Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C(O)(=O)C(O)=O>C(O)(=O)C.O>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:15])=[C:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)cc1

Procedure:
4,6-Di-t-butyl-2-(4-methoxybenzyl)phenol was prepared as follows: A solution of 2,4-di-t-butylphenol (57.5 g), 4-methoxybenzyl alcohol (34.5 g) and oxalic acid (2 g) in acetic acid (80 ml) and water (2 ml) was refluxed for 7 hours, diluted with water, and extracted with chloroform. Distillation of the chloroform extract gave an oil (b.p. 200°-210° C. at 2 mm Hg) which crystallized (58 g; 71.4%). The product was recrystallized from methanol to give glistening colorless needles, m.p. 84°-85° (Found: C, 81.0; H, 8.21. Calc. for C22H30O2 : C, 80.9; H, 9.26%). The pmr spectrum exhibited the following: δ1.30, 9H, S; δ1.38, 9H, S; δ3.79, 3H, S; δ3.83, 2H, S; δ4.62, 1H, S; δ6.84, 2H, D (J=8 Hz); δ7.02, 1H, D (J=2 Hz); δ 7.14, 2H, D (J=8 Hz); δ7.23, 1H, D (J=Hz).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.ClC(Cl)C>C(O)(=O)C>[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:8]3[C:9]4[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=4)[CH2:6][CH2:7]3)[CH2:20][CH2:19]2)=[CH:25][CH:26]=1
Reactant: Brc1ccc2c(c1)NCC2
Reactant: O=C1CCN(CCc2ccc(F)cc2)CC1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Fc1ccc(CCN2CCC(N3CCc4ccc(Br)cc43)CC2)cc1
Reaction time: 2 h
Yield: 58 %

Procedure:
Triacetoxylated sodium borohydride (298 g) was added over 30 min to a mixture of 6-bromoindoline (175 g), 1-(4-fluorophenethyl)-4-piperidone (194 g), acetic acid (250 ml) and dichloroethane (2.5 l) followed by stirring 2 hr. Then the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate (2 l), an 8 N aqueous solution of sodium hydroxide (1 l) and water (500 ml) and the layers were separated. The organic layer was washed successively with water (0.5 l) and brine (0.5 l), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot ethyl acetate (500 ml) and then cooled with ice water. The resulting crystalline precipitates were collected by filtration to give the title compound (205 g) (yield: 58%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[C@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:20])=[CH:13][CH:14]=2)[C:9]1([CH2:23][CH3:24])[CH2:21][CH3:22])(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:7][C@@H:8]1[C:9]([CH2:23][CH3:24])([CH2:21][CH3:22])[C:10]2[CH:11]=[C:12]([OH:20])[CH:13]=[CH:14][C:15]=2[CH2:16][C@H:17]1[O:18][CH3:19]
Reactant: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC1(CC)c2cc(O)ccc2C[C@@H](OC)[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.2 %

Procedure:
To a solution of trans-(1,1-diethyl-7-hydroxy-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid tert-butyl ester (6.0 g, 17.2 mmol) in dichloromethane (60 mL) was added a solution of 4.0 N HCl in dioxane (21.5 mL, 86 mmol) over approximately 2 min. After stirring at room temperature overnight, the reaction mixture was concentrated at reduced pressure and dried under vacuum to give the hydrochloride salt of the title compound (5.5 g) (m/z): [M+H]+ calcd for C15H23NO2 250.36; found 250.2. 1H NMR (d6-DMSO, 400 mHz) δ (ppm) 9.26 (s, 1H), 8.09 (br s, 3H), 6.92 (d, J=8.0 Hz, 1H), 6.61 (m, 2H), 3.77 (m, 1H), 3.41 (s, 3H), 3.30 (dd, J=15.8 Hz, 5.9 Hz, 1H), 3.17 (m, 1H), 2.43 (dd, J=15.5 Hz, 9.6 Hz, 1H), 1.85 (m, 2H), 1.66-1.50 (m, 2H), 0.66 (t, J=7.4 Hz, 3H), 0.54 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N.[C:36]([O:40][C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[CH:49])=[CH:44][CH:43]=1)([CH3:39])([CH3:38])[CH3:37]>C(#N)C.[Cu]I.CCN(CC)CC>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:49]#[C:48][C:45]2[CH:46]=[CH:47][C:42]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:50])=[CH:43][CH:44]=2)=[CH:9][CH:8]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Cu]I
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 8 h

