Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[O:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:24])/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C/C(=C\c1ccc(C(=C2CC(C)(C)OC(C)(C)C2)c2ccc(O)cc2)cc1)C(=O)O
Yield: 94.8 %

Procedure:
The general hydrolysis protocol, described for 195 was followed. Thus, 1,1-dimethylethyl (2E)-3-{4-[(4-hydroxyphenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylidene)methyl]phenyl}-2-methyl-2-propenoate (212) (0.190 g, 0.41 mmol) was treated with TFA in CH2Cl2 to afford 0.158 g (95%) of the title compound 213 as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.68 (s, 1H), 7. 40 (d, J=7.8 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.1 Hz, 2H), 2.83 (d, J=5.7 Hz, 4H), 2.11 (s, 3H), 1.22 (s, 12H). LCMS (ESI): m/z 405 (M−H)−. Anal. Calcd for C26H30O4, C, 76.82; H, 7.44; Found: C, 74.81; H, 7.42.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)CCO.C(O)(=O)C.[CH:21](N)=[NH:22]>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:22][CH:21]=[N:1]2)=[CH:7][CH:8]=1
Reactant: N=CN
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: CC(=O)O
Solvent: OCCCO
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
2-Amino-4-fluorobenzoic acid and 1,3-propanediol were stirred together and heated to 120° C. Formamidine acetate was added and the mixture stirred for 3.5 hour to yield 7-fluoroquinazoline-4-one. A solution of potassium hydroxide in 1,3-propanediol was then added to the mixture over a period of 2 hours and 50 minutes, which was then cooled 15° C. Following this, the mixture was heated to 125° C. for 5 hour before cooling to 75° C. Dilute hydrochloric acid (about 6% w/w) was gradually added to the reaction mixture until pH 4.5 was achieved. The mixture was cooled to 0° C. over 6 hour and maintained at that temperature for a further hour prior to isolation of the crude product by centrifugation. The crude material washed with water and dried in vacuo before dissolving in methanol at gentle reflux and partially concentrating under reduced pressure at a temperature of 42° C. This solution was then cooled to 0° C. over a period of 3 hour and the resultant product was isolated by filtration, prior to drying in vacuo. 7-(3-Hydroxypropoxy)quinazolin-4(3H)-one was recovered in a 73% yield.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:26][O:27][CH2:28]Cl>C1COCC1>[CH:13]1([CH2:19][C:20]2([CH2:26][O:27][CH3:28])[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COCCl
Reactant: O=C1OCCC1CC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCC1(CC2CCCCC2)CCOC1=O
Temperature: -78 °C
Reaction time: 4.5 h
Yield: 25 %

Procedure:
A solution of diisopropylamine (19.0 mL) in THF was treated dropwise with butyl lithium (82.5 mL of 1.6M solution in hexanes) at −10° C. Next the reaction mixture was cooled to −78° C. and treated dropwise with 2-(cyclohexyl-methyl)-γ-butyrolactone (18.0 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the mixture was stirred for 4.5 h at −78° C., then warmed-up to −40° C. and treated dropwise at this temperature with chloromethyl methyl ether (10.8 mL). After that, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature for 60 h. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, then washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and finally distilled in vacuum to give 5.90 g (25%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[NH2:15][C:16]1[NH:17][CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:20]=1[C:21]([NH2:23])=[O:22]>O1CCCC1.O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([C:19]2[C:20]([C:21]([NH2:23])=[O:22])=[C:16]([NH:15][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[NH:17][CH:18]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: CCN=C=O
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)c[nH]c1N
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Reaction time: 16 h
Yield: 46.7 %

