Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(NCC)C.CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(OCC)(=O)C>[N+:9]([C:7]1[CH:8]=[CH:2][C:3]([NH2:4])=[CH:5][CH:6]=1)([O-:11])=[O:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Nc1ccc([N+](=O)[O-])cc1

Procedure:
Into a 300 mL four-necked flask, 2-iodo-4-nitroaniline (22.5 g, 85.4 mmol), bis(triphenylphosphine)palladium dichloride (1.20 g, 1.71 mmol), and copper iodide (0.651 g, 3.42 mmol) were charged, and nitrogen substitution was carried out, and then diethylamine (43.7 g, 598 mmol) and N,N-dimethylformamide (128 mL) were added thereto, followed by addition of the above-described t-butyl N-propargylamino-N-t-butoxycarbonyl acetate while stirring with ice-cooling, and further stirring at room temperature for 20 hours. After completion of the reaction, 1 L of ethyl acetate was added thereto, and then washing with 150 mL of a 1 mol/L ammonium chloride aqueous solution was carried out three times and washing with 150 mL of a saturated sodium chloride aqueous solution was carried out once, followed by drying by magnesium sulfate. Thereafter, the solvent was removed by evaporation under reduced pressure to precipitate a solid material, and then the solid material was dissolved in 200 mL of ethyl acetate, followed by addition of 1 L of hexane to carry out recrystallization. The solid material was collected by filtration and dried under reduced pressure, thereby to obtain a yellow solid material of 2-{3-(N-t-butoxycarbonyl-N-t-botxycarbonylmethylamino)-1-propynyl)}-4-nitroaniline (compound (A7)). The total amount of yield was 23.0 g, and the yield rate was 66%.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][NH:2][CH2:10][CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: CN(CCn1cncn1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCn1cncn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled solution (ice bath) of 1-{2-[N-methyl-N-(t-butoxycarbonyl)amino]ethyl}-1,2,4-triazole (Method 24; 1.6 g, 7.2 mmol) in DCM (10 ml) was added trifluoroacetic acid (5 ml). The reaction mixture was stirred for 3 hours at 0° C. and then at room temperature for 1 hour. The reaction mixture was evaporated to dryness with toluene and the crude product was dissolved in DCM (3 ml) and concentrated HCl in ether was added dropwise under vigorous stirring to yield the title compound as a white solid M/z 126.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.O.O.O.[F:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13]>C(OCC)(=O)C>[NH2:1][C:2]1[S:3][C:4]([C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])[C:11]([F:19])([F:18])[F:10])=[CH:5][N:6]=1
Reactant: Nc1nccs1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(C(O)(C(F)(F)F)C(F)(F)F)s1
Temperature: 100 °C
Yield: 73.1 %

Procedure:
A catalytic amount of molecular sieves powder (4A) was added to a mixture of 2-aminothiazole 200 mg (2 mmol) and hexafluoroacetone trihydrate (880 mg, 4 mmol). The mixture was heated at 100° C. for 8 h. Ethyl acetate was added and the mixture was filtered. Organic solvents were evaporated under reduced pressure. The residue was recrystallized in THF and hexanes to afford the title product (389 mg) as a white solid. 1H NMR (DMSO-d6) δ7.12 (s, 1H), 7.45 (brs, 2H), 8.85 (s, 1H); ESIMS: m/z 267 (M+H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.O[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1.Cl.C(N=C=NCCCN(C)C)C>O.C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[N:35]=[N:34]4)=[O:23])=[CH:25][CH:26]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)no2)cc1
Reaction time: 3 h
Yield: 94.9 %

Procedure:
4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (14.7 kg) obtained in Example 3, tetrahydrofuran (147 L), dimethylformamide (118 L) and 1-hydroxybenzotriazole (7.9 kg) were added at 20–25° C. to a 1500-L glass-lined vessel. And then, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (13.6 kg) was added and stirred for 3 hours at this temperature. The reaction mixture was cooled to below 10° C., and then ethyl acetate (480 L) and water (120 L) were added dropwise at below 25° C. After cooling to 2–7° C., the slurry was stirred for 1 hour at this temperature. The product was collected on a stainless centrifuge and washed with acetonitrile (74 L). The damp solid was dried in a stainless vacuum dryer under vacuum to give 1-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyloxy]-1H-1,2,3-benzotriazole (18.6 kg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH:11](O)[CH3:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2)[CH3:12]
Reactant: CC(O)c1cccc2ncccc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Cl)c1cccc2ncccc12
Temperature: 0 °C

