Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:21][O:22][C:23]1[C:28]2[N:29]=[C:30]([CH2:32][O:33][CH3:34])[NH:31][C:27]=2[C:26]([C:35](ON2C3C=CC=CC=3N=N2)=[O:36])=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:3]1[C:2]([C:35]([C:26]2[C:27]3[N:31]=[C:30]([CH2:32][O:33][CH3:34])[NH:29][C:28]=3[C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)=[O:36])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Clc1cccc(Oc2ncccc2Br)c1
Reactant: COCc1nc2c(OC)ccc(C(=O)On3nnc4ccccc43)c2[nH]1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1nc2c(C(=O)c3cccnc3Oc3cccc(Cl)c3)ccc(OC)c2[nH]1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 18.8 %

Procedure:
A solution of 3-bromo-2-(3-chlorophenoxy)pyridine (0.43 g, Reference Example 16) in dry tetrahydrofuran (6 ml), at −70° C., was treated with butyl lithium in hexane (0.64 ml, 2.5 M). The mixture was then stirred at −70° C. for 45 minutes then treated with a solution of 1-benzotriazolyl 7-methoxy-2-methoxymethyl-3H-benzimidazole-4-carboxylate [0.177 g, Reference Example 1(a)] in dry tetrahydrofuran (2 ml) and stirring was continued at −70° C. for 10 minutes. The reaction mixture was allowed to warm to room temperature, then stirred at this temperature for 2 hours, then treated with aqueous ammonium chloride solution, and then extracted with ethyl acetate (20 ml). The organic extract was dried and concentrated to give a brown syrup which was purified by flash chromatography on silica eluting initially with a mixture of diethyl ether and pentane (1:1, v/v), then with a mixture of diethyl ether and pentane (7:3, v/v) and then with diethyl ether to give the title compound (0.04 g) as white solid, m.p. 181-183° C. [Elemental analysis:—C, 62.17, H, 4.32, N, 10.15%. Calculated :—C, 62.35, H, 4.28, N, 9.91%]. NMR (CDCl3):- δ 3.52(s, 3H), 4.13(s, 3H), 4.85(s, 2H), 6.73(d, J=8 Hz, 1H), 7.00(m, 1H), 7.12(t, J=2 Hz, 1H), 7.16(m, 1H), 7.2(dd,J=7 Hz,J=5 Hz, 1H), 7.28(t, J=8 Hz, 1H), 7.55(d, J=8 Hz, 1H), 7.85(dd,J=8 Hz,J=2 Hz, 1H), 8.83(dd,J=4 Hz,J=1 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[OH:1][CH:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(O)c4ccccc4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(O)c4ccccc4)s3)cc2)CC1

Procedure:
0.146 g of tert-butyl trans-(4-{4-[5-(3-hydroxy-3-phenylpropyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.27 mmol, 1 eq.) is placed in 2 mL of dichloromethane with stirring. 0.4 mL of TFA (5.45 mmol, 20 eq.) is added. After stirring for 4 hours, the reaction medium is evaporated and the residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 1% to 10%. The fractions of interest are concentrated, and triturated with ethyl acetate and methanol. 0.020 g of trans-(4-{4-[5-(3-hydroxy-3-phenylpropyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetic acid is obtained.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:11]=[C:10]([S:12]([O-:15])(=O)=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].P(Cl)(Cl)([Cl:18])=O>>[N+:2]([C:5]1[CH:11]=[C:10]([S:12]([Cl:18])(=[O:15])=[O:13])[CH:9]=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3]
Reactant: Nc1ccc(S(=O)(=O)[O-])cc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
A mixure of o-nitroaniline-p-sulfonic acid sodium salt (25.00 g, 104 mmol) and phosphoryl chloride (75 mL, 804 mmol) under Argon was heated to reflux and vigorously stirred for 4 hours. After cooling to ambient temperature, the reaction mixture was carefully added to a large excess of ice. The resulting slurry was stirred for 15 min., filtered and dried under vacuum to provide o-nitroaniline-p-sulfonyl chloride (21.43 g, 87%) as a yellow solid. H1-NMR (dimethylsulfoxide-D6): 5.8 (b, 2H), 6.97 (d, 1H, J=8.8), 7.57 (m, 1H), 8.18 (d, 1H, J=2.0).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[C:18]1([CH2:24][CH2:25][NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:26][CH2:25][CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=NCCc1ccccc1)NC#N
Yield: 40.9 %

