Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][Br:25])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1>C(OCC)(=O)C>[Br-:25].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21]([CH:22]=[CH:23][CH2:24][N+:33]4[C:32]([CH3:31])=[CH:36][S:35][CH:34]=4)=[O:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cscn1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CC[n+]1cscc1C
Product: [Br-]
Yield: 36.4 %

Procedure:
A solution of 0.7 g (1.4 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 0.85 g (8.6 mmol) of 4-methyl thiazole was refluxed for 17 hr. The mixture was diluted with ethyl acetate and cooled. Solid was collected and recrystallized from methanol-acetone-ethyl acetate to give 0.3 g of the title compound as a yellow powder: mass spectrum (electrospray, m/e): M+507.9, 509.8, (M+H)+22254.4, 255.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(Cl)cccc2o1
Product: Clc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 11.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (15 mg, 97=mol) and 2-(but-3-ynyl)-4-chlorobenzo[d]oxazole (20 mg, 97 μmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 3 mg (11 μmol, 11%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cccc(C(F)(F)F)c4)c3)c2cc1OC
Yield: 73.3 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 3-(trifluoromethyl)phenyl isocyanate (42 uL, 0.3 mmol) using the procedure in Example 182 to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (109 mg, 0.22 mmol, 73%). 1H NMR (300 MHz, DMSO-d6) δ 9.13 (s, 1H), 9.03 (s, 1H), 8.70 (s, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7.62-7.41 (m, 4H), 7.39-7.24 (m, 4H), 3.99 (s, 6H); LC-MS (ESI) m/z 501 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:36]=[C:37]([CH:61]=[CH:62][C:63]=1[F:64])[CH2:38][N:39]1[C:44](=[O:45])[C:43]([CH2:46]OS(C)(=O)=O)=[CH:42][C:41]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([F:60])[CH:53]=2)=[N:40]1.CN1CCNCC1>>[F:34][C:35]1[CH:36]=[C:37]([CH:61]=[CH:62][C:63]=1[F:64])[CH2:38][N:39]1[C:44](=[O:45])[C:43]([CH2:46][N:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[CH:42][C:41]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[C:54]([F:60])[CH:53]=2)=[N:40]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)c(F)c3)n2)cc1F
Yield: 55 %

Procedure:
Following the procedure of Example 1 (10), 2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as slightly-yellow neeldes (yield: 55.0%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([OH:17])[CH2:16][CH2:15][C:10]2(OCC[O:11]2)[CH2:9][CH2:8]1.Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(OCC)C>[OH:17][C:7]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9][C:10](=[O:11])[CH2:15][CH2:16]1
Reactant: OC1(c2ccccn2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C1CCC(O)(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
8-(2-Pyridinyl)-1,4-dioxaspiro[4.5]decan-8-ol (2.70 g) was dissolved in 1:1 THF/H2O (20 mL) then 3N HCl (10 mL) added. Refluxed for 2 hours then stirred overnight at room temperature. Worked up by slowly adding neat sodium bicarbonate until foaming ceased then extracted the mixture 3 times with ethyl acetate. The organic layers were combined, dried (sodium sulfate) and stripped to give an amber oil which solidified. The solids were dissolved in diethyl ether (10 mL). Hexanes (10 mL) were added which precipitated the solids which were then filtered to give 4-hydroxy-4-(pyridin-2-yl)cyclohexanone (680 mg) as a tan solid. MS found: (M+H)+=192.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[N:7][NH:8][C:9]1[N:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[Br:21]Br>CC(O)=O.O>[Br:21][C:6](=[N:7][NH:8][C:9]1[N:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: BrBr
Reactant: CCOC(=O)C=NNc1ccc(Cl)nn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(Br)=NNc1ccc(Cl)nn1
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of compound 1-ethoxycarbonylmethylene-2-(6-chloro-3-pyridazinyl) hydrazine (11.4 g, 0.05 mol) and sodium acetate (11 g, 0.05 mol) in 50 mL of HOAc, bromine (8 g, 0.05 mol) in HOAc was added dropwise during 20 min. Stirring was continued for 3 h, the mixture was diluted with water (1 L), the precipitated crystals were filtered off, washed with water to give product ethyl 2-bromo-2-(2-(6-chloropyridazin-3-yl)hydrazono)acetate as a yellow solid (10 g, 66%). 1H NMR (300 MHz, d6-DMSO): δ 9.33 (br, 1H), 7.69-7.66 (d, J=9.0 Hz, 1H), 7.50-7.47 (d, J=9.0 Hz, 1H), 4.44-4.37 (q, 2H), 1.43-1.39 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[C@H:10]([F:16])[C@H:9]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].CP(C)C.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[C@H:10]([F:16])[C@H:9]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])[C@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F

