Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10]([C:13]1[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[CH:15][C:14]=1[OH:21])(=[O:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[C:10]([C:13]1[CH:18]=[C:17]([CH2:19][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)[CH:16]=[CH:15][C:14]=1[OH:21])(=[O:12])[CH3:11]
Reactant: OCCN1CCNCC1
Reactant: CC(=O)c1cc(CCl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(CN2CCN(CCO)CC2)ccc1O
Reaction time: 8 h

Procedure:
2-Piperazin-1-yl-ethanol (260 mg, 2 mmol) and 2-acetyl-4-chloromethyl phenol (368 mg, 2 mmol) were stirred in chloroform at room temperature. Sodium carbonate (106 mg, 1 mmol) was added and the reaction mixture was stirred overnight. The solid was filtered off and the organic layer washed with water followed by brine, dried over sodium sulfate, filtered and evaporated to obtain the crude product, which was crystallized from ethyl acetate-hexane to receive the title product as yellowish-white crystals (400 mg 72%), mp=72-75° C. C15H22N2O3 requires: N 10.06 found: N 9.70.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[CH3:73][N:74]([CH3:79])[CH2:75][CH2:76][CH2:77]O>C1COCC1>[CH3:73][N:74]([CH3:79])[CH2:75][CH2:76][CH2:77][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34]
Reactant: CN(C)CCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 38.7 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.102 g, 0.221 mmol) was dissolved in THF (5.1 mL), and the solution was treated with triphenylphosphine (0.116 g, 0.442 mmol), 40% DEAD-toluene solution (0.201 mL, 0.442 mmol) and 3-(dimethylamino)propanol (0.130 mL, 1.10 mmol), followed by purification by flash column chromatography (chloroform/methanol=4/1) to obtain 4-[3-(dimethylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0467 g, yield 39%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[NH:16][C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2.[C:36](=O)([O-])[O-].[Cs+].[Cs+].CI>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[NH:28][C:27]4=[O:35])[CH2:22][CH2:21]3)[N:16]([CH3:36])[C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2cc(F)ccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CI
Product: Cn1c(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)cc(C(=O)N2CCc3cc(F)ccc32)cc1=O
Reaction time: 0.25 h

Procedure:
50 mg (0.11 mmol) of 4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one were placed in 0.50 mL DMSO at RT. To this were added 88 mg (0.27 mmol) caesium carbonate and the mixture was stirred for 15 min. Then a solution of 6.5 μL (0.11 mmol) methyl iodide in DMSO was added and the mixture was stirred for 2 h at RT. More methyl iodide was added (3.3 μL, 0.055 mmol) and the mixture was stirred for a further 2 h at RT. The reaction mixture was purified by preparative HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: Cl[C:2]1[NH:7][C:6](=[O:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)([OH:15])[CH2:11][CH2:10]2)[N:3]=1>[OH-].[Pd+2].[OH-]>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2([OH:15])[CH2:13][CH2:14][N:9]([C:4]3[N:3]=[CH:2][NH:7][C:6](=[O:8])[N:5]=3)[CH2:10][CH2:11]2)=[CH:17][CH:18]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc(Cl)[nH]1
Agent: [Pd+2]
Agent: [OH-]
Product: O=c1nc(N2CCC(O)(c3ccc(F)cc3)CC2)nc[nH]1
Yield: 122.9 %

