″), 8.00 (d, 1H, Harom), 8.08 (d, 1H, HPy,6, J=5.5 Hz), 10.63 (s, 1H, NHamide). 19F NMR δ (DMSO): −56.28 (s, 3F, CF3), −141.42 (d, 1F, aromF, J=21.5 Hz), −152.31 (d, 1F, aromF, J=21.5 Hz), −156.04 (t, 1F, F3, J=21.5 Hz).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:39][CH:38]=2)[C:19](=[O:35])[C:20]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][C:30]([CH3:33])([CH3:32])[CH2:29][C:28]=3[CH:34]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:49]3[NH:3][C:4](=[O:7])[O:5][N:50]=3)=[CH:41][CH:42]=2)[C:19](=[O:35])[C:20]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][C:30]([CH3:32])([CH3:33])[CH2:29][C:28]=3[CH:34]=2)=[C:21]([CH3:23])[N:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)c(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.84 g), sodium hydrogen carbonate (1.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[2-butyl-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.72 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.35 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.68 g, 85%).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:23](O)[CH2:24][CH2:25]CC>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:1]=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]1[N:18]([CH3:21])[CH2:19][CH2:20][C:11]21[CH3:22])[C:3]([O:5][CH2:6][CH2:7][CH2:23][CH2:24][CH3:25])=[O:4]
Reactant: CCCCCO
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Agent: [Ti+4]
Agent: CC[O-]
Product: CCCCCOC(=O)C(=O)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: 25 °C

Procedure:
A solution of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, ethyl ester (2.89 g) in 1-pentanol (61 ml) was treated at 0° C. under a nitrogen atmosphere with titanium (IV) ethoxide (0.80 ml). The solution was warmed to room temperature and then slowly heated for 2.5 hours keeping the temperature between 60°-80° C. The excess 1-pentanol was removed by distillation under high vacuum. The residue was washed successively with 50 ml of saturated aqueous NH4Cl solution, two 100 ml portions of saturated aqueous NaHCO3 solution and 50 ml of brine. The organic phase was dried (Na2SO4), filtered and concentrated to afford an oil which was purified by chromatography using preparative HPLC (silica gel, 5% methanol in ethyl acetate). The appropriate fractions were combined and concentrated under vacuum to yield 2.2 g of 1,2,3,3a,8,8a-hexahydro-α-oxo-1,3a,8-trimethyl-5-pyrrolo[2,3-b]indole acetic acid, n-pentyl ester as an oil.
Reaction SMILES: Br.Br.[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:10].C1(=O)N([O:31][C:32](=O)[C@H:33]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])C(=O)CC1.C(OCC)(=O)C>CN(C)C=O.C(N(CC)CC)C>[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:10][C:32](=[O:31])[C@H:33]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
L-Phenylalanyl-L-histidine methyl ester dihydrobromide(1.75 g) is dissolved in a mixture of dimethylformamide (10 ml) and triethylamine(1.4 ml), and N-tert-butoxycarbonyl-L-phenylalanine succinimido ester (1.34 g) is added thereto. The mixture is stirred at room temperature overnight. Ethyl acetate is added to the mixture, and insoluble materials are filtered off. The filtrate is washed with an aqueous sodium bicarbonate solution, and an aqueous sodium chloride solution is added thereto. The precipitated crystals are washed with ethyl acetate and water and then dried to give N-tert-butoxycarbonyl-L-phenylalanyl-L-phenylalanyl-L-histidine methyl ester(1.5 g) as colorless crystals. Yield: 71.8%
Reaction SMILES: [N:1]1C=CC=CC=1C1N=NN(C2C=CC(NC3C4N(C=CN=4)C(C4C=CC(C(N)=O)=CC=4)=CN=3)=CC=2)C=1.[CH3:37][N:38]([CH3:54])[CH2:39][C:40]1[N:41]=[N:42][N:43]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][CH:46]=2)[CH:44]=1.[Sn](Cl)Cl>C1COCC1.CCO>[NH3:1].[CH3:54][N:38]([CH2:39][C:40]1[N:41]=[N:42][N:43]([C:45]2[CH:46]=[CH:47][C:48]([NH2:51])=[CH:49][CH:50]=2)[CH:44]=1)[CH3:37]
Reactant: CN(C)Cc1cn(-c2ccc([N+](=O)[O-])cc2)nn1
Reactant: NC(=O)c1ccc(-c2cnc(Nc3ccc(-n4cc(-c5ccccn5)nn4)cc3)c3nccn23)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)Cc1cn(-c2ccc(N)cc2)nn1
Product: N
Yield: 59 %

