Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:28]N[CH2:26][CH2:25][NH:24]1.CS(C)=O.C1(C)C=CC=CC=1>C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][CH2:20][O:19][CH3:18])[CH2:28]3)[C:13]3[CH:12]=[CH:11][S:10][C:9]=3[NH:8][C:7]=2[CH:17]=1
Reactant: COCCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccc(F)cc2Nc2sccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3sccc32)CCN1
Temperature: 105 °C
Reaction time: 48 h
Yield: 21.4 %

Procedure:
Combine 6-fluoro-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (742.0 mg, 2.75 mmol), (S)-2-(3-methoxy-propyl)-piperazine (870.7 mg, 5.50 mmol), DMSO (2.0 ml), and toluene (8.0 ml). Stir and heat the mixture at 105° C. After 48 hours, cool the mixture to ambient temperature. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (85:15) to give 220.1 mg (21%) of the title compound: mass spectrum (ion spray): m/z 375.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:3]=1[NH:4][C:5](=[O:7])[CH3:6]>[Pt].O1CCCC1.C(OCC)(=O)C.C(O)C>[NH2:13][C:9]1[C:10]([F:12])=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[NH:4][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(F)cc1Cl
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(N)c(F)cc1Cl
Reaction time: 22 h

Procedure:
A mixture of 2′-chloro-4′-fluoro-5′-nitroacetanilide (26.1 g, 112 mmol) and 5% platinum on carbon (7.8 g, 30 wt %) in a tetrahydrofuran/ethyl acetate/ethanol solution (1:1:1) is hydrogenated at 50 psi for 22 hours and filtered. The resultant filtrate is concentrated in vacuo to obtain a solid which is recrystallized from an ethanol/water solution to give the title product as off-white plates (14.5 g, mp 176-178° C.).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].C(OC(=O)C)C.[C:25]1([CH:35]=[N+]=[N-])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CO>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18][CH2:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)O)C2C(=O)CC2C1
Reactant: [N-]=[N+]=Cc1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)NCCSC1=C(C(=O)OCc2cccc3ccccc23)C2C(=O)CC2C1
Reaction time: 1 h

Procedure:
A solution of 100 mg of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid in 5 mL of a mixture of ethylacetate and methanol was treated with a slight excess of α-naphthyldiazomethane. After the solution was stirred for 1 hr and then concentrated on a rotary evaporator, the crude product was purified by preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with 5% methanol in methylene chloride affording 130 mg (85.5%) of 3-(2'-acetamidoethylthio)7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, 1-naphthylmethyl ester, as a glass. IR (neat): 3200, 1780, 1690, 1660 cm-1 ; NMR (220 MHz; CDCl3): δ 1.86 (3H, s), 2.6-3.0 (5H, m), 3.0-3.5 (4H, m), 4.43 (1H, m), 5.61 (1H, d, J=18), 5.64 (1H, d, J=18 ), 6.30 (1H, m), and 7.3-8.2 (7H, m); MS (chemical ionization) confirmed molecular weight of 409.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17]([O:22]CC)([O:19]CC)=[O:18])(=[O:4])[CH:2]=[CH2:3].[Si](Br)(C)(C)C.Cl>C(Cl)Cl>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:18])([OH:22])[OH:19])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCCCCCCP(=O)(OCC)OCC
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCCCCP(=O)(O)O
Reaction time: 2 h
Yield: 40.2 %

Procedure:
11-(diethoxyphosphoryl)undecyl acrylate (420 mg, 1.16 mmol) was dissolved in ˜5 mL dry DCM. TMS bromide (0.33 mL, 2.55 mmol) was added via syringe and the rbf was greased and capped and allowed to stir for 2 hours. The solvent was concentrated by rotary evaporation and the product mixture redissolved in ˜3 mL methanol and ˜5 mL water and stirred for 2.5 hours during which a white precipitate formed. 1 M HCl was added and the product was extracted into dichloromethane, dried over magnesium sulfate, and pumped dry. The yellow/brown solid was dissolved in hot acetonitrile and put in the freezer overnight. Filtration afforded a white solid (143 mg, 40% yield). 1H NMR (300 MHz, CDCl3) δ 9.82 (br, s, 2H), 6.40 (dd, J=17.32, 1.61 Hz), 6.12 (dd, J=17.32, 10.41 Hz), 5.81 (dd, J=10.40, 1.60 Hz), 4.15 (t, J=6.73 Hz, 2H), 1.82-1.50 (m, 6H), 1.42-1.18 (m, 14H). 13C{1H} NMR (125.77 MHz, CDCl3) δ 166.76, 130.85, 129.05, 65.12, 30.87 (d, J=17.38 Hz), 29.89, 29.88, 29.76, 29.65, 29.46, 29.01, 26.33, 25.76 (d, J=143.86 Hz), 22.45 (d, J=4.85 Hz). Analysis found (calculated) %: C, 55.09 (54.89); H, 8.79 (8.88). 31P{1H}NMR (161.97 MHz, CDCl3): δ 38.76.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[NH3:24]>ClC1C=CC=CC=1Cl>[C:1](=[NH:24])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: N=C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 26 %