Procedure:
The alcohol, 1-quinolin-5-yl-ethanol (5.0 g, 28.9 mmol) in chloroform was treated with a dropwise addition of thionyl chloride (5.26 mL, 72.1 mmol) at rt. After 1 h the mixture was cooled to 0° C. and carefully quenched with a sat. solution of NaHCO3 followed by 2M NaOH until the pH was >8. The aqueous layer was extracted with chloroform and the organic fractions were combined, dried over MgSO4, filtered, and freed of solvent. The residue was purified by chromatography on SiO2 eluting with 30% ethyl acetate:hexane. The product, 5-(1-chloro-ethyl)-quinoline (Intermediate E1) was obtained as a clear oil, 4.22 g (76%).
Reaction SMILES: [CH2:1]([C:4]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:5]=1[CH2:6][O:7][CH2:8][C:9]1[CH:40]=[C:12]2[N:13]=[C:14]([CH3:39])[C:15]([C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:16]([N:17]3[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=[CH2:27])([CH3:23])[CH2:19][CH2:18]3)[N:11]2[N:10]=1)C=C.[BH4-].[Na+]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[C:35]([O:34][C@@H:28]([C:15]1[C:14]([CH3:39])=[N:13][C:12]2=[CH:40][C:9]3=[N:10][N:11]2[C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([CH3:23])([O:24][CH2:25][CH2:26][CH2:27][CH2:1][C:4]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:5]=2[CH2:6][O:7][CH2:8]3)[CH2:19][CH2:18]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:37])([CH3:38])[CH3:36]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cc(F)ccc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A mixture of (S)-ethyl 2-(2-(((2-allyl-4-fluorobenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (70 mg, 0.112 mmol) and Grubbs II catalyst (95 mg, 0.112 mmol) in DCM (70 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). Sodium borohydride (4.25 mg, 0.112 mmol) was added and the reaction mixture was stirred at rt for 1 h. It was then extracted with EtOAc, washed with water. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOac/hexane to isolate ethyl (2S)-2-(tert-butoxy)-2-{16-fluoro-4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetate (30 mg, 0.050 mmol, 44.7% yield) as a white solid. LCMS (M+1)=597.3.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][OH:8])=[C:4]([CH3:9])[CH:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:6][C:5]([CH2:7][OH:8])=[C:4]([CH3:9])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)sc1CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1CO
Temperature: 100 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
A mixture of 62.5 (0.100 g, 0.48 mmol), 4-(trifluoromethyl)benzeneboronic acid 61.1 (0.183 g, 0.97 mmol), K2CO3 (0.200 g, 1.45 mmol), and Pd(PPh3)4 (0.056 g, 0.05 mmol) in toluene (3.2 mL) was stirred overnight at 100° C. The mixture was cooled to room temperature, filtered through a pad of silica gel (EtOAc), and concentrated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexane) to afford 62.6 (0.063 g, 48%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, 2H), 7.61 (d, 2H), 7.14 (s, 1H), 4.79 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:33])([CH3:32])[O:6][CH:7]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:8]([C:10]1[CH:25]=[CH:24][C:13]2[N:14]=[C:15](Cl)[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]=2[CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O.C(Cl)Cl>C1COCC1>[CH2:34]([NH:41][C:15]1[N:16]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:33])[CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:25]=[CH:24][C:13]=2[N:14]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)S(=O)(=O)n1c(Cl)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(NCc2ccccc2)nc2ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c3ccccc3)cc21
Temperature: 40 °C
Yield: 80 %

