Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[OH:14])=[CH:7][CH:6]=1.[N+](=[CH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N-].O>C1(C)C=CC=CC=1.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[O:14][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:7][CH:6]=1
Reactant: OC1CCc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COC1CCc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reaction time: 8 h

Procedure:
Rhodium (II) acetate dimer (approximately 10mg) was suspended in a solution of the indanol (Example 3, step B, 0.5g) in dry toluene (10 cm3). A solution of ethyl diazoacetate (0.18g) in a small volume of dry toluene was slowly added dropwise to the reaction mixture. Effervescence was observed, the solid dissolved and the solution turned a blue green colour. The mixture was allowed to stand at room temperature overnight then poured into water. The aqueous mixture was extracted with diethyl ether, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Preparative thin layer chromatography (silica/hexane-ether, 7:3) gave compound 3, ethyl (RS)-6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indan-1-yloxyacetate, as a colourless oil (0.17g,27%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:9]([C:11]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13])#[N:10]>C(Cl)Cl>[C:9]([C:11]([CH2:21][CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:13])#[N:10]
Reactant: C1COCCN1
Reactant: CCC(C#N)(C(=O)Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCC(C#N)(C(=O)N1CCOCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
4.4 g (0.05 mole) of morpholine are dissolved in 50 ml of methylene chloride, 20 ml of a 20% aqueous sodium hydroxide solution are added to it, and the mixture is cooled to a temperature below -10° C. with salted ice. 10.5 g (0.05 mole) of 2-cyano-2-ethyl-2-phenylacetyl chloride are added to the mixture in portions, under vigorous stirring. The reaction mixture is stirred at 0° C. for one hour, thereafter the phases are separated from each other, the organic phase is washed twice with dilute aqueous hydrochloric acid, dried over a mixture of anhydrous magnesium sulfate and potassium carbonate, filtered, and the solvent is evaporated. 10.3 g (81%) of 2-cyano-2-ethyl-2-phenylacetic acid morpholide are obtained; m.p.: 87°-89.5° C.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:41])[N:35]6[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]6)[C:20]5=[N:19][C:18]=4[CH3:42])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:45]1(=[O:51])[O:50][C:48](=[O:49])[CH2:47][CH2:46]1.C(N(C(C)C)CC)(C)C.O>ClCCl>[F:1][C:2]1[CH:44]=[CH:43][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:35]6[CH2:40][CH2:39][N:38]([C:45](=[O:51])[CH2:46][CH2:47][C:48]([OH:50])=[O:49])[CH2:37][CH2:36]6)=[O:41])[C:20]5=[N:19][C:18]=4[CH3:42])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCNCC1
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCN(C(=O)CCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-9-((6-oxo-6-(piperazin-1-yl)hexyl)oxy)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in Step B, (239 mg, 0.39 mmol) in dichloromethane (5 mL), under argon, was treated with succinic anhydride (43.15 mg, 0.43 mmol) and diisopropylethylamine (68.35 μL, 0.39 mmol). After stirring for 2 h at room temperature, the reaction mixture was poured into water (5 mL), and the aqueous layer was extracted with dichloromethane/methanol (95/5, three times 5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC and triturated with diisopropylether, to give the title compound. (ESI-MS (M+1) 709); 1H NMR: (CDCl3, 360 MHz): δ ppm 1.10-2.80 (m, 31H), δ 3.20-4.00 (m, 13H), δ 4.24-4.30 (m, 1H), δ 7.07 (td, J=8.97, 1.83 Hz, 1H), δ 7.24 (d, J=1.83 Hz, 1H), δ 7.76 (dd, J=8.60, 4.94 Hz, 1H)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2([CH3:23])[O:22][CH2:21][CH2:20][O:19]2)=[CH:11][CH:10]=1)=[O:7])[CH3:4].O.[Na+].[Cl-].C1[CH2:31][O:30][CH2:29]C1>>[CH3:23][C:18]1([CH2:17][CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([N:8]3[CH2:4][C@H:3]([CH2:29][O:30][CH3:31])[O:5][C:6]3=[O:7])=[CH:14][CH:13]=2)[O:19][CH2:20][CH2:21][O:22]1