Procedure:
36.2 Grams of benzophenone, 50 ml of o-dichlorobenzene and 0.5 g of benzoic acid were fed to a reactor. Ammonia gas was passed through the reaction mixture under 6 atmospheres at 160° C. of the reaction temperature at a feed rate of 0.2 l/min. (NTP) continuously. The reaction was conducted for 3 hours and benzophenoneimine was obtained in yield of 26%.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1
Reactant: COC(=O)c1ccc(C#N)cc1OC
Reactant: NO
Solvent: CCO
Product: COC(=O)c1ccc(C(N)=NO)cc1OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of methyl 4-cyano-2-methoxybenzoate, obtained in step 1 (155 mg; 0.81 mmol; 1 eq.) in EtOH (1.55 mL) was added hydroxylamine (50% in water) (0.24 mL; 4.05 mmol; 5 eq.). The reaction mixture was stirred at 60° C. for 60 min. Solvents were removed to dryness, to afford the title compound as a yellow powder. 1H NMR (DMSO-d6, 400 MHz) δ 10.62 (br s, 1H), 9.85 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.40 (s, 1H), 7.35-7.31 (m, 2H), 5.95 (br s, 2H), 3.85 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.Cl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:25]4[CH:24]=[CH:23][C:22]([F:21])=[CH:27][N:26]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: C[C@H](Nc1ncc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 17, 0.35 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.25 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.3 g of desired product. MS (electrospray): 385 (M+1) for C17H16FN8O2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[F:14][C:15]([F:27])([F:28])[O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[O:25])=[CH:21][CH:22]=1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.3 %

Procedure:
To a mixed solution of t-butyl (S)pyrrolidin-3-ylcarbamate (93 g), 4-trifluoromethoxyphenylacetic acid (112 g), and THF (550 mL) were added EDC.HCl (114 g) and HOBt-1H2O (114 g), and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, then diluted with chloroform, and washed with saturated aqueous sodium hydrogencarbonate, water, and brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting solids were washed with chloroform to obtain t-butyl ((S)-1-(2-(4-trifluoromethoxyphenyl)ethanoyl)pyrrolidin-3-yl)carbamate (144 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[C:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2c(C(=O)c3ccccn3)cnc3c(C(F)(F)F)cccc23)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-t-butylphenylboronic acid in place of phenyl boronic acid. MS (ESI) m/z 435 ([M+H]+); Anal. Calcd for C26H21F3N2O: C, 71.88; H, 4.87; N, 6.45. Found: C, 71.51; H, 5.09; N, 6.22.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([O:18][CH3:19])[N:17]=[C:13]3[NH:12][C:11]([CH3:20])=[C:10]2[C:21]#[N:22])=[CH:5][CH:4]=1)#[N:2].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.N1C(C)=CC=CC=1C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([O:18][CH3:19])[N:17]=[C:13]3[N:12]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=3)[C:11]([CH3:20])=[C:10]2[C:21]#[N:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1nc2n(n1)C(c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-(4-cyanophenyl)-2-methoxy-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (50 mg, 171 μmol) was stirred in abs. dichloromethane (7 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (97 mg, 513 μmol, 3 eq.), anhydrous copper(II) acetate (93 mg, 513 μmol, 3 eq.), abs. pyridine (8 ml) and triethylamine (72 μl, 513 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 48 h. More anhydrous copper(II) acetate (31 mg, 171 μmol, 1 eq.) and 2,6-lutidine (60 μl, 513 μmol, 3 eq.) were then added, and the mixture was stirred under an atmosphere of dry air at RT for a further 7 d. The reaction mixture was then concentrated to dryness. The residue was suspended in ethyl acetate (10 ml) and filtered. The filtrate was washed with water (5 ml) and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Reprosil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The brown solid obtained in this manner was decolorized by filtration through a small silica gel cartridge using a mobile phase mixture of cyclohexane and ethyl acetate (2:1) and then lyophilized. The product was obtained as a solid (10.8 mg, 15% of theory).
Reaction SMILES: C[O:2][C:3](=S)[NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:14]3[S:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[CH:15]=3)[CH:13]=1)[NH:10][N:9]=[CH:8]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][NH2:32]>C(O)C>[S:18]1[C:14]([C:12]2[CH:13]=[C:5]([NH:4][C:3]([NH:32][CH2:31][CH2:30][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:2])[CH:6]=[C:7]3[C:11]=2[NH:10][N:9]=[CH:8]3)=[CH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]1=2
Reactant: NCCc1ccccn1
Reactant: COC(=S)Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Solvent: CCO
Product: O=C(NCCc1ccccn1)Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A mixture of 7-benzo[b]thiophen-2-yl-1H-indazole-5-yl-thiocarbamic acid methyl ester (Preparation #14, 25.0 mg, 0.074 mmol) and 2-pyridin-2-yl-ethylamine (23 mg, 0.185 mmol) in ethanol (2 mL) was stirred at about 50° C. for about 8 hours. The solvent was removed under reduced pressure and the product was purified by crystallization in ethanol to give 1-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-3-(2-pyridin-2-yl-ethyl)-urea (12 mg, 39% yield); RP HPLC (Table 1, Method e) Rt=1.82 min; MS m/z: (M−H)− 412.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[N+:16]([C:19]1[C:20](=O)[NH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=1)([O-:18])=[O:17].C(=O)(O)[O-].[Na+]>O>[Cl:3][C:20]1[C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=[C:22]([C:25]([F:28])([F:27])[F:26])[N:21]=1
Reactant: O=c1[nH]c(C(F)(F)F)ccc1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)nc1Cl
Temperature: 140 °C
Yield: 87 %