Procedure:
In the same way as described for Compound 154, step 2 using dimethyl-[1-(4-nitro-phenyl)-1H-[1,2,3]triazol-4-ylmethyl]-amine (0.178 g, 0.722 mmol), tin(II) chloride dehydrate (0.578 g, 2.54 mmol) in (1:1) THF/EtOH (4 mL). The residue is purified on Isolute FlashSilicaII cartridge eluting with 95:5 DCM:NH3 (7M in MeOH), to afford the desired compound as a yellow solid (93.2 mg, 59%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][OH:19])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:18][OH:19])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](/C=C/c1ccc(Br)cc1)CO
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a solution of [(E)-(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-allyl]-carbamic acid tert-butyl ester (14.7 g) in methanol (150 ml) was added 10% Pt/C (1.68 g) and the resulting mixture was stirred under a H2 balloon at room temperature for 3 hours (whereby the reaction progress was checked continuously by 1H NMR). The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford [(S)-3-(4-bromo-phenyl)-1-hydroxymethyl-propyl]-carbamic acid tert-butyl ester as a yellow solid (11.5 g, 78%). MS (ISP): 346.0 ([{81Br}M+H]+), 344.0 ([{79Br}M+H]+), 289.9 ([{81Br}M+H—C4H8]+), 288.0 ([{79Br}M+H—C4H8]+), 246.1 ([{81Br}M+H—C4H8—CO2]+), 244.1 ([{79Br}M+H—C4H8—CO2]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=2)[NH:32][C:33](=[O:35])[CH3:34])O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:31]([NH:32][C:33](=[O:35])[CH3:34])[CH:36]=[CH:37][CH:38]=4)[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)Nc1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acetanilide (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 112. NMR (CDCl3): 2.27 (3H, s), 4.33 (3H, s), 7.34 (1H, br), 7.52-7.68 (5H, m), 7.84 (1H, d), 7.85 (1H, s), 8.10 (1H, s), 8.26 (1H, s), 8.96 (1H, s). MS: MH+ 383.12 (100%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9]3[C:21]4[NH:20][C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]=4[C:12]4[C:22](=[O:25])[NH:23][CH2:24][C:11]=4[C:10]=3[C:4]=2[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>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>[C:26]1([C:2]2[CH:7]=[CH:6][C:5]3[CH2:8][C:9]4[C:21]5[NH:20][C:19]6[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=6)[C:13]=5[C:12]5[C:22](=[O:25])[NH:23][CH2:24][C:11]=5[C:10]=4[C:4]=3[CH:3]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(Br)cc1-3
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: O=C1NCc2c3c(c4[nH]c5ccccc5c4c21)Cc1ccc(-c2ccccc2)cc1-3
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of 3-bromo-5H,6H,12H,13H-indeno[2,3-a]pyrrolo[3,4-c]carbazole-7(7H)one (Compound I-9) (100 mg, 0.26 mmol), phenylboronic acid (35 mg, 0.29 mmol) and bis(triphenylphosphine)palladium(II) chloride (25 mg) in DMF (5 ml) was heated in a sealed reaction tube at 100°-110° C. for 24 hours. The mixture was cooled to ambient temperature, filtered through a pad of Celite® and concentrated at reduced pressure. The product was triturated with THF to give 77 mg of a brown solid which contained product and starting material. HPLC purification gave Compound I-27 as a tan solid. The melting point was greater than 300° C. The following NMR data were obtained: 1H NMR (DMSO-d6, 300 MHz): δ 4.2 (s, 2H), 5.05 (s, 2H), 7.3-7.55 (m, 5H), 7.7 (d, 2H, J=8 Hz), 7.8-7.9 (m, 3H), 8.2 (s, 1H); 8.6 (s, 1H), 9.4 (d, 1H, J=9 Hz), 12.0 (s, 1H). MS(FAB): m/e 387 (m+1)+.
Reaction SMILES: C(Cl)CCl.[C:5]1([CH3:14])[C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH2:25][NH:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[CH3:27][N:26]([CH2:25][C:17]1[N:16]([CH3:15])[C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:11](=[O:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH3:14]
Reactant: Cc1ccccc1C(=O)O
Reactant: CNCc1cc2ccccc2n1C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)N(C)Cc1cc2ccccc2n1C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
EDC (0.22 g, 1.15 mmole) was added to a solution of ortho-toluic acid (0.15 g, 1.10 mmole), 1-methyl-2-(methylaminomethyl)indole (0.20 g, 1.15 mmole), and HOBt.H2O (0.15 g, 1.11 mmole) in DMF at RT. The reaction was stirred overnight, then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over MgSO4. Flash chromatography on silica gel (20% EtOAc/hexanes) gave a colorless gum, which was triturated with Et2O to afford the title compound (0.2 g, 37%) as a white solid: 1H NMR (300 MHz, CDCl3) indicated an approximately 5:1 mixture of amide rotamers; for the major rotamer: δ 7.60 (d, J=7.7 Hz, 1H), 7.05-7.40 (m, 7H), 6.52 (s, 1H), 5.01 (s, 2H), 3.85 (s, 3H), 2.71 (s, 3H), 2.30 (s, 3H); for the minor rotamer: δ 7.60 (d, J=7.7 Hz, 1H), 7.05-7.40 (m, 7H), 6.44 (s, 1H), 4.52 (s, 2H), 3.50 (s, 3H), 3.14 (s, 3H), 2.37 (s, 3H); MS (ES) m/e 293 (M+H)+. Anal. Calcd for C19H20N2O.0.35H2O: C, 76.40; H, 6.99; N, 9.38. Found: C, 76.10; H, 6.83; N, 9.33.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.CCOC(C)=O.CCCCCC.[N+:24]([CH3:27])([O-:26])=[O:25]>>[N+:24]([CH:27]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)([O-:26])=[O:25]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])C=Cc1ccc2[nH]ccc2c1
Yield: 11 %