Procedure:
A solution of (2R,3R,4R)-4-azido-2-(3-chloro-2-fluoro-benzylcarbamoyl)-3-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (described in Scheme B19) (485 mg, 1.16 mmol), trimethylphosphine in THF (2.33 mL, 2.33 mmol) and water (0.04 mL, 2.33 mmol) in THF (20 mL) was stirred for 16 h at RT. The reaction mixture was quenched with water and extracted twice with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 95:5). MS (UPLC/MS): 390/392 [M+H]+, 434/436 [M+HCOO]−; tR (HPLC conditions f): 1.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])(=[O:25])=[O:24])=[CH:21][CH:22]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc3)n2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(S(=O)(=O)NCCC(=O)O)cc3)n2)cc1Cl
Yield: 70.5 %

Procedure:
To a solution of tert-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)propanoate (0.28 g, 0.536 mmol) in dichloromethane (6.0 ml) was added TFA (2.0 ml, 26.0 mmol). After about 3 h the reaction mixture was concentrated in vacuo and the resulting solid was triturated with ether, filtered and dried to provide 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)propanoic acid (0.176 g, 70%) as a colorless solid. LCMS (Table 1, Method c) Rt=2.54 min, m/z 466 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([OH:14])=[C:9]([CH3:15])[C:8]=1[CH3:16].[CH3:17][C:18](=C)[CH2:19]O.[C:22](=O)(O)[O-].[Na+]>ClCCl>[NH2:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:22])[C:10]2[O:14][C:18]([CH3:19])([CH3:17])[CH2:15][C:9]=2[C:8]=1[CH3:16]
Reactant: O=C([O-])O
Reactant: C=C(C)CO
Reactant: Cc1cc(O)c(C)c(C)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Yield: 16.9 %

Procedure:
Sulfuric acid (2.0 ml) was added to a solution of 4-amino-2,3,5-trimethylphenol (2.0 g, 13.2 mmol) and 2-methyl-2-propenol (1.15 g, 15.8 mmol) in dichloromethane (20 ml) and the mixture was heated under reflux for 18 hours under an argon atmosphere. The reaction solution was made weak alkaline with aqueous saturated sodium bicarbonate solution and the organic layer was separated. The organic layer was washed with water, dried and then concentrated. The residue was purified by column chromatography on silica gel eluting with isopropyl ether. The product obtained was recrystallized from hexane to obtain the desired product as crystals (460 mg, yield: 16.9%), m.p. 110°-111° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][N:8]=2)[CH:2]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:11]=[C:10]([C:12]([Cl:18])=[O:14])[O:9][N:8]=2)[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2cccnc2)no1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(-c2cccnc2)no1
Temperature: 25 °C