Procedure:
6-Chloro-4-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one (239 mg, 0.74 mmol) synthesized in Reference Synthesis Example 13 and palladium hydroxide-activated carbon catalyst (24 mg) were used to obtain the title compound (264 mg, quantitative) by synthesis in a similar manner to Reference Synthesis Example 3.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br.[Br:15][CH2:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=O>>[BrH:15].[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:16]=2)[CH:20]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Agent: Br
Product: COC(=O)c1ccc(-c2nc(-c3cccnc3)cs2)cc1
Yield: 80 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetylpyridine hydrobromide to obtain methyl 4-[4-(3-pyridyl)-2-thiazolyl]benzoate hydrobromide. The product was recrystallized from ethanol. Yield: 80%. Pale yellow prisms. Melting point: 241 to 242° C.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.CO.O.[N:18]#[C:19]Br>C1COCC1>[C:9]1([C:1]2[CH:6]=[CH:5][C:4]3[NH:7][C:19]([NH2:18])=[N:8][C:3]=3[CH:2]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CBr
Reactant: Nc1ccc(-c2ccccc2)cc1N
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2cc(-c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of biphenyl-3,4-diamine (0.99 mmol) in THF:MeOH:water (5 mL:10 mL:10 mL) was added cyanogen bromide (5M solution in acetonitrile, 1.06 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was partitioned between EtOAc and aqueous sodium hydroxide and the aqueous layer re-extracted with EtOAc.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: Sc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccncc2)c(F)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
21 g (188.9 mmol) of 4-mercaptopyridine, 30.05 g (188.9 mmol) of 3,4-difluoro-nitrobenzene and 60.05 g (434.5 mmol) of potassium carbonate are dissolved in dimethylformamide, and the mixture is stirred at 40° C. for 3 hours. The reaction solution is then diluted with 500 mL of ethyl acetate and 300 mL of water. The aqueous phase is extracted five times with in each case 100 mL of ethyl acetate. The combined organic phases are washed with 200 mL of saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure using a rotary evaporator. The residue is purified by MPLC (mobile phase: ethyl acetate:cyclohexane 1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.Br[N:28]1C(=O)CC[C:29]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.CN.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)(Cl)Cl.ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][NH:28][CH3:29])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CN
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNCc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2OC)o1
Temperature: 70 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (241 mg, 0.69 mmol) in carbon tetrachloride (2 mL) was added N-bromosuccinimide (122 mg, 0.69 mmol) and 2,2′-azobis(2-methylpropionitrile) (11 mg, 0.07 mmol) and the reaction mixture was stirred for 18 h at 70° C. It was diluted with dichloromethane (10 mL) and washed with aqueous sodium hydrogencarbonate (1 N, 10 mL). The aqueous phase was extracted with dichloromethane and dried over sodium sulfate. The resulting crude material was suspended in methylamine solution (2 M in THF, 2.0 mL, 4.0 mmol) and potassium carbonate (110 mg, 0.80 mmol)was added. The reaction mixture was stirred for 2 h at 50° C. The mixture was diluted with ethyl acetate (20 ml), washed twice aqueous sodium carbonate (half saturated) and was extracted with ethyl acetate. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane:methanol 40:40:20:0 to 0:75:20:5) afforded the tide compound (119 mg, 46%) as a white solid. MS: m/e 381.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Si](C(C)C)(C(C)C)[S:18][C:19]1[CH:20]=[C:21]([C:25]2([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)(C)C.CC(C)([O-])C.[K+].C1COCC1.Cl>CC(O)C.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.O>[CH3:13][N:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:18][C:19]3[CH:20]=[C:21]([C:25]4([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=[N:11]1
Reactant: Cn1nccc1-c1ccc(Br)cc1
Reactant: CC(C)[Si](Sc1cccc(C2(C(N)=O)CCOCC2)c1)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1nccc1-c1ccc(Sc2cccc(C3(C(N)=O)CCOCC3)c2)cc1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 5-(4-bromophenyl)-1-methyl-1H-pyrazole (0.50 g, 2.10 mmols,), 4-{3-[(tri-isopropylsilyl)thio]phenyl}tetrahydro-2H-pyran-4-carboxamide (0.83 g, 2.10 mmols), Tetrakis(triphenylphosphine)palladium(0) (243 mg, 0.10 equivalents), bis[(2-diphenyl-phosphino)]phenyl ether (113 mg, 0.10 equivalents), and 1.0 M potassium tert-butoxide in THF (6.3 mmols, 3 equivalents) in iPrOH (15 mL) that contained 5% water was heated for 4 hours at 90 degrees Celcius in an atmosphere of nitrogen. The reaction mixture was cooled to room temperature and 7 mL of 1N HCl was added. The product was precipitated by the addition of water (30 mL). The precipitate was collected by suction filtration and washed with water (2×20 mL) and cold ethyl ether (4×20 mL). The tan brown solid was dissolved in a small volume of methylene chloride containing 1% methanol and applied to a 140 g cartridge of silica gel. The cartridge was eluted with an acetone:hexane gradient. The appropriate fractions were concentrated and triturated with methanol to produce a white solid (710 mg) as product. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.84 (m, 3H) 2.40 (d, J=13.54 Hz, 3H) 3.43-3.51 (m, 1H) 3.72 (d, J=11.34 Hz, 3H) 3.84 (s, 3H) 6.40 (d, J=1.46 Hz, 1H) 7.02 (s, 1H) 7.22-7.30 (m, 2H) 7.34 (d, J=8.05 Hz, 1H) 7.38-7.43 (m, 2H) 7.45-7.52 (m, 3H). HRMS calc M+H, 394.1589, found 394.1630.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:18])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cc[n+]([O-])cc1

