Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:18]>CCOCC>[Cl:18][C:1]1[NH:2][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Reactant: Cl
Solvent: CCOCC
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 0 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
To a solution of ethyl 2-cyano-4-oxo-4-phenylbutanoate (8 g, 34.6 mmol) in Et2O (100 ml) was bubbled HCl gas at 0° C. for 30 min. After reaction mixture was stirred for 1 day at 0° C., the resulting solution was evaporated under reduced pressure. The residue was purified with silica gel column (EtOAc:Hx=1:3) to produce title compound (7.3 g, 84.5%) as light yellow solid.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].[CH3:22][N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=[C:24]1S(C)(=O)=O.O>CN(C=O)C>[CH3:22][N:23]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]=[C:24]1[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:6]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:4]3[CH:3]=[CH:2][N:1]=[C:5]23)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2cccnc21
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (175 mg) obtained in Example 9, step C) in DMF (2 ml) was added sodium hydride (60% in oil, 32 mg) at room temperature by small portions. After stirring for 10 min, a solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (169 mg) in DMF (1.5 ml) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (THF) and recrystallized from methanol/water to give the title compound (179 mg).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[S:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=[C:2]1[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1nc2ncccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro[1,3]thiazolo[4,5-b]pyridine (25 g, 147 mmol) in CH3CN (500 mL) was added 4-hydroxybenzaldehyde (19.8 g, 147 mmol, 1 equiv.) and K2CO3 (22.3 g, 147 mmol, 1 equiv.). The heterogeneous mixture was heated at reflux for 72 h and then cooled to rt. Purification was conducted using one of the following methods.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4](C1C=CC(C)=CC=1)=[O:5].ClC1C=CC=C(C(OO)=[O:26])C=1.P([O-])([O-])(O)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl.O>[CH3:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([OH:5])=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2C)cc1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
2.3 g (10 mmol) of 2-methyl-4-fluoro-4'-methylbenzophenone were added dropwise at 20° C., under inert gas, to 3.8 g (12 mmol) of 3-chloroperbenzoic acid (55%) in 40 ml of dichloromethane and 14.2 g (0.1 mol) of disodium hydrogenphosphate and the reaction mixture was then heated for 8 h at 40° C. It was monitored by gas chromatography and, if the conversion was incomplete, a further 2.5 g (8 mmol) of 3-chloroperbenzoic acid were added. 100 g of water were added 4 hours later and the mixture was neutralized with sodium hydrogencarbonate solution. The phases were separated, the aqueous phase was extracted with dichloromethane and the solvent was distilled off. The residue was boiled for 4 h with 100 g of 70% sulfuric acid and then poured on to 200 g of ice. Extraction and crystallization gave 1.15 g (7.5 mmol, 5%) of 2-methyl-4-fluorobenzoic acid. If the reaction is carried out under these conditions with 9.2 g (15 mmol) of ®Oxone (=potassium peroxomonosulfate) instead of with 3-chloroperbenzoic acid, essentially the same result is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[SH:15].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[S:15][CH2:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1S
Reactant: O=C(CBr)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CSc1c(O)cc(-c2ccccc2)oc1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-3-mercapto-6-phenyl-2-pyrone (0.175, 0.840 mmol, prepared as in R. F. Harris, J. E. Dunbar, U.S. Pat. No. 3,818,046) in CH2Cl2 (3.0 mL) under an N2 atmosphere was treated with triethylamine (0.12 mL, 0.84 mmol) followed by bromoacetophenone (0.167 g, 0.840 mmol). The mixture was allowed to stir for 30 min. at ambient temperature then the solvent removed in vacuo. The residue was then diluted with diethyl ether and extracted with saturated Na2CO3 (3×50 mL). The aquous layers were then combined, acidifed with conc. HCl, and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried with Na2SO4, and the solvent removed in vacuo to give the title compound (0.066 g, m.p. 164°-166° C.) which was dried in vacuo. 1H NMR (300 MHz, CDCl3) δ 9.900 (bs, 1 H), 7.970 (d, 2 H, J=7.1 Hz), 7.810 (d, 2 H, J=8 Hz), 7.615 (t, 1 H, J=4 Hz), 7.505-7.443 (m, 5 H), 6.619 (s, 1 H), 4.334 (s, 2 H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30](Cl)=O.C(N(CC)CC)C>C(#N)C>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([Cl:34])=[C:29]([C:30]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:33]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Br)ccc2Cl)n1
Temperature: 150 °C
Yield: 26 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.05 g, 0.154 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 5-bromo-2-chlorobenzoyl chloride (0.134 g, 0.529 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.021 g (26% yield) of pure product: MS (ES) m/z 523 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]2[Cl:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c2ccc(Cc3ccccc3)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(Cc3ccccc3)cc2c1Cl
Temperature: 0 °C