Procedure:
5-Formyl indole (14.5 g) was refluxed with NH4OAc (10.0 g) in nitromethane ((100 mL) for 3 hours. The mixture was cooled and evaporated under reduced pressure. The residue was recrystallized from isopropanol to give the first portion of intermediate and the mother liquid was purified by chromatograph (EtOAc:hexane=1:4 to 2:3) to the second portion intermediate of 5-(2-nitro-vinyl)-1H-indole (2.09 g combined, in 11% yield), which was treated with NaBH4 (1.85 g) in methanol (150 mL) at room temperature for 35 min then quenched with acetic acid (4 mL), concentrated and followed by chromatography purification (EtOAc:hexane=1:9) to afford 5-(2-nitro-ethyl)-1H-indole (1.37 g) in 65% yield. This nitro compound was hydrogenated with Pd—C (10%) under atmosphere hydrogen in methanol overnight to afford 2-(1H-indol-5-yl)-ethylamine in 99% yield. LC-MS showed the product had the expected M+H+ of 161.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:10]([O:8][C:1](=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:6])[OH:3])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: CCCCCO
Product: CCCCCOC(=O)CC(O)C(=O)OCCCCC
Temperature: 115 °C
Yield: 55.6 %

Procedure:
To the reaction flask, DL-malic acid (100.43 g), 1-pentanol (325 mL) and Amberlyst® 15 ion exchange resin (14.2 g) were added. The mixture was placed under nitrogen and heated to reflux. At 108° C., two phases started to collect in the Dean-Stark trap. The reaction was maintained at 110-120° C. for 4 hr 15 min and water was continuously removed. The product was separated from the catalyst via filtration over silica using 300 mL diethyl ether. The organic layer was washed 4 times with saturated sodium bicarbonate, washed once with water, and dried over magnesium sulfate. Diethyl ether was removed via rotary evaporation. Dipentyl-DL-malate was obtained as a low viscosity, slightly hazy, very light yellow liquid with a slight pleasant odor (116.5 g, 55.6% yield) after pumping on the sample in vacuo to remove residual 1-pentanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[K+].CO.O.[C:14](=S)=[S:15]>>[SH:15][C:14]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: Nc1ncccc1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Sc1nc2ncccc2o1