Procedure:
To phosphorous oxychloride (11 ml, 117 mmol) was added quinoline (8.4 ml, 70 mmol) followed by 3-nitro-6-trifluoromethyl-2(1H)-pyridone (24.0 g, 115 mmol), and the resulting solution heated at 140° C. for 18 h. The solution was then cooled to 100° C., when water (50 ml) was carefully added. After cooling to room temperature, saturated sodium bicarbonate (200 ml) was added and the mixture extracted with ethyl acetate (2×200 ml). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as a brown oil (22.7 g, 0.1 mol, 87% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[N:24]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([NH:32][C:33](=O)[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:27][CH:26]=3)=[O:22])=[CH:16][CH:15]=1.Cl>ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][CH2:33][NH:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47])[C:23]([C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:16]=1)=[O:22])=[CH:31]2
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(N)cc1)n2Cc1ccccc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CCNc1ccc2c(c1)cc(C(=O)Nc1ccc(NS(C)(=O)=O)cc1)n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22.5 mg (0.20 mmol) of methanesulphonyl chloride are dissolved in 1 ml of dichloromethane, and 38.9 mg (0.49 mmol) of pyridine are added. A solution of 100 mg (0.20 mmol) of N-(4-aminophenyl)-5-[(3,3-dimethylbutyl)amino]-1-(2-fluorobenzyl)-1H-indole-2-carboxamide hydrochloride (Example 57) in 1 ml of dichloromethane is added dropwise to this mixture, and the reaction mixture is stirred at RT overnight. For work-up, 22 ml of 1-molar hydrochloric acid are added, and the mixture is extracted repeatedly with dichloromethane. The combined organic phases are washed in each case once with saturated copper sulphate solution, saturated sodium bicarbonate solution and water. They are then dried over sodium sulphate and filtered, and the solvent is removed under reduced pressure. This gives 96.2 mg (73%) of the product.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(Oc3ccccc3)cc2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 0 %

Procedure:
To a solution of 4-phenoxyphenol (1.0 g, 5.4 mmol) in N,N-dimethylformamide (20 mL) were added 4-fluorobenzaldehyde (0.67 g, 5.4 mmol) and potassium carbonate (0.75 g, 5.4 mmol), and the mixture was stirred at 100° C. for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to give the title compound (1.4 μg, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2
Reactant: COc1ccc(-c2cc(Cl)c3cc(O)ccc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3cc(O)ccc3c2)cc1