Procedure:
600 mg (3.16 mmol) of 3-(pyridin-3-yl)-1,2-oxazole-5-carboxylic acid were initially charged in dichloromethane, and three drops of DMF were added. 1.16 g (9.15 mmol) of oxalyl chloride were added dropwise under argon (vigorous evolution of gas). The reaction solution was stirred at room temperature and then the solvent was removed on a rotary evaporator. 30 ml of toluene were added to the residue. After the toluene had been removed on a rotary evaporator, the residue was converted further directly.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:17]([OH:20])(=[O:19])=[O:18].Cl.C[O-].[Na+:24]>C(Cl)(Cl)Cl>[S:17]([O-:20])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:19])=[O:18].[Na+:24]
Reactant: CCCCCCC(C)CCCCCCO
Reactant: O=S(=O)(O)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methyltridecanol (107 g, 0.5 mol), prepared as an intermediate in Example I. Chlorosulfonic acid (61.3 g, 0.52 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with an ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until a aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added methanol (1 L) and 300 ml of 1-butanol. Vacuum filter off the inorganic salt precipitate and remove methanol from the filtrate on a rotary evaporator. Cool to room temperature, add 1 L of ethyl ether and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (76 g, 90% active by cat SO3 titration).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([C:16]2[S:53][C:19]3[N:20]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]5[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:40][C:39]=4[F:52])[C:21](=[O:36])[N:22]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:27])[C:23](=[O:24])[C:18]=3[CH:17]=2)[CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[CH:13]1([C:16]2[S:53][C:19]3[N:20]([CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[C:50]5[NH:3][C:4](=[O:7])[O:5][N:51]=5)=[CH:40][C:39]=4[F:52])[C:21](=[O:36])[N:22]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:27])[C:23](=[O:24])[C:18]=3[CH:17]=2)[CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: COc1ccc(C(=O)Cn2c(=O)c3cc(C4CC4)sc3n(Cc3ccc(-c4ccccc4C#N)cc3F)c2=O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cn2c(=O)c3cc(C4CC4)sc3n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2=O)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 41.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[6-cyclopropyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.95 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (40 mL). N,N′-Carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.44 g, 42%).
Reaction SMILES: C([O:4][C:5]1C2[C:9](=[CH:10][CH:11]=[CH:12]C=2)[CH2:8][CH2:7][CH:6]=1)(=O)C.[O:15]=[O+][O-].N#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C[C:41]([CH3:43])=[O:42]>CO>[O:4]=[CH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:43]=1[C:41]([OH:15])=[O:42]
Reactant: O=[O+][O-]
Reactant: CC(=O)OC1=CCCc2ccccc21
Reactant: CC(C)=O
Agent: Cl
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: O=CCCc1ccccc1C(=O)O
Temperature: -10 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
At -50° C., 200 mL of MeOH were added to a solution of the enol acetate of Step 1 (214 g, approx. 1.04 mol) in 800 mL of acetone. At -78° C., ozone was bubbled through this solution for 7 h (or until the excess of O3 produced a green color). The excess of ozone was blown away by a stream of N2 and a solution of triphenylphosphine (327 g, 1.25 mol) in 1 L of acetone was then added slowly at -78° C. The temperature was slowly raised to -10° C. over 30 min. 1N HCl (700 mL) was slowly added and the mixture was stirred at 3° C. for 16 h. The organic solvent were evaporated, 500 mL of EtOAc were added and the mixture was alkalinized with an excess of NaHCO3 (approx. 270 g). The aqueous phase was washed with EtOAc (2×1 L) and the organic layers were reextracted with 1 L of saturated NaHCO3 by agitation over 2 h. The combined aqueous extracts were then acidified with conc. HCl and extracted with EtOAc. The extract was dried over Na2SO4, the solvent was evaporated and the acetic acid was co-evaporated with toluene to yield 139.6 g of the title compound (75% for Steps 1 and 2) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:17]2([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[C:19]([NH2:27])=[N:18]2)[CH:14]=[CH:15][CH:16]=1>>[F:26][C:23]1[CH:24]=[C:25]2[C:20]([C:19]([NH2:27])=[N:18][C:17]2([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[C:13]2[CH:12]=[CH:11][CH:16]=[C:15]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:14]=2)=[CH:21][CH:22]=1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cc(F)ccc21
Reactant: OB(O)c1cccnc1
Product: NC1=NC(c2ccncc2)(c2cccc(-c3cccnc3)c2)c2cc(F)ccc21

Procedure:
The title compound was prepared as described in Example 78 (Scheme #14, N) using pyridin-3-ylboronic acid and 1-(3-bromophenyl)-6-fluoro-1-pyridin-4-yl-1H-isoindol-3-amine (Example 82) (18.5% yield): 1H NMR (DMSO-d6) δ 8.77 (m, 1 H), 8.55 (dd, J=4.80, 1.52 Hz, 1 H), 8.46 (m, 2 H), 7.95 (m, 1 H), 7.87-7.81 (m, 2 H), 7.59 (m, 2 H), 7.47 (m, 1 H), 7.39-7.44 (m, 2 H), 7.37-7.31 (m, 3 H), 6.96 (br s, 2 H); MS (ESI) m/z 381 [M+1]+.
Reaction SMILES: [O-:1]O.[C:3]1([CH:9](C)C)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CC(C)=O>[C:3]1([OH:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:4][C:3]([CH3:9])=[O:1]
Reactant: [O-]O
Reactant: CC(C)c1ccccc1
Solvent: CC(C)=O
Product: Oc1ccccc1
Temperature: 57 °C