Reactant: CCOC(=O)Nc1ccc(CCCC2(C)OCCO2)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC[C@H]1CN(c2ccc(CCCC3(C)OCCO3)cc2)C(=O)O1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a suspension of 1.96 g (0.041 mol) of NaH (50% in oil) in 100 ml of THF, are added 5 g (0.017 mol) of compound 360274 (Method 3--Step 2), dissolved in 25 ml of THF. After 30 min. of stirring at 30° C.-40° C., are added 4.64 g (0.017 mol) of compound 360065 dissolved in 25 ml of THF and the reaction medium is heated at 50° C.-60° C. for 22 h. The reaction medium is cooled and poured on 500 ml of water. The aqueous phase is saturated with NaCl and extracted with ethyl acetate and then with methylene chloride. The organic phases are dried over Na2SO4 and concentrated. The residue is taken up in ethyl ether. After treatment by animal black, the ethereal solution is concentrated and the product is recrystallized from isopropanol alcool with a 30% yield. The obtained product has the same physical characteristics as those obtained by Method 1.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+].[CH2:29]([NH2:31])[CH3:30]>C1COCC1>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][NH:31][CH2:29][CH3:30])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Reactant: CCN
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCNCc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (37 mg) and potassium iodide (5 mg) were mixed in ethylamine in THF (2M, 3 ml) and the reaction stirred at room temperature for 18 hours. The excess amine was evaporated under vacuum and the residue purified by preparative HPLC. After evaporation of the solvent this gave N-cyclopropyl-4′-{5-[(ethylamino)methyl]-1,3,4-oxadiazol-2-yl}-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.CN1CCN([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)CC1>>[CH2:2]1[C:42]2[C:41](=[CH:47][CH:46]=[C:44]([NH:45][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-(4-methyl-1-piperazinyl)aniline by a procedure similar to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.48-2.54 (m, 4H overlapping with d6-DMSO), 3.02-3.10 (m, 4H), 6.52 (d, 1H, J=5.2 Hz), 6.88 (d, 2H, J=8.8 Hz), 7.15 (t, 1H, J=6.0 Hz), 7.29 (t, 2H, J=8.0 Hz), 7.37 (d, 1H, J=7.8 Hz), 7.46-7.66 (m, 5H), 7.85 (d, 1H, J=8.7 Hz), 8.04 (s, 1H), 8.25 (d, 1H, J=5.2 Hz), 8.45 (bd, 1H, J=8.9 Hz), 8.97 (d, 1H, J=6.9 Hz), 9.31 (s, 1H), 10.98 (s, 1H); ESIMS (M+H)+=617.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc23)CC1
Yield: 41.9 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol) 4-nitrobenzoic acid, 13.8 mg (41.8%) of the title compound were recovered.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[C:6]([NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[CH:20]=3)[C:17](=[O:28])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH:20]=3)[C:26]#[N:27])[C:17](=[O:28])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)#[N:2]
Reactant: N#Cc1cccc(C(=O)Nc2nonc2-c2noc(=O)n2-c2ccc(F)c(C#N)c2)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Product: N#Cc1cccc(CNc2nonc2-c2noc(=O)n2-c2ccc(F)c(C#N)c2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of 3-cyano-N-{4-[4-(3-cyano-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}benzamide (30 mg, 72 μmol) in benzene (2 mL) at 0° C. was treated with phosphorus pentachloride (45 mg, 0.22 mmol) and stirred at 90° C. for 2 h. The reaction mixture was concentrated, diluted with ethanol (2.5 mL), treated with sodium cyanoborohydride (14 mg, 0.22 mmol), and stirred for 16 h. The reaction mixture was purified by preparative LCMS to give the intermediate 5-[3-{4-[(3-cyanobenzyl)amino]-1,2,5-oxadiazol-3-yl}-5-oxo-1,2,4-oxadiazol-4(5H)-yl]-2-fluorobenzonitrile. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.2 mL), and stirred for 45 min. Purification of the crude reaction mixture by preparative HPLC gave the desired product (3 mg, 11%). LCMS for C18H13FN7O2 (M+H)+: m/z=378.0.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1>CO.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(C=Cc2ccnc(N)c2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(CCc2ccnc(N)c2N)cc1
Reaction time: 17 h
Yield: 59.1 %

Procedure:
1.52 g of 2-amino-4-(2-p-tolyl-ethenyl)-3-nitropyridine (starting material N2) are dissolved in 30 ml of methanol and, after addition of 0.25 g of 10% strength palladium on carbon, are hydrogenated at 45° C. for 17 hours. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is chromatographed on a silica gel column (dichloromethane/methanol 25:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 0.80 g of the title compound as a brownish solid of m.p. 119–121° C. The mass spectrum shows the molecular peak MH+ at 228.2 Da.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:45]/[O:46]C(=O)C)/[C:22]([NH:24][C@@H:25]2[C:43](=[O:44])[N:27]3[C:28]([C:40]([OH:42])=[O:41])=[C:29]([S:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH2:30][S:31][C@H:26]23)=[O:23])[N:20]=1.[Cl-].[NH4+].Cl>O.CO>[NH2:15][C:16]1[S:17][CH:18]=[C:19](/[C:21](=[N:45]/[OH:46])/[C:22]([NH:24][C@@H:25]2[C:43](=[O:44])[N:27]3[C:28]([C:40]([OH:42])=[O:41])=[C:29]([S:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)[CH2:30][S:31][C@H:26]23)=[O:23])[N:20]=1
Reactant: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cccnc3)CS[C@H]12)c1csc(N)n1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cccnc4)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.9 %

Procedure:
A solution of 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(3-pyridyl)methylthio]-3-cephem-4-carboxylic acid bis(trifluoroacetic acid) salt (3.85 g, 5.05 m mol) and ammonium chloride (810 mg, 15.2 m mol) in a mixture of water (116 ml) and methanol (11.6 ml) was stirred at room temperature for 2.5 hours with keeping pH 8. The reaction mixture was adjusted to pH 6 by addition of 1N HCl. Methanol in the mixture was removed by evaporation in vacuo. The aqueous solution was adjusted to pH 5 and chromatographed on HP-20 (100 ml) and eluted with 5-10% aqueous isopropanol. The eluent was lyophilized. To the crude product was added water and acetonitrile. The precipitates were collected by filtration, washed with water and dried in vacuo to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(hydroxyimino)acetamido]-3-[(3-pyridyl)methyl-thio]-3-cephem-4-carboxylic acid (445 mg, 0.903 m mol).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:14]=1[CH2:22][CH2:23][CH:24]=O>>[F:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([F:21])=[CH:15][C:14]=1[CH2:22][CH2:23][CH:24]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: COc1cc(F)c(CCC=O)cc1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)c(OC)cc1F

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (9.700 mmol) and 3-(2,5-difluoro-4-methoxy-phenyl)-propionaldehyde (2.135 g; 10.670 mmol) afforded 8-[2-(2,5-difluoro-4-methoxy-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.72 min.; [M+H]+=447.67 g/mol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH:26]1[CH2:25][CH:24]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[N:9]2)[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanecarboxylate (0.81 g, 0.0018 mol) in dichloromethane (5 mL) was slowly added a 20% solution of trifluoroacetic acid in dichloromethane (10 mL) at 0° C. under an atmosphere of nitrogen. The mixture was warmed to room temperature and stirred for eighteen hours. The solvent was removed under reduced pressure. An aqueous solution of 5 N sodium hydroxide was added to the residue to pH 11 at 0° C. The water phase was extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.44 g, 0.0012 mol).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31].C(NS(C1SC(CC(C)C)=CC=1C1C=CC(CN2C=CN=C2)=CC=1)(=O)=O)(C)(C)C>CC(C)=O.C(OCC)(=O)C>[CH2:28]([NH:32][C:33]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCN=C=O
Agent: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Reaction time: 0.17 h
Yield: 33 %

Procedure:
The crude product from step (c) above was dissolved in acetone (5 mL) under N2 (g). NaOH (0.20 mL, 1M, 0.20 mmol) was added to the mixture, which was then stirred for 10 min. Butyl isocyanate (109 μL, 0.97 mmol) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. Purification using column chromatography with CHCl3:MeOH (10:1) as eluent yielded the title compound (15.1 mg, 0.032 mmol) in 33% yield (from 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonic acid tert-butylamide).