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g) and 2-phenylethylamine (7.2 g) in acetonitrile (50 ml) was heated under reflux for 24 hours. Following concentration and ether extraction to remove excess 2-phenylethylamine the crude product was chromatographed on a column of silica gel and eluted with ethyl acetate-isopropyl alcohol (4:1). Recrystallisation from ethanol-ether afforded the title compound (1.4 g) m.p. 135°-136°. (Found: C, 59.8; H, 6.8; N, 24.8; S, 9.4%. C17H22N6S requires: C, 59.6; H, 6.5; N, 24.5; S, 9.4%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: OB(O)c1ccco1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: O=[N+]([O-])c1cccc(Cc2ccco2)c1
Yield: 92 %

Procedure:
Using the same method as in Example 19-(ii), 2-furanboronic acid was reacted with the 3-nitrobenzyl bromide to give 2-(3-nitrobenzyl)furan (yield: 92%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.I[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:18]2[C:19]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[CH:16][CH:17]=2)[CH:7]=1
Reactant: Cc1ccc(=O)[nH]c1
Reactant: Ic1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: Cc1ccc(=O)n(-c2cccc3ccccc23)c1
Yield: 68 %

Procedure:
5-Methyl-1-(1-naphthyl)-2-(1H)-pyridone is prepared by the reaction of 5-methyl-2-(1H)-pyridone and α-iodonaphthalene following the procedure of Example 1 but substituting anhydrous sodium carbonate for the potassium carbonate; yield 68%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.Cl[Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1.CCCCCC>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1Br
Reaction time: 0 h
Yield: 81 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with chlorotributylstannane (Bu3SnCl) (0.32 M) in THF (flow rate: 6 mL/min, 1.92 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The resulting solution was passed through the tube reactor R2 and was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=50 cm) was 1.78 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was concentrated, then the residue was subjected to silica gel column chromatography (hexane) to refine, 2-bromophenyltributylstannane was obtained as colorless oil in 81% yield, 146.6 mg. 1H NMR (400 MHz, CDCl3) δ: 0.88 (t, J=7.2 Hz, 9H), 1.12-1.17 (m, 6H), 1.27-1.38 (m, 6H), 1.51-1.60 (m, 6H), 7.10-7.15 (dt, J=7.6, 1.6 Hz, 1H), 7.18-7.23 (dt, J=7.6, 1.2 Hz, 1H), 7.27-7.31 (dd, J=7.6, 1.6 Hz, 1H), 7.44-7.50 (dd, J=7.6, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 11.0, 13.8, 27.4, 29.1, 126.1, 129.8, 131.5, 133.2, 137.8, 146.5. HRMS (EI) m/z: calcd. for C14H22BrSn (M+-C4H9) 388.9927, found 388.9925.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[NH2:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>C1COCC1>[OH:41][C:37]1[CH:36]=[C:35]([NH:34][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:33])[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3cccc(O)c3)c2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 50, 70 mg, 0.157 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (21 mg, 0.1924 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was recrystallized with ˜5 μmL of i-prOH affording the title compound in 67% yield (0.056 g, 0.1046 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(COc2ccc(-c3cc4ccccc4[nH]3)cc2)cc1
Reaction time: 4 h
Yield: 73.5 %

Procedure:
While stirring and under nitrogen, a mixture of 3.14 g (0.15 mol) of 2-(4'-hydroxy-phenyl)-indole, prepared as in Example 2, 2.1 g of anhydrous potassium carbonate and 100 ml of anhydrous acetone was refluxed and a solution of 50 ml of anhydrous acetone containing 1.8 ml (0.015 mol) of benzyl bromide was then added, drop-by-drop. The solution was heated for 4 hours and 0.4 ml (0.003 mole) of benzyl bromide was added with 0.5 g of potassium carbonate. Heating was continued for 4 hours and the hot solution was filtered. The filter was washed with 50 ml of acetone, the filtrate was concentrated under vacuum and was taken up in 100 ml of boiling methylethylketone. The hot reaction medium was filtered and the filtrate was cooled in an ice-bath for 30 minutes. The precipitate which was obtained was centrifuged and recrystallized from methylethylketone to give 3.3 g of 2-(4'-benzyloxy-phenyl)-indole.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Product: O=C1C(CCO)Oc2ccccc2N1Cc1ccccn1

Procedure:
2-(2-tert-Butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine was alkylated with 2-chloromethylpyridine by method F and the crude product was deprotected by method H without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:25][C:26]1([F:34])[CH2:31][CH2:30][CH:29]([CH:32]=O)[CH2:28][CH2:27]1>C1COCC1>[F:25][C:26]1([F:34])[CH2:31][CH2:30][CH:29]([CH:32]=[CH:4][C:3]([O:2][CH3:1])=[O:24])[CH2:28][CH2:27]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCC(F)(F)CC1
Solvent: C1CCOC1
Product: COC(=O)C=CC1CCC(F)(F)CC1
Reaction time: 6 h
Yield: 82.6 %