Procedure:
4-Bromo-benzoic acid tert.-butyl ester, 5.1 g of triphenylphosphine and 375 ml of NEt3 are introduced into 1 l of absolute acetonitrile under nitrogen and N2 is passed through the solution for 20 minutes. 10.5 g of (Pφ3)2PdCl2 and 1.5 g of copper(I)iodide are then added and 166.5 g of 4-ethinyl-benzoic acid tert.-butyl ester dissolved in 1 l of absolute acetonitrile are slowly added dropwise under reflux and the reaction mixture is stirred overnight. The resulting reaction mixture is then suction filtered after cooling, stirred up in water, again suction filtered, dissolved in CH2Cl2 and filtered after the addition of a small quantity of Tonsil, and the solvent is then evaporated off under vacuum. 225 g of 4,4'-Tolan-dicarboxylic acid-di-tert.-butyl ester are obtained.
Reaction SMILES: C(OC(C1CCCN1C(=O)C(NC(=O)[C:18]1[CH:23]=[CH:22][C:21](N)=[C:20]([Cl:25])[CH:19]=1)C)=O)(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35]CC2C=CC=CC=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[Cl:25][C:20]1[CH:21]=[CH:22][C:23]([CH2:35][O:34][CH:32]2[CH:31]([NH:43][C:44]([CH:46]3[CH2:50][CH2:49][CH2:48][N:47]3[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]3[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=3)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]2)=[CH:18][CH:19]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccc(Cl)cc1
Yield: 65 %

Procedure:
Prepared from 97a and syn-[2-(4-chloro-benzyloxy)-5-oxo-tetrahydro-furan-3-yl]-carbamic acid allyl ester following the method used for 98a to afford 154 mg (65% yield) of the title compound as a pale pink solid. HPLC (C18 column) 10.597 min; 1H-NMR (500 MHz, CDCl3) δ 1.14 (d, J=6.8 Hz, 0.75H), 1.34, (d, J=6.8 Hz, 2.25H), 1.6 (br, 0.25H), 1.91 (m, 1H), 2.03 (m, 1H), 2.10 (m, 1H), 2.29 (m, 0.75H), 2.40 (dd, J=17.3, 10.3 Hz, 0.75H), 2.51 (m, 0.25H), 2.82 (dd, J=17.3, 8.5 Hz, 0.75H), 3.08 (dd, J=17.9, 10.9 Hz, 0.25H), 3.58 (m, 1H), 3.72 (dd, J=16.5, 8.7 Hz, 0.75H), 4.10 (m, 0.25H), 4.22 (d, J=8.0 Hz, 0.25H), 4.39 (d, J=10.8 Hz, 0.25H), 4.54 (dd, J=9.1, 2.9 Hz, 0.75H), 4.60 (d, J=11.9 Hz, 0.75H), 4.68 (m, 1H), 4.85 (d, J=11.7 Hz, 0.75H), 4.86 (m, 1H), 5.49 (d, J=5.2 Hz, 0.75H), 5.81 (d, J=5.2 Hz, 0.25H), 6.2 (br, 0.25H), 6.74 (m, 2H), 7.05 (d, J=8.5 Hz, 0.5H), 7.17 (d, J=8.4 Hz, 0.5H), 7.30 (m, 3.25H), 7.48 (dd, J=8.4, 2.0 Hz, 0.75H), 7.56 (d, J=1.9 Hz, 0.25H), 7.73 (d, J=1.9 Hz, 0.75H), 8.42 (d, J=5.7 Hz, 0.25H) ppm; LC-MS (ES+) m/e=563, 565 (M+H).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][CH2:5]1.CN(C)C=O.Cl[C:22]1[N:31]=[C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]3[O:40][CH2:41][O:42][C:36]=3[CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:43])[CH:28]=2)[N:23]=1>O>[C:10]1([CH:7]2[O:6][CH2:5][CH:4]([O:3][C:22]3[N:31]=[C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]5[O:40][CH2:41][O:42][C:36]=5[CH:35]=4)[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:43])[CH:28]=4)[N:23]=3)[CH2:9][O:8]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(OC3COC(c4ccccc4)OC3)nc(NCc3ccc4c(c3)OCO4)c2c1
Temperature: 80 °C
Yield: 27.8 %