Reaction SMILES: [F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:26](=[O:27])[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:19])=[C:13]([CH3:28])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:26](=[O:27])[C:25]3[C:20](=[N+:21]([O-:37])[CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:19])=[C:13]([CH3:28])[CH:12]=1)([C:7]([F:9])([F:8])[F:10])[C:3]([F:6])([F:5])[F:4]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N1C(=O)c2cccnc2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N1C(=O)c2ccc[n+]([O-])c2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
In 25 ml of chloroform was dissolved 3.1 g of N-[4-(heptafluoro-2-propyl)-2-methylphenyl]pyridine-2,3-dicarboximide, and 5.0 g of m-chloroperbenzoic acid was added thereto at room temperature. After the resulting mixture was stirred at room temperature for 3 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography using ethyl acetate/n-hexane as an eluent, to obtain 820 mg (yield: 84%) of the desired compound.
Reaction SMILES: C([N:4](CC=C)[S:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[CH:25]=[N:26][C:27]([O:31][CH3:32])=[C:28]([Cl:30])[CH:29]=2)[CH:19]=1)(=[O:17])=[O:16])(=[O:7])=[O:6])C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.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>[Cl:30][C:28]1[CH:29]=[C:24]([C:20]2[CH:19]=[C:18]([S:15]([NH:14][C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[S:5]([NH2:4])(=[O:6])=[O:7])(=[O:16])=[O:17])[CH:23]=[CH:22][CH:21]=2)[CH:25]=[N:26][C:27]=1[O:31][CH3:32]
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)c1cccc(-c2cnc(OC)c(Cl)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: COc1ncc(-c2cccc(S(=O)(=O)Nc3ccncc3S(N)(=O)=O)c2)cc1Cl
Temperature: 100 °C
Yield: 49 %

Procedure:
A solution of N,N-diallyl-4-(3-(5-chloro-6-methoxypyridin-3-yl)phenylsulfonamido)pyridine-3-sulfonamide (0.19 g, 0.36 mmol) in dichloromethane (5 mL) was added to tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.022 mmol) and 1,3-dimethylbarbituric acid (0.336 g, 2.15 mmol) under an atmosphere of argon. The reaction was heated at 100° C. for 15 min in a microwave reactor and the reaction mixture was concentrated. Purification by column chromatography, using chloroform/methanol (95:5-9:1) as the eluent, gave the title compound in 49% yield.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])=[C:8]([NH:19][C:20](=[O:38])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:23][CH:22]=2)[CH:7]=1)(=[O:5])[CH3:4].CO.O1CCCC1>O>[C:3]([C:6]1[CH:18]=[CH:17][C:9]([O:10][CH2:11][C:12]([OH:14])=[O:13])=[C:8]([NH:19][C:20](=[O:38])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:23][CH:22]=2)[CH:7]=1)(=[O:5])[CH3:4]
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)c1ccc(OCC(=O)O)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
A 1N sodium hydroxide aqueous solution was added to a mixture of 0.5 g of ethyl 4-acetyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 53, 5 ml of methanol and 5 ml of tetrahydrofuran and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 10 ml of water. The mixture was concentrated under reduced pressure to remove methanol and tetrahydrofuran. Diluted hydrochloric acid was added to the residue to render acidic. The formed crystals were taken by filtration and recrystallized from isopropyl alcohol to obtain 0.39 g of 4-acetyl-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetic acid.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[CH3:7][C:8]([S:11]([NH2:13])=[O:12])([CH3:10])[CH3:9]>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH3:7][C:8]([S:11]([N:13]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:12])([CH3:10])[CH3:9]
Reactant: CCC(=O)CC
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)=NS(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a 40 mL vial, pentan-3-one (1.049 ml, 9.90 mmol) was dissolved in THF (17 ml). Titanium ethoxide (3.42 ml, 16.50 mmol) was added followed by addition of 2-methylpropane-2-sulfinamide (1.0 g, 8.25 mmol) and the reaction was heated to 90° C. for 36 hr. The reaction was poured into equal volume of brine and stirred for 30 min before filtration through a silica gel pad. The filtrate was dried with sodium sulfate, concentrated and purified over silica gel (hexane-EtOAc 4:1 as eluent) to provide title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 (m, 3 H) 1.06-1.13 (m, 3 H) 1.14 (s, 9 H) 2.50 (m, 2 H) 2.62 (m, 2 H). MS (DCI) m/z 190 (M+H)+.