Procedure:
Methyl(triphenylphosphoranylidene)acetate (8.827 g, 26 mmol, 1.1 eq) is added at room temperature to a solution of 4,4-difluorocyclohexanecarbaldehyde (3.55 g, 24 mmol, 1 eq) in dry THF (60 ml). The mixture is stirred for 6 h and the solvent is evaporated. Hexane (50 ml) is added to the crude, the mixture is put a few minutes in an ultrasonic bath, stirred for 1 h and filtered. The filtrate is concentrated under reduced pressure to afford 4.05 g of methyl 3-(4,4-difluorocyclohexyl)prop-2-enoate a1-16.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:30]1([C:36]2[CH:43]=[CH:42][C:39]([CH2:40][OH:41])=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.CCOCC>C(Cl)(Cl)Cl>[CH:30]1([C:36]2[CH:37]=[CH:38][C:39]([CH:40]=[O:41])=[CH:42][CH:43]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: OCc1ccc(C2CCCCC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=Cc1ccc(C2CCCCC2)cc1
Reaction time: 0.33 h

Procedure:
18-Crown-6 (Aldrich; 4 molar eq.) and pyridinium chlorochromate (Aldrich; 4 molar eq.) were added together in chloroform and stirred for 20 minutes. 4-Cyclohexylbenzylalcohol (from Example D22 below; 1 molar eq.) was added and stirring continued for 3 hours. Ether was added and the mixture filtered through a plug of silica eluting with ether. The solvent was removed via rotary evaporation. The residue was dissolved in ether and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]#[C:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[N:16][N:17]=[C:18]2[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH2:1]([N:8]([CH2:10][CH:11]=[CH:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[N:16][N:17]=[C:18]2[CH2:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCN(C)Cc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C=CCN(C)Cc1ccccc1
Yield: 60.8 %

Procedure:
A solution of benzyl-{3-[1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl]-prop-2-ynyl}-methyl-amine (0.17 g, 0.36 mmoles), prepared as described in example 74, in THF (5 ml) and 10% Pd/C (0.07 g) was charged in a Parr apparatus at 2.7 atmospheres for 1.5 hours. The mixture was filtered over celite and dried to give an oil which was flash chromatographed (eluent: CH2Cl2/CH3OH/NH3 98:2:0.2, then 98:2:0.5). The resultant oil was crystallised from isopropyl ether to give 0.105 g of the title compound (yield: 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](C(C1C=CC=CC=1)C1C=CC=CC=1)[C:8](=[O:24])[CH:7]2[C:25]1[C:26]([OH:34])=[CH:27][C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C3(C4C=C(C)C(OC)=CC=4OC3)C2=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:24])[C:7]12[CH2:35][O:34][C:26]2[CH:27]=[C:28]3[C:29](=[CH:33][C:25]1=2)[CH2:30][CH2:31][O:32]3
Reactant: COc1cc2c(cc1C)C1(CO2)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: O=C1C(c2cc3c(cc2O)OCC3)c2cccc(Cl)c2N1C(c1ccccc1)c1ccccc1
Product: O=C1Nc2c(Cl)cccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 3 and making non-critical variations using 7-chloro-1-(diphenylmethyl)-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one to replace 1′-(diphenylmethyl)-6-methoxy-5-methylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one, 7′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp>250° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ11.01 (s, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.70 (d, J=7.1 Hz, 1H), 7.00-6.94 (m, 1H), 6.56 (s, 1H), 6.40 (s, 1H), 4.80 (d, J=9.4 Hz, 1H), 4.68 (d, J=9.4 Hz, 1H), 4.49 (m, 2H), 2.95 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.5, 161.0, 160.5, 139.4, 134.7, 128.4, 123.4, 122.3, 120.1, 119.8, 118.9, 113.8, 92.3, 79.8, 72.0, 58.0, 28.2; MS (ES+) m/z 313.7 (M+1), 315.7 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH:7]=[CH2:8].[OH-].[Na+]>C(C1C=CC=CC=1O)C=C.O>[CH2:1]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:6][CH:7]=[CH2:8])[CH:3]1[O:5][CH2:4]1
Reactant: C=CCc1ccccc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1ccccc1OCC1CO1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
This allyl phenyl ether was introduced into an autoclave and held at 200° C. for 5 hours with stirring. In this stage, a rearrangement reaction occurred to obtain 2-allylphenol. Into a reaction vessel, 134 g (1 mol) of the 2-allylphenol and 1.3 g of a boron trifluoride ether complex as a catalyst were introduced. In a nitrogen atmosphere, the contents were heated to 100° C. with stirring, and epichlorohydrin was added dropwise thereto in an amount of 1 mol per mole of the 2-allylphenol, with stirring the contents and maintaining that temperature. Thereafter, 100 g of 48% aqueous sodium hydroxide solution was added dropwise thereto at 60° C., and the resultant mixture was aged at 60° C. for 2 hours. Subsequently, 400 g of water was added thereto, and this mixture was stirred at 80° C. for 30 minutes and then allowed to stand still at 80° C. for 1 hour. The lower layer (aqueous layer) which had separated was removed, followed by dehydration at 100° C. under vacuum to obtain 2-allylphenyl glycidyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=O.O.NN.C(O)C>O>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C1CCSc2c(O)cccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: Oc1cccc2c1SCCC2
Temperature: 200 °C
Yield: 55 %

