Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[NH:13][N:14]=2)=[N:4][C:5]([NH:27][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][N:23]=2)[CH3:26])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Nc2cc(C3CC3)n[nH]2)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Br)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 175 °C
Yield: 86 %

Procedure:
A mixture of 5-bromo-2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)pyrimidin-4-amine (Method 8; 0.062 g, 0.196 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 0.025 g, 0.178 mmol), and DIEA (0.04 ml, 0.214 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 175° C. for 20 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.064 g, 86%). 1H NMR (400 MHz) 12.48 and 12.09 (s, 1H), 9.32 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.00 (b, 1H), 7.92 (s, 1H), 7.64 (m, 1H), 7.41 (m, 1H), 5.94 and 5.85 (b, 1H), 5.06 (m, 1H), 1.84 (m, 1H), 1.45 (d, J=7.2 Hz, 3H), 0.95 (m, 1H), 0.86 (m, 1H), 0.74 (m, 1H), 0.63 (m, 1H). MS: Calcd.: 417. Found: [M+H]+418.
Reaction SMILES: Cl.Cl.C([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:25]2[C:24]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]4[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]4)=[C:29]([Cl:40])[CH:28]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH:19]=[CH:18]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.[F:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:55]=1[N:61]=[C:62]=[O:63]>O.O1CCCC1>[ClH:40].[Cl:40][C:29]1[CH:28]=[C:27]([NH:26][C:24]2[C:25]3[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:11])[CH:18]=[CH:19][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]1[CH2:35][CH2:36][N:37]([C:62]([NH:61][C:55]2[C:56]([F:60])=[CH:57][CH:58]=[CH:59][C:54]=2[F:53])=[O:63])[CH2:38][CH2:39]1
Reactant: O=C=Nc1c(F)cccc1F
Reactant: O=C(OCCOCCn1ccc2ncnc(Nc3ccc(OC4CCNCC4)c(Cl)c3)c21)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1c(F)cccc1F)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.4 %

Procedure:
To a mixture of 2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL) and tetrahydrofuran (5 mL) was added 2,6-difluorophenyl isocyanate (93 mg) with vigorous stirring. The mixture was stirred at room temperature for 2 hrs, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). 1N Aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→15:85). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (202 mg) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)([O-:3])=[O:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[C:7]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 89 %

Procedure:
Ethyl 4-nitroindole-2-carboxylate (26 g) [prepared according to S. M. Parmerter el. al. J. Amer. Chem. Soc., 1958, 80, 4621], 3,4-dichlorobenzyl chloride (16 ml), potassium carbonate (17 g) and potassium iodide (2 g) in DMF (250 ml) were stirred at 60° C. for 2 hours. The reaction was concentrated in vacuo and the residue partitioned between water and dichloromethane. Iso-hexane was added to the combined organic extracts resulting in crystallisation of the product as yellow needles (39 g. 89%) NMR d (CD3SOCD3) 1.30 (t, 3H), 4.32 (q, 2H), 5.93 (s, 2H), 6.88 (dd, 1H), 7.18 (d, 1H), 7.52 (d, 1H), 7.56 (dd, 1H), 7.78 (s, 1H), 8.17 (m, 2H); M/z (+) 395 (MH+), 393.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH:38]([CH3:40])[NH:37][CH:36]([CH3:41])[CH2:35]1)(=[O:33])=[O:32]>>[CH3:40][CH:38]1[NH:37][CH:36]([CH3:41])[CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:39]1
Reactant: CC1CN(S(=O)(=O)c2ccccc2Br)CC(C)N1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CC1CN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC(C)N1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and Racemic-1-((2-bromophenyl)sulfonyl)-3,5-dimethylpiperazine. MS (ESI): mass calcd. for C22H24FN5O2S, 441.16; m/z found, 442.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 8.24 (d, J=1.4, 1H), 8.17-8.14 (m, 1H), 7.99 (m, 1H), 7.79-7.73 (m, 1H), 7.68-7.63 (m, 1H), 7.49-7.46 (m, 1H), 7.37-7.32 (m, 2H), 3.49-3.42 (m, 2H), 3.14-3.01 (m, 2H), 2.47-2.39 (m, 2H), 1.17 (d, J=6.6, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Brc1nccs1
Product: FC(F)(F)c1ccc(-c2nccs2)cc1