Procedure:
A mixture of ethyl 6-benzyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (A, 1.96 g) and phosphorus oxychloride (10 mL) was refluxed for 15 min. The solution was poured into ice water containing concentrated ammonia solution (15 mL), and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford crude the title compound (2.77 g) as a brown oil: 1H NMR (400 MHz, CDCl3) δ 1.48 (t, J=6.8 Hz, 3H), 4.31 (s, 2H), 4.55 (q, J=6.8 Hz, 2H), 7.18-7.41 (m, 5H), 7.99 (d, J=8.8 Hz, 1H), 8.39 (s, 1H), 8.61 (d, J=8.8 Hz, 1H), and 9.38 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[C:9]([CH3:44])=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:30][CH2:29]5)=[N:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:14]=2)[C:9]([CH3:44])=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 81.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (186 mg. 0.277 mmol) was alkylated using (S)-2-methyloxirane (32 mg, 0.554 mmol), DIPEA (72 mg, 0.554 mmol) and ethanol (4 mL) to get 157 mg (82% yield) of the titled compound. MS: m/z=694.2 (M+1).
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:20]OC(F)(F)F>ClC(F)(F)F>[F:20][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3]
Reactant: C[Si](C)(C)OC(=Cc1ccccc1)c1ccccc1
Reactant: FOC(F)(F)F
Agent: FC(F)(F)Cl
Product: O=C(c1ccccc1)C(F)c1ccccc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
A solution of 18.8 g (0.07 mol) of the aforesaid α-trimethylsiloxystilbene in 200 ml of chlorotrifluoromethane was cooled to -70° C. and 7.3 g (0.07 mol) of trifluoromethyl hypofluorite were passed into the solution over a 3 hour period. The reaction mixture then was warmed to room temperature and evaporated to dryness under reduced pressure to give a white solid. Recrystallization from heptane gave 10.81 g (72% yield) of α-fluoro-α-phenylacetophenone as colorless crystals: mp 50°-51° C.; 19F NMR (CDCl3) δ-176.5 ppm (d, J=49 Hz); 1H NMR (CDCl3) δ 6.52 ppm (d, J=49 Hz, 1H), 7.2-8.2 ppm (m, 10H). Anal. Calcd. for C14H11FO: C, 78.49; H, 5.18; F, 8.87; Found: C, 78.52; H, 5.13; F, 8.65.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:23]=[C:24]([CH:37]=[CH:38][CH:39]=4)[C:25]([NH:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([CH3:30])[CH3:29])=[O:26])[CH:21]=[C:16]3[C:15]=2[CH:41]=[O:42])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:40][C:17]3=[N:18][CH:19]=[C:20]([C:22]4[CH:39]=[CH:38][CH:37]=[C:24]([C:25](=[O:26])[NH:27][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)([CH3:30])[CH3:29])[CH:23]=4)[CH:21]=[C:16]3[C:15]=2[C:41]([OH:1])=[O:42])=[CH:10][CH:9]=1
Reactant: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C=O)c3c2)c1)c1ccccc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(C(=O)O)c3c2)c1)c1ccccc1
Reaction time: 72 h
Yield: 33.3 %

Procedure:
Oxone (28 mg, 0.046 mmol) was added to a stirring solution of 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (20 mg, 0.042 mmol) in DMF (0.5 mL) at room temperature. It was allowed to stir for 3 days. An additional amount of Oxone (28 mg, 0.046 mmol) was added and the reaction was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 2-(4-fluorophenyl)-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)furo[2,3-b]pyridine-3-carboxylic acid (7 mg, 0.014 mmol, 34% yield) consistent by LCMS and NMR. 1H NMR (500 MHz, MeOD) δ ppm 7.42 (1H, d, J=2.14 Hz), 7.31-7.39 (2H, m), 6.93-7.02 (2H, m), 6.87 (1H, s), 6.59 (2H, t, J=8.70 Hz), 6.34 (1H, t, J=7.63 Hz), 6.20 (2H, d, J=7.63 Hz), 5.97-6.07 (4H, m), 5.92 (1H, t, J=7.32 Hz), 0.52 (6H, s). LC-MS retention time: 1.15 min; m/z (MH+): 495. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[Mg].[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[CH:18]=[C:19]([CH3:21])[CH3:20]>C1COCC1>[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[CH2:18][C:19]([CH3:21])([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:3]=1)[CH3:20]
Reactant: CC1(c2cccc(Br)c2)OCCO1
Reactant: CC(C)=CC(=O)C(F)(F)F
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2(C)OCCO2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 43.1 %