Procedure:
The title compound was prepared by reacting 8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.10 g, 0.35 mmol) with boron tribromide (0.9 mL of 1N solution, 0.9 mmol) according to method D to yield 0.080 g (85%) of product which was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 204-206° C.; 1H NMR (DMSO-d6): δ 6.87 (2H, d, J=8.61 Hz), 7.17 (1H, dd, J=2.34 Hz, J=8.83 Hz), 7.38 (1H, d, J=2.26 Hz), 7.62 (2H, d, J=8.59 Hz), 7.85 (1H, d, J=1.64 Hz), 7.90 (1H, d, J=8.92 Hz), 8.01 (1H, bs), 9.62 (1H, s), 10.14 (1H, s); MS (ESI) m/z 269/(M−H)−.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][C@H:7]1[CH2:12][C@@H:11]([CH2:13]O)[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:8]1)([CH3:4])[CH3:3].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][C@H:7]1[CH2:12][C@@H:11]([CH2:13][N:31]2[C:27](=[O:37])[C:28]3[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30]2=[O:32])[CH2:10][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH2:8]1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](CO)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.9 %

Procedure:
To cis-phenylmethyl (3RS,5RS)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-(hydroxymethyl)-1-piperidinecarboxylate (550 mg; 1.4 mmol) in THF (25 ml) was added phthalimide (250 mg; 1.7 mmol), triphenylphosphine (450 mg; 1.7 mmol), and diethyl azodicarboxylate (300 mg; 1.7 mmol). The reaction was allowed to stir at room temperature under N2 for 16 hours. The reaction was partitioned between EtOAc (150 ml) and water (50 ml), the layers were separated, the organic layer was washed with brine and dried with Na2SO4. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 10%-100% EtOAc/hexanes gradient to provide the desired compound (690 mg; 93%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:17])[NH:12]2.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2F)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccccc4F)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.9 %

Procedure:
To a solution of 4-(2-fluorophenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3 carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (62.5 mg, 53%).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[C@@:11]([CH:31]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH2:12][O:13][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[O:10][C@@H:9]([N:48]2[CH:55]=[CH:54][C:52](=[O:53])[NH:51][C:49]2=[O:50])[CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(CNC([C@]2(CO)O[C@@H](N3C=C(C)C(=O)NC3=O)C[C@@H]2O)NCC2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:34]1([CH2:33][NH:32][CH:31]([C@:11]2([CH2:12][OH:13])[O:10][C@@H:9]([N:48]3[CH:55]=[CH:54][C:52](=[O:53])[NH:51][C:49]3=[O:50])[CH2:8][C@@H:7]2[OH:6])[NH:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@]1(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(NCc1ccccc1)NCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cn([C@H]2C[C@H](O)[C@](CO)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]c1=O
Agent: [F-]
Solvent: C1CCOC1
Product: O=c1ccn([C@H]2C[C@H](O)[C@](CO)(C(NCc3ccccc3)NCc3ccccc3)O2)c(=O)[nH]1

Procedure:
3′-O-[(tertbutyl)dimethylsilyl]-5′-O-[(tertbutyl)diphenylsilyl]-4′-C-(1,1′-diphenylmethylaminomethyl)-2′-deoxyuridine (11) (0.13 g, 0.16 mmol) was treated with tetrabutylammonium fluoride solution (0.45 mL) in tetrahydrofuran (5 mL) according to the procedure used for the preparation of compound (3). The title compound (12) was obtained as a clear glass (0.056 g, 78%). δH(300 MHz, d6-DMSO) 11.25(1H, s, br, N3—H), 7.90(1H, d, H-6), 7.40–7.15(10H, m, Ph2CHNH), 6.19(1H, dd, H-1′), 5.93(1H, d, br, 3′-OH), 5.91(1H, s, br, Ph2CHNH), 5.11(1H, t, br, 5′-OH), 4.78(1H, s, Ph2CHNH), 4.33(1H, dd, H-3′), 3.61(1H, d, H-5′), 2.52–2.49(2H, m, 4′-C—CH2), 2.18(2H, m, H-2′); δC(75.45 MHz, d6-DMSO) 163.13, 150.43, 144.50, 144.25, 140.62, 128.34, 126.97, 126.92, 126.72, 101.60, 88.63, 83.50, 72.0, 66.85, 58.8, 51.15; ES +ve m/z 424(M+H)+.