Procedure:
Using (4-(trifluoromethyl)phenyl)boronic acid (0.5 g, 3.06 mmol) and 2-bromo thiazole (1.1 g, 61.3 mmol) and following the procedure described in Example 7, Step 1, the title compound was obtained after purification by flash chromatography (60-120 mesh, 2% ethyl acetate in hexane) as white solid (0.5 g, 83% Yield). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (d, 2H), 8.00 (d, 1H), 7.90 (d, 1H), 7.85 (d, 2H); LC-MS m/z calculated for [M+H]+ 230.02, found 230.1.
Reaction SMILES: C(OC(=O)[N:7]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])[C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]([Si](C(C)C)(C(C)C)C(C)C)[CH:16]=2)=[C:10]([F:37])[N:9]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][CH:16]=2)=[C:10]([F:37])[N:9]=1
Reactant: COc1cnc2c(c1)c(C(O)c1ccc(N(Cc3ccccc3Cl)C(=O)OC(C)(C)C)nc1F)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
To (2-chloro-benzyl)-{6-fluoro-5-[hydroxy-(5-methoxy-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (176, 400 mg, 0.598 mmol) in 20.0 mL of dichloromethane, triethylsilane (2.00 mL, 12.5 mmol) and trifluoroacetic acid (1.00 mL, 13.0 mmol) were added. The reaction was stirred at room temperature for 4 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound as a white solid (P-2034, 60.7 mg). MS (ESI) [M+H+]+=397.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[C:17]1([CH2:16][CH2:15][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH3:13])=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc2ccccc2n1CCc1ccccc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 37.9 %

Procedure:
Methyl 1H-indole-2-carboxylate (526 mg) and (2-bromoethyl)benzene (1.11 g) were dissolved in DMA (15 ml), cesium carbonate (2.93 g) was added, and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7) was concentrated under reduced pressure to give the object product (318 mg) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]I.[Cu]>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:28][C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(c1cccnc1Cl)N1CCCc2ccccc21
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=C(c1cccnc1Oc1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Temperature: 200 °C
Yield: 3.1 %

Procedure:
To a solution of (2-chloro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone (50 mg, 0.18 mmol, 1.0 equiv) and 3,4-dichloro-phenol (29.9 mg, 0.18 mmol, 1.0 equiv; [CAS RN 95-77-2]) in anhydrous DMF (1 mL) was added potassium carbonate (50.7 mg, 0.37 mmol, 2.0 equiv; [CAS RN 584-08-7]), copper(I) iodide (3.5 mg, 0.018 mmol, 0.1 equiv; [CAS RN 7681-65-4]) and copper(0) nanopowder with an averaged particle size of 100 nm (3.5 mg, 0.055 mmol, 0.3 equiv; [CAS RN 7440-50-8]). The reaction mixture was heated by microwave irradiation to 200° C. for 30 min. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 2.2 mg (3%) of the title compound. MS (ISP): 399.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[C:23]([F:24])=[C:22](Cl)[N:21]=[CH:20][N:19]=1)/[C:5]1[O:10][CH2:9][CH2:8][O:7][N:6]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[OH:33].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.CO.O.CN(C=O)C>[CH3:1][O:2]/[N:3]=[C:4](/[C:5]1[O:10][CH2:9][CH2:8][O:7][N:6]=1)\[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]1[N:19]=[CH:20][N:21]=[C:22]([O:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])[C:23]=1[F:24]
Reactant: Oc1ccccc1Cl
Reactant: CO/N=C(/C1=NOCCO1)c1ccccc1Oc1ncnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CO/N=C(/C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 75 %

Procedure:
To a solution of (E)-(2-((6-chloro-5-fluoropyrimidin-4-yl)oxy)phenyl)(5,6-dihydro-1,4,2-dioxazin-3-yl)methanone O-methyl oxime (14)(100 g, 0.564 mol) in toluene was added 2-chlorophenol (54 g, 0.846 mol), K2CO3 (50 g, 0.733 mol), and DMF (50 mL) at ambient temperature. The reaction mixture was stirred at 50-60° C. for 3-4 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, aqueous NaOH (10%) (200 mL) was charged followed by water (300 mL). The mixture was stirred and the toluene layer was separated. The toluene layer was washed with a solution of brine (600 mL). The final toluene layer was recovered completely to get the crude product. To the above crude product, methanol was charged and heated to 60° C. until the clear solution is formed. The solution was stirred at room temperature to get the pure product precipitated. The pure fluoxastrobin product was filtered and washed with methanol. The product was further dried to obtain the pure fluoxastrobin product meeting the desired specifications. Yield—75-88%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=3)[CH:21]=[CH:22][CH:23]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36][N:35]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2cccc(-c3ccc(C(=O)O)nc3)c2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2cccc(-c3ccc(C(=O)O)nc3)c2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 5-{3-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-pyridine-2-carboxylic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3:1) as a white solid, MS (ESI+): m/z=452.4 [M+H]+.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]3[C:25]([O:27]CC)=[O:26])=[CH:4][C:3]=2[O:2]1.OC1(C2C=CC3OCOC=3C=2)C2C(=CC=CC=2)C(C2C=CC=CC=2)=C1C(OCC)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]3[C:25]([OH:27])=[O:26])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Ethyl (RS)-1-(3,4-Methylenedioxyphenyl)-3-phenylindane-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in CH2Cl2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol). The reaction mixture was allowed to stir for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=S)[NH:11][NH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>Cl.C(O)C>[ClH:14].[CH2:19]([O:18][C:16]([C:15]1[C:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:11][NH:12][C:21]=1[CH3:23])=[O:17])[CH3:20]
Reactant: NNC(=S)NCCN1CCCCC1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NCCN2CCCCC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
A stirred solution of 6 g (0.03 mole) of 4-(2-piperidinoethyl)-3-thiosemicarbazide in 30 mL of 2N ethanolic hydrogen chloride was diluted to 60 mL with absolute ethanol, treated with 4.9 g (0.03 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 3 hr, and heated at reflux for 2 hr. The reaction mixture was filtered hot to remove amorphous sulfur and the filtrate concentrated to an orange oil. Trituration with refluxing 2-propyl ether and cooling gave a plastic mass with crystals. The 2-propyl ether was decanted and the residual material recrystallized from 2-propyl alcohol/2-propyl ether to give 8 g of crude product. A second recrystallization from 2-propyl alcohol/2-propyl ether gave 5.3 g of beige crystalline product, mp 198°-200° C. as the dihydrochloride salt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11]Br)[O:7][C:6]=2[CH:13]=1.[CH2:15]([NH2:18])[CH2:16][CH3:17]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:18][CH2:15][CH2:16][CH3:17])[O:7][C:6]=2[CH:13]=1
Reactant: CCCN
Reactant: Fc1cc(Br)cc2c1COC(CBr)O2
Solvent: CCO
Product: CCCNCC1OCc2c(F)cc(Br)cc2O1
Yield: 82.2 %