Procedure:
The 4-acetyl-pyridine N-oxide used is prepared in the following manner: 11.0 ml (100 mmol) of 4-acetyl-pyridine and 31.3 g (100 mmol) of 55% m-chloro-perbenzoic acid are boiled under RF for 16 h in 200 ml of methylene chloride. Precipitation with 200 ml of diethyl ether gives 4-acetyl-pyridine N-oxide; m.p. 132°-133°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.Cl.[CH3:15][C:16]1[S:17][C:18]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:19]=2[N:25]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:23][CH2:24][C:18]4[SH:17]=[C:16]([CH3:15])[NH:25][C:19]=4[CH2:20][CH2:21]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1nc2c(s1)CCNCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Agent: Cl
Product: CC1=[SH]C2=C(CCN(C(=O)c3cc4ncc(Br)cn4n3)CC2)N1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 13 mg (16% of theory). ESI-MS: m/z=392 (M+H)+;
Reaction SMILES: [CH3:1][C:2]([CH3:36])([Si:4]([CH3:35])([CH3:34])[O:5][CH2:6][C@@H:7]([N:20]([CH2:28][C:29](=[O:33])/[CH:30]=C/C)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:8](=C)[CH2:9][CH2:10][O:11][Si:12]([CH3:18])([CH3:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:3]>C1(C)C=CC=CC=1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Si:12]([O:11][CH2:10][CH2:9][C:8]1[C@@H:7]([CH2:6][O:5][Si:4]([C:2]([CH3:36])([CH3:3])[CH3:1])([CH3:35])[CH3:34])[N:20]([C:21]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:27])[CH2:28][C:29](=[O:33])[CH:30]=1)([C:13]([CH3:15])([CH3:16])[CH3:14])([CH3:18])[CH3:17]
Reactant: C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)/C=C/C)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(=O)C=C(CCO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 92.7 %

Procedure:
A solution of (S,E)-tert-butyl (2,2,3,3,11,11,12,12-octamethyl-7-methylene-4,10-dioxa-3,11-disilatridecan-6-yl)(2-oxopent-3-en-1-yl)carbamate (Intermediate 279, 10 g, 18.45 mmol) in toluene (400 mL) was purged with nitrogen for 15 minutes. The Hoveyda-Grubbs Catalyst 2nd Generation (2.320 g, 3.69 mmol) was then added. The reaction was heated at 100° C. overnight. Another 0.05 eq of catalyst was added and the reaction mixture was heated at 100° C. for another 2 hours. The reaction mixture was concentrated onto silica gel. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the title compound (8.55 g, 93%) as a light brown oil.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:3]=1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([CH2:24][OH:23])[CH:30]=3)[CH:14]=[CH:13][C:5]=2[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: OCc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(CO)c2)cc1Nc1ccc(F)cc1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
To N,N-dimethylacetamide 2.5 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 80 mg were added 3-(hydroxymethyl)phenylboronic acid 50 mg, sodium carbonate 58 mg and polymer-carried di(acetato)dicyclohexylphenylphosphine palladium(II) 7.0 mg, and it was stirred at 110° C. for 19 hours. After the reaction mixture was cooled to room temperature, polymer-carried di(acetato)dicyclohexylphenylphosphine palladium (II) 7.0 mg were added to it, and it was stirred at 110° C. for 30 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 10% citric acid aqueous solution and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-(4-fluoroanilino)-4-(3-(hydroxymethyl)phenyl)benzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Ni].C(O)C(C)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)c(C)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)CO
Product: Cc1ccc(C(=O)c2ccc(N)cc2)c(C)c1