Procedure:
To a stirred solution of starting 2-(tert-butyl-dimethyl-silyloxy)-1-[2-chloro-3-(propane-2-sulfonyl)-3H-benzimidazol-5-yl]-2-phenyl-ethanone (588 mg, 1.16 mmol, 1 equiv) in 2 mL of dry THF, add benzyl amine (0.4 mL, 3.48 mmol, 3 equiv) dropwise. Heat the resulting yellow solution at 40° C. for 30 minutes, cool down to room temperature, and add water and CH2Cl2. Separate the phases and back extract the organic one with more CH2Cl2 (three times). Dry the combined organic phases over MgSO4, filter, and concentrate in vacuo to afford crude product. Purify by chromatography using CH2Cl2:hexanes (3:1) to provide the title compound (80% yield). MS(ES+): m/z=578.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH:27]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:29][C@H:30]([C:32]([O:34][CH3:35])=[O:33])[CH3:31].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:29][C@H:30]([C:32]([O:34][CH3:35])=[O:33])[CH3:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Reactant: COC(=O)[C@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)[C@H](C)NCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 35 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (395 mg), methyl L-alaninate (206 mg) and acetic acid (60 mg) in DCM (10 mL) was added NaBH(OAc)3 (424 mg). The mixture was stirred at 35° C. overnight. After cooled to room temperature, the reaction mixture was diluted with DCM (10 mL), washed with water and saturated sodium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulphate. The solvent was evaporated and the residue was purified by Mass Directed Auto Prep to afford methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-L-alaninate (D81) as a white solid (160 mg). MS (ES): C26H27ClN4O4 requires 482; found 380.1 (M—C4H8NO2+).
Reaction SMILES: [N:1]1([CH2:6][C:7]([N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]3[C:20](=[O:23])[NH:21][N:22]=[C:12]3[C:11]3[CH:24]=[CH:25][CH:26]=[N:27][C:10]2=3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N:30]1([CH2:35][CH2:36]Cl)[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C=O.C1(C)C(C)=CC=CC=1>[N:30]1([CH2:35][CH2:36][N:21]2[C:20](=[O:23])[N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:9]([C:7](=[O:8])[CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:10]4[N:27]=[CH:26][CH:25]=[CH:24][C:11]=4[C:12]3=[N:22]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ClCCN1CCCC1
Reactant: O=C(CN1CCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: O=C(CN1CCCC1)N1c2ccccc2-n2c(nn(CCN3CCCC3)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 2,9-dihydro-9-[(pyrrolidino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling (2-pyrrolidinoethyl)chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-(2-pyrrolidinoethyl)-9-(pyrrolidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[CH:3]=[C:2]1[CH:12]=[O:13].[BH4-].[Na+]>CO>[OH:13][CH2:12][C:2]1[O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[CH:3]=1
Reactant: O=Cc1cc(=O)c2ccccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1cc(CO)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
A mixture of 4H-1-benzopyran-4-one-2-carboxaldehyde (400 mg, 0.0023 m) and sodium borohydride (8.8 mg. 0.0023 m) in methanol (20 ml) was stirred at room temperature for 30 minutes. The solvent was removed at reduced pressure to give a white solid. The solid was washed with water, sucked dry, and recrystallized from ethanol to give white crystals (220 mg, 55%), m.p. 165°-167°.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH3:11][PH:12](=[O:14])[CH3:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][P:12]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)([CH3:13])=[O:14]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C[PH](C)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CP(C)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 79.5 %

Procedure:
To a solution of 1-iodo-3-nitrobenzene (2.4 g, 9.6 mmol) in dry 1,4-dioxane (24 ml) in a pressure bottle under nitrogen at room temperature was added dimethylphosphine oxide [WO 2005/009348] (1.5 g, 19.2 mmol), Pd2(dba)3 (0.44 g, 0.48 mmol), Xantphos (0.56 g, 0.96 mmol) and cesium cabonate (4.38 g, 13.5 mmol). The mixture was degassed by bubbling nitrogen into the solution for 10 min. The pressure bottle was closed and heated at 90° C. for 3 h. The solvent was removed under reduced pressure and the residue was purified via Biotage (linear gradient 0-20%, methanol/ethyl acetate; 25M column) to afford title compound 286 as a brown solid (1.52 g, 7.63 mmol, 79%). MS (m/z): 200.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[O:12][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: CCCc1ccc(O)c(OC)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1ccc(Oc2ccc(OC)cc2)c(OC)c1