Procedure:
Preparation according to Example 3. 7-bromo-2-(bromomethyl)-5-fluoro-4H-1,3-benzodioxine (0.20 g, 0.60 mmol), propan-1-amine (1.0 ml, 12.2 mmol) and EtOH (3.0 ml)was heated at 130° C. for 20 min. Purification by flash column chromatography (EtOAc/MeOH 10:1) gave the title compound (0.15 g, 82%). The amine was converted into the oxalic acid salt and was crystallised with MeOH/DEE (0.17 g). M.p. 215° C. MS m/z (rel. intensity, 70 eV) 304 (M+, 3), 302 (M+, 3), 205 (10), 203 (10), 72 (bp).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[CH3:32])[CH:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[CH3:32])[CH:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)CC1CCc2cc(O)c(C)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CCc2cc(OS(=O)(=O)C(F)(F)F)c(C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of pyridine (0.13 mL, 1.61 mmol) in dichloromethane (1.0 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (0.25 mL, 1.47 mmol) was added. The resultant mixture was stirred for 5 min and methyl (5-hydroxy-6-methylindan-1-yl)acetate (295 mg, 1.34 mmol, from Step D) was added as a solid. The reaction mixture was warmed to ambient temperature, stirred for 30 min and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 405 mg of the title compound as a pale yellow liquid: 1H NMR (500 MHz, CDCl3) δ 1.69-1.91 (m, 1H), 2.33 (s, 3H), 2.38-2.56 (m, 2H), 2.69-2.79 (m, 1H), 2.79-3.01 (m, 2H), 3.49-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:26]([O-:28])=[O:27])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[N:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:11]=1)=[O:8].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C)C=O>[N+:26]([C:5]1[CH:4]=[CH:3][C:2]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[N:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:11]=1)=[O:8])([O-:28])=[O:27]
Reactant: O=C(Nc1ncn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ncn(-c2cccc(C(F)(F)F)c2)n1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 5-chloro-2-nitro-N-(1-(3-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-3-yl)benzamide (500 mg, 1.21 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), and piperidine (500 mg, 5.88 mmol, 4.84 equiv). The resulting solution was stirred overnight at 90° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of ethyl acetate. The resulting mixture was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 500 mg (90%) of product as white oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)(O)[O-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>O1CCCC1.O.C(OC(=O)C)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:20])[CH:18]=[CH2:19])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
2 g (12.81 mmol) of 4-fluoro-3-nitroaniline and 3.2 g (38.43 mmol) of sodium bicarbonate were diluted in 20 mL of tetrahydrofuran and 5 mL of distilled water, and 1.14 mL (14.09 mmol) of acryloyl chloride was slowly added thereto at 0° C., and stirred for 1 hour. Upon the completion of the reaction, the resulting mixture was diluted with ethylacetate and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, dried over anhydrous Na2SO4, and filtered and distilled under a reduced pressure to obtain 2 g of the title compound (yield: 74%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16]C)=O)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=O)C.C(OCC)(=O)C.[OH-].[NH4+:25]>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([NH2:25])=[O:16])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: COC(=O)Cc1ccc2c(ccn2C(C)=O)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)Cc1ccc2[nH]ccc2c1

Procedure:
A solution of 1-acetyl-1H-indole-5-acetic acid, methyl ester (1.46 g) in methanol (10 ml) and conc. ammonium hydroxide (20 ml) was stirred at ambient temperature for 48 h. The resulting solution was poured into ethyl acetate (100 ml). The layers were separated and the aqueous layer was washed with ethyl acetate (3×50 ml) and chloroform (3×50 ml). The organic layers were dried (MgSO4) and the solvent was evaporated to give a solid (0.72 g). Crystallisation from ethyl acetate gave the title compound as a white solid, (0.3 g) m.p. 146°-7°.