Procedure:
100 mg of sodium hydride was added to a mixture comprising 300 mg of 5-hydroxy-2-phenyl-1,3-dioxane and 5 ml of dimethylformamide. The obtained mixture was heated to 80° C. After the bubbling had been discontinued, 300 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline was added in a crystalline state. The obtained mixture was heated at 140° C. for 2 hours and cooled, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography using an ethyl acetate/benzene mixture to give 118 mg of 2-(2-phenyl-1,3-dioxan-5-yl)oxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. 100 mg of this compound was hydrolyzed with concentrated hydrochloric acid/ethanol by a conventional process to give 60 mg of the title compound through rearrangement.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:12]I.O>O1CCCC1>[CH3:12][O:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)(C)C(=O)OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A solution of methyl 3-hydroxy-2,2-dimethylpropionate (25.0 g) in tetrahydrofuran (300 ml) was added dropwise to a suspension composed of a 60% oil suspension of sodium hydride (8.32 g) and tetrahydrofuran (100 ml) under ice cooling, and the mixture was stirred at 60° C. for 1 hour. Methyl iodide (53.7 g) was added to the reaction mixture, and the resultant mixture was stirred at room temperature for 2 hours. Water was carefully added to conduct extraction twice with methylene chloride. After the resultant organic layer was washed with saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resultant oil was distilled to obtain the title compound (12.8 g).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH:14]([CH:17]=O)[CH:15]=O>>[Br:13][C:14]1[CH:15]=[C:11]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]2=[N:12][CH:17]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Product: Brc1cnc2[nH]nc(-c3ccccc3)c2c1
Yield: 13 %

Procedure:
5-bromo-3-phenyl-1H-pyrazolo[3,4-b]pyridine x151 is synthesized according to the method described in example 20.1 using 3-phenyl-1H-pyrazol-5-amine x150 and bromomalonaldehyde x9.
Reaction SMILES: [H-].[Na+].Cl[C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C1OCCOCCOCCOCCOC1.O>O1CCCC1>[C:17]([O:16][C:14]([N:13]1[CH:5]2[CH2:6][C:7]3[C:12]([CH:4]12)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1Cc2ccccc2[C@H]1Cl
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Temperature: 50 °C
Yield: 97.8 %

Procedure:
To a suspension of NaH (80% disp. in oil, 2.016 g, 67.2 mmol) in dry tetrahydrofuran (300 ml) was added (±)trans-1-chloro-2-tert-butoxycarbonylaminoindane (15 g, 56 mmol) and 15-crown-5 (50 μl). The mixture was then warmed at 50° C. under nitrogen for 18 h after which it was poured into water (700 ml) and extracted with diethyl ether (3×150 ml). The combined organic extracts were dried (Na2SO4) and solvents were removed in vacuo to afford the title compound as a brown solid (12.67 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(Cl)Cl>[C:9]([NH:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])[CH3:10]
Reactant: Nc1cccnc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cccnc1N
Yield: 56.6 %

Procedure:
2,3-Diaminopyridine (28 g, 0.256 mole) and acetic anhydride (30 mL, 0.38 mole) were stirred at room temp in methylene chloride (770 mL) for 30 min. The mixture was concentrated in vacuo to a brown solid. Recrystallization from methylene chloride/hexane (10/1) gave off-white crystals (21.9 g, 57%) of 3-acetamido-2aminopyridine. This acetamide was combined with 3-chloro-2,4-pentanedione (20 g, 0.146 mole) in abs. ethanol (350 mL) and stirred under reflux for 20 hrs. After cooling, the mixture was diluted with methylene chloride (300 mL) and washed with water (3×300 mL). The organic phase was dried over magnesium sulfate and concentrated to a green solid. Recrystallization from methylene chloride/hexane (1/1) gave the title compound as green crystals (7.3 g, 21%, m.p. 173°-175° C.).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Cl:10][C:11]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:12]=1[CH2:13][S:14]([CH2:17][C:18](O)=[O:19])(=[O:16])=[O:15]>C(O)(=O)C>[Cl:10][C:11]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:12]=1[CH2:13][S:14]([C:17]1[C:18](=[O:19])[O:4][C:3]2[C:2]([CH:1]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:15])=[O:16]
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1Cl
Reactant: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: O=c1oc2ccccc2cc1S(=O)(=O)Cc1ccc(Cl)cc1Cl
Yield: 86 %