Procedure:
40 Grams of 8-hydroxy-thiochroman-4-one were added portion-wise to a mixture of 53.5 ml of hydrazine hydrate and 220 ml of ethanol. The reaction mixture was refluxed for 1 hour and then evaporated to dryness in vacuo. The residue was taken up in 250 ml of ethyleneglycol, and then 22.1 g of sodium hydroxide were added in pellet form. The whole was heated to refluxing, while the water of reaction was distilled off as it formed. The mixture was then heated for 4 hours at 200° C., allowed to cool and the bulk of glycol was expelled under vacuum. The residue was diluted with water and then acidified. The liberated phenol was extracted with chloroform. The chloroform extract was dried and evaporated and the residue distilled under vacuum, to yield 20.1 g of 8-hydroxy-thiochroman, boiling at 105°-110° C. under 0.08 mm Hg pressure, in a yield of 55%. After recrystallization from cyclohexane it melted at 86°-88° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH:14](=[O:18])[CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:18])[CH2:15][CH2:16][CH3:17])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCCC=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CCCC(O)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2,5-Dibromopyridine (1.08 g, 4.6 mmol) was azeotroped with toluene several times, then dissolved in anhydrous toluene (12 mL) under a nitrogen atmosphere. The resulting solution was cooled to −78° C. and n-butyl lithium (2.4 mL, 2.1 M in hexane, 5.0 mmol) was added dropwise, maintaining an internal temperature below −70° C. The resulting orange solution was stirred for 30 minutes at −78° C., then butyraldehyde was added. The resulting solution was stirred for 30 minutes at −78° C. then quenched by addition of saturated ammonium chloride. The resulting mixture was warmed to room temperature and diluted with ethyl acetate (25 mL) and water (25 mL). The layers were separated. The organics were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/−)-1-(5-bromopyridin-2-yl)butan-1-ol (738 mg, 70%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 8.57 (d, J=2.3 Hz, 1H), 7.77 (dd, J=8.3, 2.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 4.72-4.66 (m, 1H), 3.58 (d, J=5.7 Hz, 1H), 1.79-1.57 (m, 2H), 1.47-1.35 (m, 2H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=4)[C:20]([O-:22])=[O:21])[CH:16]=[C:11]3[C:10]([CH3:26])=[N:9]2)=CC=1.F[C:30](F)(F)[C:31](O)=O>C(Cl)(Cl)Cl>[CH3:26][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([O:22][CH2:30][CH3:31])=[O:21])[CH:16]=2)[NH:8][N:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(C(=O)[O-])c4)cnc32)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cccc(-c2cnc3[nH]nc(C)c3c2)c1
Temperature: 50 °C

Procedure:
To a solution of 3-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (118) (70 mg, 0.74 mmol) dissolved in chloroform (5 mL) was added trifluoroacetic acid (8 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 40% ethyl acetate in hexane as pale yellow solid of ethyl 3-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate 119 obtained in 10 mg quantity. MS m/z 281.9 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>CN(C=O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:13][C:14]2[N:15]=[N:16][NH:17][N:18]=2)=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: Nc1nnn[nH]1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.4 %

Procedure:
To a solution of 4-carboxybenzaldehyde (40.2 g, 0.27 mol) in DMF (400 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (65.5 g, 0.33 mol) followed by 5-aminotetrazol monohydrate (36.6 g, 0.35 mol). The mixture was stirred for 24 hours at ambient temperature. The reaction volume was then reduced to one half by rotary evaporation, and water (800 mL) was added. The precipitate was collected by filtration, washed with cold acetonitrile and dried overnight in a vacuum oven to afford 46.0 g (80%) of 4-formyl-N-(2H-tetrazol-5-yl)benzamide.