Procedure:
Following the procedures of Example 2, to a 250-ml round-bottom flask fitted with condenser, heater, stirrer and feed control, is charged a mixture of 60.0 g of acetone and 0.1 g of heteropoly acid (12-molybdophosphoric acid, 12-tungstosilicic acid and 12-molybdosilic acid) modified Clay-24 prepared by the method of Example 1. The mixture is heated to reflux (57° C.) with stirring and 40.0 g of the 80% cumene hydroperoxide solution of Comparative Example A added dropwise such that the pot temperature does not exceed 68° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[CH:11]1[N:10]=[CH:9][N:8]2[CH2:2][CH2:3][CH2:4][C:5](=[O:6])[C:7]=12
Reactant: O=C(CCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCCn2cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
4-Hydroxy-1-(1-trityl-1H-imidazol-4-yl)butan-1-one (25.22 g) was dissolved in tetrahydrofuran (120 ml). Triethylamine (0.021 ml) and methanesulfonyl chloride (0.012 ml) were added and the mixture was stirred at room temperature for 1 h. Water (100 ml) was added under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Acetonitrile (100 ml) was added and the mixture was refluxed under heating for 2 h. The reaction mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=20:1→5:1) and washed with diethyl ether to give the title compound (2.10 g) as a pale-brown powder.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17](Cl)(=[O:21])[O:18][CH2:19][CH3:20].[OH-:23].[Na+]>C(Cl)(Cl)Cl>[CH:11]1([N:10]([C:17]([O:18][CH2:19][CH3:20])=[O:23])[CH2:9][CH2:8][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:17]([O:18][CH2:19][CH3:20])=[O:21])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)Cl
Reactant: [OH-]
Reactant: C1CCC(NCCNC2CCCCC2)CC1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(CCN(C(=O)OCC)C1CCCCC1)C1CCCCC1

Procedure:
The N,N'-dicyclohexyl-N,N'-bis(ethoxycarbonyl)-ethylenediamine (m.p. 108° C.) is prepared by reacting N,N'-dicyclohexylethylenediamine with ethyl chlorocarbonate in chloroform at 10°-20° C. in the presence of aqueous NaOH. The obtained product has a purity of 99.7% and is used directly.
Reaction SMILES: Cl.[I:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([N:35]([CH3:42])[C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>ClCCl.O>[NH2:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:5]([CH:13]3[CH2:17][CH2:16][N:15]([C:37](=[O:38])[C:36]([N:35]([CH3:42])[C:33](=[O:34])[O:32][CH2:31][CH:29]4[C:28]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:22]5[C:30]4=[CH:18][CH:19]=[CH:20][CH:21]=5)([CH3:41])[CH3:40])[CH2:14]3)[N:4]=[C:3]([I:2])[C:11]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)N1CCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 125.4 %

Procedure:
To a solution of rac-3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrochloride (0.100 g, 0.273 mmol) in dichloromethane (5 mL) was added 2-[[(9H-9-fluorenylmethoxy)carbonyl](methyl)amino]-2-methylpropanoic acid (0.120 g, 0.354 mmol), 1-hydroxy-7-azabenzotriazole (0.041 g, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.068 g, 0.35 mmol), and diisopropylethyl amine (0.18 g, 0.24 mL, 1.4 mmol). The reaction mixture was stirred at room temperature for 5 h and then poured into water (10 mL). The organic phase was separated and washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford rac-9H-9-fluorenylmethyl N-{2-[3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)tetrahydro-1H-1-pyrrolyl]-1,1-dimethyl-2-oxoethyl}-N-methylcarbamate as a yellow solid (0.223 g) which was used in subsequent reactions without further purification. RP-HPLC Rt 13.688 min, 63% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 652 (MH+).