Procedure:
A solution of salicylaldehyde (1 mmol) and 2-(2,4-dichlorobenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate an 86% yield of the title compound; m.p. 228-229° C.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[C:10]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>CC(O)=O>[N+:6]([C:13]1[CH:12]=[CH:11][C:10]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[CH:15][CH:14]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Temperature: 25 °C

Procedure:
A solution of conc. H2SO4 (2.65 mL) in AcOH (40 mL) and a solution of conc. HNO3 (2.1 mL) in AcOH (20 mL) are added sequentially and dropwise to a solution of 4-phenylpiperidine in AcOH (40 mL), maintaining the temperature below 20° C. Then, conc. H2SO4 (40 mL) is added (no cooling applied; internal temperature reaches 60° C.). The reaction mixture is allowed to cool to RT, poured onto ice/water (100 g), neutralized by addition of solid NaHCO3 (150 g), and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by trituration in Et2O to afford the title compound as a yellow solid. ESI-MS: 207.1 [MH]+; tR=2.42 min (system 1).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>ClCCl>[Br:37][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: OCCOc1ccc(Oc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of 2-(4-Phenoxy-phenoxy)-ethanol (2.2 g, 9.55 mmol), triphenylphosphine (2.76 g, 10.5 mmol), and dichloromethane (DCM) (36.7 mL) after stirring at 0° C., was added N-Bromosuccinimide (1.87 g, 10.5 mmol). The resulting mixture was stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. Reaction mixture was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (2.5 g, 89%): 1H NMR (400 MHz, CDCL3).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]1([CH2:7][CH2:8][NH:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1NCCc1ccccc1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mass of 4.8 g (0.04 mol) of 2-phenylethylamine was added dropwise, at ambient temperature, to a mixture of 5.6 g (0.04 mol) of 2-fluoronitrobenzene and 11.06 g (0.08 mol) of anhydrous potassium carbonate in 30 ml of DMSO. The mixture was heated at 100° C. for 3 hours. The mixture was then cooled to ambient temperature and was added to 100 ml of water, which resulted in the precipitation of a light orange compound. The solid was recovered by filtration and dried using a desiccator at reduced pressure. A mass of 9.4 g of orange crystals was obtained with a yield of 98%. The melting point found was coherent with the theoretical value, i.e. 64-66° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C@H:4]([CH2:6][SH:7])[NH2:5].[CH:9]([CH2:11][CH2:12][CH2:13][C@H:14]([N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])[C:15]([OH:17])=[O:16])=O>O1CCCC1.C(Cl)(Cl)Cl>[C:15]([CH:14]([N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23])[CH2:13][CH2:12][CH2:11][CH:9]1[NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:8])[CH2:6][S:7]1)([OH:17])=[O:16]
Reactant: O=CCCC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)[C@@H](N)CS
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1CSC(CCCC(C(=O)O)N2C(=O)c3ccccc3C2=O)N1