Procedure:
The 4-nitro-2',4'-dimethylbenzophenone obtained in b) was mixed with 900 ml of isobutanol and 3.5 g of activated nickel powder and hydrogenated under a slight superatmospheric pressure (1.25 bar) of hydrogen at 50°-60° C. to give 4-amino-2',4'-dimethylbenzophenone. The catalyst was filtered off and then the organic solvent was distilled off to recover it, and water at 95° C. was added to the residue at 100°-110° C. and the mixture was stirred until room temperature was reached. 4-Amino-2',4'-dimethylbenzophenone crystallized out at 90° C. The crystalline product was filtered off with suction, washed with water and dried. 215 g of amino compound (melting point 121° C.) were obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([F:10])[C:5]([C:11]#[N:12])=[C:4](F)[C:3]=1[F:14].[OH-:15].[Na+].Cl>O>[F:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([F:1])[C:3]([F:14])=[C:4]([OH:15])[C:5]=1[C:11]#[N:12]
Reactant: [OH-]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1c(O)c(F)c(F)c(C#N)c1F

Procedure:
A 2.0 g amount of tetrafluoroisophthalonitrile and 0.7 g of sodium hydroxide were added to 40 ml of water and the mixture was heated under reflux for 1.5 hours. After cooling, the mixture was neutralized with concentrated hydrochloric acid and was then extracted with ether. After the ether extract was washed with water, the extract was dried with magnesium sulfate. The solvent was distilled off and the resultant crude crystal was recrystallized to obtain 1.39 g of the desired compound No. 19.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].C[Si]([N:36]=[C:37]=[O:38])(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:27][CH2:28][N:29]([C:37]([NH2:36])=[O:38])[CH2:30][CH2:31]4)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCN(C(N)=O)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (8.0 mg, 0.0174 mmol), trimethylsilyl isocyanate (4.02 mg, 0.0349 mmol), DIPEA (0.02 mL, 0.09 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 1.93-2.05 (m, 2H), 2.07-2.16 (m, 2 H), 2.95-3.06 (m, 2 H), 4.17 (d, J=13.6 Hz, 2 H), 4.41 (tt, J=11.5, 4.2 Hz, 1 H), 5.25-5.34 (m, 1 H), 7.19 (t, J=8.7 Hz, 1 H), 7.36 (d, J=1.5 Hz, 1 H), 7.38-7.52 (m, 2 H), 7.58 (s, 1 H), 7.90 (s, 1 H), 8.32 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 501.02 (100) [MH+]. HPLC: tR=3.15 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2O.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1ccc2ncnc(O)c2c1
Product: COc1ccccc1-c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
A suspension of 6-(2-methoxyphenyl)quinazolin-4-ol (250 mg, 0.99 mmol) in POCl3 (10 mL) was heated at reflux for 1 h, during which time a clear solution was observed. The mixture was cooled to room temperature, concentrated in-vacuo, then concentrated from methylene chloride (3×100 mL) to remove any remaining POCl3. The residue was partitioned between ethyl acetate (25 mL) and saturated NaHCO3 (30 mL), and the mixture was stirred until gas evolution ceased (10 min). The layers were separated, the organic phase was washed with saturated NaHCO3, water, and brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 1:3 ethyl acetate/heptane, to yield 217 mg of 4-chloro-6-(2-methoxyphenyl)quinazoline as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 9.03 (s, 1H), 8.36 (s, 1H), 8.19 (d, J=7.15 Hz, 1H), 8.10 (d, J=8.80 Hz, 1H), 7.42 (m, 2H), 7.10 (t, J=7.42 Hz, 1H), 7.04 (d, J=8.25 Hz, 1H), 3.86 (m, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C@@H:9](Br)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[C:26](=O)(O)[O-:27].[Na+]>CO>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH:9]([O:27][CH3:26])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@@H](Br)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [Na+]
Solvent: CO
Product: COC1C=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a clear solution of 3β-acetoxy-7α-bromoandrost-5-ene-17-one, 25, (0.5 g) in methanol (20 mL) was added silica gel (2.0 g, 70-230 mesh) and the mixture was stirred for 2 h at room temperature. The methanolic solution was cooled, neutralized with saturated sodium bicarbonate solution, and filtered on a thin bed of celite. The clear filtrate was cooled at 0° C. to obtain the white crystalline 7-methoxy derivative 26. Yield 0.32 g (72.7%), m.p. 175-78° C. The NMR spectrum of the white solid showed 55% 7β-methoxy- and 45% 7α-methoxy-compound. Spectral data described below were deduced from the spectrum of the mixture. The biological activity was assayed as the mixture (Table I).