Procedure:
A mixture of 2-amino-3-hydroxypyridine and MeOCS2K [prepared from potassium hydroxide (6.2 g), methanol (96 ml), water (17.4 ml) and carbon disulfide (7.1 g)] was refluxed for 20 hr and filtered. The filtrate was neutralized with acetic acid and the resulting precipitate was collected, washed with water and dried to give 2-mercapto-oxazolo[4,5-b]pyridine (8.2 g).
Reaction SMILES: [Na+:1].[CH3:2][C:3]1[C:11]([CH3:19])([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[CH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24]>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:1].[CH3:19][C:11]1([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]([CH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:24])=[O:25])=[C:3]1/[CH:2]=[CH:12]/[CH:11]=[CH:3]/[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC1=[N+](CCCS(=O)(=O)O)c2ccccc2C1(C)CCCS(=O)(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(CCCS(=O)(=O)O)C(/C=C/C=C/Nc2ccccc2)=[N+](CCCS(=O)(=O)O)c2ccccc21
Temperature: 120 °C
Reaction time: 4 h

Procedure:
0.822 g (2 mmol) 2,3-dimethyl-1,3-bis-(3-sulfo-propyl)-3H-indolium sodium salt 7 and 0.65 g (2.5 mmol) malonaldehyde-bisphenylimine-hydrochloride are dissolved in a mixture of 10 ml acetic acid and 20 ml acetic anhydride and stirred at 120° C. for four hours. The solvent is removed in vacuum after cooling to room temperature. The residue is washed carefully with ethyl acetate. A dark brown solid is obtained which is processed without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]([F:12])([F:11])[F:10])=[C:3]1[CH3:13].N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:23]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]([F:10])([F:11])[F:12])=[C:3]1[CH3:13])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC1=C(CC(F)(F)F)C(=O)CC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1=C(CC(F)(F)F)C(=O)CC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
After 10 g of (RS)-4-hydroxy-3-methyl-2-(2,2,2-trifluoroethyl)cyclopent-2-en-1-one and 4.2 g of imidazole were dissolved in 100 ml of dry dimethylformamide, 8.54 g of t-butyldimethylchlorosilane was added to the solution at an ambient temperature. After stirring at an ambient temperature for 12 hours, the reaction solution was added to 5% aqueous citric acid under ice-water cooling, and extracted three times with diethyl ether. The combined organic layer was washed successively with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was subjected to silica gel column chromatography to yield 14.3 g of (RS)-4-t-butyldimethylsilyloxy-3-methyl-2-(2,2,2-trifluoroethyl)cyclopent-2-en-1-one. Yield 90% (Eluent: n-hexane/ethyl acetate=5/1 (v/v))
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH:9]([OH:15])[C:10]([O:12]CC)=[O:11])=[CH:3][CH:2]=1.O.O1CCCC1.Cl>[OH-].[Na+]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH:9]([OH:15])[C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(O)CSc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(O)CSc1ccc(-c2ccccc2)cc1
Yield: 76.4 %

Procedure:
A mixture of ethyl 3-(4-biphenylylthio)lactate (0.093 g, 0.31 mmole), in NaOH (0.5 ml), water (2 ml) and tetrahydrofuran (1 ml) was stirred overnight at 25° C. The mixture was acidified (1 N HCl, 0.5 ml) and then extracted with methylene chloride (3×5 ml). The residue from evaporation of the methylene chloride was recrystallized from acetonitrile to yield 0.065 g of 3-(4-biphenylylthio)-2-hydroxypropionic acid, m.p. 175.5°-176° C.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:40])[NH:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=5)=[CH:27][C:26]=4[NH:41][C:42]4[C:43]5[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=5[N:45]=[CH:46][N:47]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=3)=[O:40])=[CH:27][C:26]=2[NH:41][C:42]2[C:43]3[CH:51]=[CH:50][C:49]([CH:52]([CH3:54])[CH3:53])=[N:48][C:44]=3[N:45]=[CH:46][N:47]=2)=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Cl)cn4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A solution of the product of Example 52F (167 mg, 0.2185 mmol) in 1,4-dioxane (4 mL) was treated with a solution of lithium hydroxide monohydrate (18.3 mg, 0.437 mmol) in water (2 mL) at ambient temperature, then heated at 60° for 40 minutes. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (30 mL), adjusted the aqueous pH to 6 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 5% methanol/methylene chloride afforded the title compound as a yellow solid (84 mg, 71%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.15-3.30 (m, 1 H) 5.62 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.77-6.89 (m, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.64 (d, J=8.09 Hz, 1 H) 7.87 (d, J=8.46 Hz, 1 H) 7.95 (dd, J=8.82, 2.57 Hz, 1 H) 8.04 (s, 1 H) 8.21 (d, J=9.19 Hz, 1 H) 8.42 (d, J=2.57 Hz, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.92 (s, 1 H); MS (ESI+) m/z 542/544 (M+H)+.