Procedure:
To a solution of 2-(3-bromophenyl)-2-methyl-[1,3]dioxolane (1 g) in THF (5 mL) was added portionwise magnesium metal (0.2 g) and the reaction heated at refluxed for 30 minutes. The mixture was cooled to room temperature and CuBr-DMS complex (846 mg, 4.11 mmol) was added. The mixture was stirred 3 minutes at room temperature, cooled to 0° C. and 1,1,1-trifluoro-4-methylpent-3-en-2-one (62 mg, 4.11 mmol) in 20 mL of THF was added dropwise. The mixture was stirred for 30 minutes at 0° C., warmed to room temperature, stirred overnight and quenched with aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford a residue that was purified by flash chromatography. Concentration in vacuo of the product-rich fractions afforded 0.56 g of 1,1,1-trifluoro-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]pentan-2-one.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.CI.[C:12]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][N:3]1[C:2]([CH3:1])=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=[N:4]1
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1c([N+](=O)[O-])cnn1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-pyrazole (4.01 g, 31.6 mmol) in DMF (60 mL) were added CH3I (8.93 g, 63.0 mmol) and K2CO3 (8.73 g, 63.2 mmol). The reaction mixture was stirred at 60° C. in a sealed tube overnight and concentrated in vacuo. The residue was diluted with water (50 mL), and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as a beige solid (1.01 g, 22.7%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][CH:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][CH:37]([NH:44][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Product: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccccc1

Procedure:
(2-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamic acid tert-butyl ester was prepared from [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 1 supra) by following the method in Example 61.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:11](Cl)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](Cl)=[O:15].C(O)(=O)C(O)=O>[N+](C1C=CC=CC=1)([O-])=O.CCO>[CH:1]1[C:6]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
7.2 g (0.2 mols) of benzene were added at ambient temperature and in a gentle stream of dry nitrogen to 26.6 g (0.2 mols) of anhydrous AlCl3 in 300 ml nitrobenzene. The mixture was heated to 100° C.; after agitation for 15 minutes at this temperature, 20.2 g (0.1 mols) of phthalic acid dichloride dissolved in 100 ml nitrobenzene were added during about 20 minutes. The volume of the solution was made up to 500 ml with nitrobenzene and the temperature was kept at 100° C. with agitation for 30 minutes, after which the reacting substance was cooled and 300 ml of saturated aqueous solution of oxalic acid was added with intense agitation. Three extractions were made, each time with 200 ml ethyl ether and the combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by crystallization from toluene, giving 17.7 g (85% yield) of 9,10-anthraquinone (1), m.p. 285° C. (literature: 286° C., EtOH).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>C(N(CC)CC)C>[F:17][C:18]([F:31])([F:32])[O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCCCOc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1ccc(OC(F)(F)F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.88 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 3-(4-trifluoromethoxyphenoxy)propylamine (1.18 g) and triethylamine (0.50 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[F:30])(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3F)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 2-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-2-fluoro-benzenesulfonamide (97 mg, 65.1%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC#N>[O:23]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.7 %

Procedure:
To a solution of 6-(Boc-amino)hexylamine (4.95 g, 23 mmol) and Et3N (2 eq, 6.4 ml, 46 mmol) in 25 ml CH3CN was added dropwise 4-phenoxybenzenesulfonyl chloride solution (1 eq, 6.16 g, 23 mmol) in 15 ml CH3CN. The reaction was stirred for 2 days at room temperature. The precipitate was filtered and the solvent was evaporated. The residue was purified by silica gel chromatography [eluent: CH2Cl2/1-2% MeOH] to yield 6.68 g (64%) a colorless oil, which solidified to a white solid, m.p.=77-78° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([CH2:21][O:22][C:23]2[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[N:24][C:23]([O:22][CH2:21][CH:18]4[CH2:20][CH2:19]4)=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1cnc(OCC2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=418.3 [M+H]+.