Procedure:
A mixture containing 2-methoxy-4-propylphenol (0.625 mmol; 100 μl), copper(II) acetate (0.625 mmol; 114 mg), 4-methoxyphenylboronic acid (1.25 mmol; 190 mg), triethylamine (3.12 mmol; 0.43 ml), some crushed molecular sieves 4 Å in dichloromethane (3 ml) was stirred at rt under air for 24 h. The residue is filtered with chloroform on Celite. The organic phase is washed with saturated NH4Cl, saturated NaHCO3 and brine. After drying (MgSO4), concentration and purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—20/80), the title compound is collected as a colorless oil (70 mg; 0.26 mmol; 41%).
Reaction SMILES: [Cl:1][CH:2](Cl)[B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1.[CH2:13]([Mg]Br)[CH2:14][CH3:15]>O1CCCC1>[Cl:1][CH:2]([B:3]1[O:7][C:6]([CH3:9])([CH3:8])[C:5]([CH3:11])([CH3:10])[O:4]1)[CH2:13][CH2:14][CH3:15]
Reactant: CC1(C)OB(C(Cl)Cl)OC1(C)C
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(Cl)B1OC(C)(C)C(C)(C)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 73.4 %

Procedure:
0.5 g (2.37 mmol) of 2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was dissolved in 10 ml of tetra-hydrofuran and the solution was cooled under a nitrogen atmosphere to -78° C. 2.4 ml (2.4 mmol) of 1M propylmagnesium bromide were added dropwise and the solution was stirred at room temperature for 18 hours. The solution was partitioned between ethyl acetate, saturated sodium chloride solution and 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulphate. After evaporation there was obtained 0.38 g of 2-[1(RS)-chlorobutyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as an oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2](CC1C=CC=CC=1)[C@@H:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C@H:4]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CO.[Pd]>[CH3:1][NH:2][C@@H:3]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C@H:4]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN(Cc1ccccc1)[C@@H]1CCCc2ccccc2[C@H]1N1CCCC1
Agent: [Pd]
Solvent: CO
Product: CN[C@@H]1CCCc2ccccc2[C@H]1N1CCCC1
Yield: 99.2 %

Procedure:
A solution of 2 g of the product of Step B in 40 ml of methanol and 2.6 ml of 22 Be hydrochloride acid was hydrogenated with 1.25 g of palladium under 1800 mmbars for 45 minutes. The mixture was filtered, rinsed with methanol and concentrated under reduced pressure at 50° C. The residue was dissolved in 10 ml of water which was alkalized with 2.6 ml of sodium hydroxide solution, and extracted with methylene chloride. The extracts were washed with water, dried, filtered and concentrated under reduced pressure to obtain 1.45 g of yellow oil which was dissolved in isopropyl ether. The insoluble substance was filtered and the residue was treated with active charcoal, filtered and concentrated to dryness under reduced pressure at 50° C. to obtain 1.24 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:9]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH:31](O)=O>C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[CH:16][C:11]3=[C:10]([CH:17]3[CH2:18][CH2:19][N:20]([CH3:31])[CH2:21][CH2:22]3)[C:9]=2[C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(C3CCNCC3)c2-c2ccncc2)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2c(-c3ccncc3)c(-c3ccc(F)cc3)nc3[nH]ncc23)CC1
Temperature: 75 °C
Yield: 19 %

Procedure:
To a suspension of 6-(4-fluorophenyl)-4-(4-piperidyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.24 g, 0.6 mmol, obtained in example 170) in formic acid (0.64 mL), 35-40% aqueous formaldehyde (0.96 mL) was added. It was heated to 70-80° C. for 24 h. It was allowed to cool and 1 N NaOH was added. It was extracted with CHCl3 and the combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using CHCl3—MeOH—NH3 mixtures of increasing polarity as eluent, to afford 47 mg of the desired compound (yield: 19%).