Procedure:
A solution of L-cysteine methyl ester (1.71 g) and 5-formyl-2(S)-phthalimidopentanoic acid (3.49 g) in 120 ml of tetrahydrofuran was stirred under nitrogen for 2.5 hours and then taken to dryness to yield a white foam. This residue was dissolved in 250 ml of chloroform and washed with water (2×30 ml). The combined aqueous layers were back extracted with chloroform (2×30 ml). The organic layers were dried (Na2SO4) and then concentrated in vacuo to give a white foam, 4.83 g. Tlc on silica [4:1 Ethyl acetate:acetic acid] indicated a major spot at Rf =0.72. Exact mass measurement showed a molecular ion at 392.1024 (calcd. 392.1041). 'H NMR spectrum (CDCl3) showed a multiplet at δ7.72 (4H) and a singlet at δ3.78(3H).
Reaction SMILES: ClCl.[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:15]=[C:14](S)[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]=1[N+:17]([O-:19])=[O:18].C(O)(=O)C.[S:25]([Cl:29])(Cl)(=[O:27])=[O:26]>O>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:14]([S:25]([Cl:29])(=[O:27])=[O:26])[CH:15]=[C:6]([C:5]([O:4][CH3:3])=[O:20])[C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: COC(=O)c1cc(S)cc(C(=O)OC)c1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)Cl
Agent: ClCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(S(=O)(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
Chlorine gas is passed into a stirred slurry of 6.4 g. of dimethyl-2-nitro-5-mercaptoisophthalate in a mixture of 50 ml. of acetic acid and 15 ml. of water. The temperature of the reaction rises to 70° C. as all the solid goes into solution. Introduction of chlorine is continued as a heavy precipitate forms. Stirring is continued for 15 min.; then the mixture is diluted with 300 ml. of water. The solid is collected, washed with water and dried, giving 7.5 g. of the sulfonyl chloride, m.p. 124°-125° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:25]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([SH:37])=[CH:33][C:32]=1[CH3:38])[CH3:26].O>C(#N)C>[CH2:25]([O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][C:3]2[O:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])=[CH:33][C:32]=1[CH3:38])[CH3:26]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Reactant: CCOC(=O)COc1ccc(S)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(SCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (0.30 g, 1.8 mmol) and Cs2CO3 in 8 mL acetonitrile is added (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.25 g, 1.1 mmol). The solution is stirred for 6 hrs and poured into water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organics are washed with water (10 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product is purified using flash column chromatography (10%-20% ethyl acetate/hexanes) to afford 0.40 g (79%) of {2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethylsulfanyl]-phenoxy}-acetic acid ethyl ester. To a stirred solution of this ester (0.21 g, 0.44 mmol) is added m-CPBA (50%) (0.31 g, 0.89 mmol) at 0° C. After 10 min. the solution is poured into water (50 mL) and extracted with methylene chloride (3×20 mL). The combine methylene chloride layers are washed with 1 N NaOH (25 mL), water (25 mL) and brine (25 mL), dried (Na2SO4), filtered and concentrated in Vacuo. The crude sulphone is purified using flash column chromatography (10%-25% ethyl acetate hexanes) to give 0.15 g (68%) of {2-Methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethanesulfonyl]-phenoxy}-acetic acid ethyl ester. Hydrolysis of this sulphone (0.15 g, 0.30 mmol) occurred under the usual conditions (3 eq. of a 1N solution of LiOH in 1 mL of a 3:2:1 solution of THF:MeOH:H2O) to provide the title compound 0.11 g (78%) after workup with aq. NH4Cl and ethyl acetate.
Reaction SMILES: [NH2:1][OH:2].[C:3]1([C:9]2([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[O:14][CH2:13]C=[CH:11][O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C>C(O)C>[OH:2][N:1]=[C:19]([C:18]1[CH:17]=[CH:16][C:15]([C:9]2([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:14][CH2:13][CH2:11][O:10]2)=[CH:22][CH:21]=1)[NH2:20]
Reactant: NO
Reactant: N#Cc1ccc(C2(c3ccccc3)OC=CCO2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccc(C2(c3ccccc3)OCCO2)cc1
Yield: 102 %

Procedure:
) Hydroxylamine (0.0449 mol) was added to a mixture of 4-(2-phenyl-1,3-dioxin-2-yl)benzonitrile (0.022 mol) in ethanol (88 ml). Then, N,N-diethylethanamine (0.0449 mol) was added dropwise and the resulting reaction mixture was stirred and refluxed for 3.5 hours. The solvent was evaporated. The residue was washed with water and this mixture was extracted with EtOAc. The separated organic layer was dried (Na2SO4), filtered and the solvent was evaporated, yielding 6.38 g of N′-hydroxy-4-(2-phenyl-1,3-dioxolan-2-yl)benzenecarboimidamide (interm. 10)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:30][C:31](O)=[O:32])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[NH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[N:11]=[C:10]3[N:27]([CH2:30][C:31]([NH2:34])=[O:32])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Reactant: N
Product: NC(=O)Cn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Yield: 36 %

Procedure:
Following a similar procedure to that described in example 48, but using 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid (obtained in example 45) instead of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid, and aqueous NH3 instead of morpholine, the title compound was obtained (yield: 36%).