Procedure:
0.074 cm3 (0.891 mmol) of ethyl isocyanate and 0.005 mg (0.040 mmol) of dimethylaminopyridine are added, at a temperature close to 25° C., to a solution of 0.2 g (0.81 mmol) of 2-amino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide in 15 cm3 of tetrahydrofuran. After stirring for 16 hours at a temperature close to 60° C., the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is stirred in 100 cm3 of water and then extracted with three times 50 cm3 of ethyl acetate. The organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (95/2.5/2.5 by volume)]. After concentrating the fractions under reduced pressure, 0.120 g of 4-(4-nitrophenyl)-2-(3-ethylureido)-1H-pyrrole-3-carboxamide is obtained in the form of a yellow powder. ES+: m/z=318 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:44][C@@H:45]([CH3:48])[CH2:46][OH:47])=[O:14])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a cooled (0° C.) solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 1) (0.80 g, 1.77 mmol) in DMA (3.2 mL) was added isobutyl chloroformate (0.28 mL, 2.13 mmol) and 4-methylmorpholine (0.25 mL, 2.30 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added (S)-(+)-2-amino-1-propanol (0.21 mL, 2.66 mmol) and DMAP (0.02 g, 0.18 mmol). Stirred at ambient temperature overnight. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=509) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a pale yellow foam (0.61 g, 67%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][C:14]([OH:16])=O.C([Li])CCC.Cl>C1COCC1.CCCCCC>[F:11][C:8]([F:9])([F:10])[C:6]1[CH:7]=[C:2]2[C:3]([CH2:12][CH2:13][C:14]2=[O:16])=[CH:4][CH:5]=1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCc2ccc(C(F)(F)F)cc21
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
To a solution of 3-[2-bromo-4-(trifluoromethyl)phenyl]propanoic acid (6.40 g, 21.5 mmol) in THF (300 mL) and hexane (80 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexane (19 mL). After being stirred for 15 min, the mixture was poured into a 2 N HCl solution (150 mL). The two layers were separated and the water layer was extracted by ether. The combined organic layers were washed with NaHCO3 solution, water, brine, dried over MgSO4 and concentrated. Column chromatography on silica (10-20% EtOAC in hexane) provided the title compound (2.2 g, 51%) as an oil. MS calculated for C10H7F3O: (M+H)+201; found 201.0.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CN(C)C=O.C(OCC)(=O)C>[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[CH2:15][S:13][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(SCc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
79.7 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 303.1 mg of 4-acetamidothiophenol in 6 ml of dimethylformamide at room temperature, followed by the addition of a solution of 454.8 mg of 2-bromomethyl-benzothiazole in 1 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was diluted with ethyl acetate, washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 462.7 mg (yield 81%) of the title compound as a solid having a melting point of 147° to 149° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1)[CH2:9]2.[C:24](OC(=O)C)(=[O:26])[CH3:25].CO>C(Cl)Cl>[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:19][CH:20]=1)[CH2:9]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CCN(Cc1ccc([C@H](C)N)cc1)C2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1cccc2c1CCN(Cc1ccc([C@H](C)NC(C)=O)cc1)C2
Temperature: 25 °C

Procedure:
To 80 mg (0.24 mmol) (S)-1-[4-(5-methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-ethylamine hydrochloride (example XXXIII.2) in 2.0 mL DCM are added 67 μL (0.48 mmol) TEA and 34 μL (0.26 mmol) acetic anhydride and the resulting mixture is stirred at r.t. over night. 200 μL MeOH are added and the reaction mixture is purified by HPLC.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([NH:9][C:11]1[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCOC(=O)c1csc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCNc1nc(C(=O)OCC)cs1

Procedure:
The reaction described in Preparation 26 was repeated, but using 2.7 g of octylamine, 4.0 g of ethyl 2-chlorothiazole-4-carboxylate, 4.2 g of triethylamine and 15 ml of dimethylformamide, giving the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]2([CH3:15])[CH3:14])=[CH:6][C:5]=1[CH2:18][CH3:19])[CH3:3].[ClH:20].C[CH:22]([NH2:37])[C:23]1C=[CH:27][C:26](CCC2C=CC=CC=2)=[CH:25][CH:24]=1>>[ClH:20].[CH2:18]([C:5]1[CH:6]=[C:7]2[C:12]([C:11]([CH3:15])([CH3:14])[CH2:10][CH2:9][C:8]2([CH3:17])[CH3:16])=[CH:13][C:4]=1[CH:2]([N:1]=[C:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:37]1)[CH3:3])[CH3:19]
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CCc1cc2c(cc1C(C)N)C(C)(C)CCC2(C)C
Agent: Cl
Product: CCc1cc2c(cc1C(C)N=C1CCCCCN1)C(C)(C)CCC2(C)C

Procedure:
Following essentially the same procedure described in Example IV above and substituting 7-(α-aminoethyl)-6-ethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-[1-(7-ethyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)ethylimino]hexahydro-1H-azepine hydrochloride, having a M.P. of 246.5°-7.5° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](SC)[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:19]=1[NH2:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:20][C:19]3[C:18]([Cl:17])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:25])[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: CSC1=Nc2ccc(Cl)cc2C(=O)N(C)C1
Reactant: Nc1c(Cl)cccc1Cl
Product: CN1CC(Nc2c(Cl)cccc2Cl)=Nc2ccc(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 20.38 g (0.08 m) of 7-chloro-3,4-dihydro-4-methyl-2-methylthio-5H-1,4-benzodiazepine-5-one and 64.81 g (0.40 m) of 2,6-dichloroaniline is stirred and heated to 225° for 1 1/2 hr. The reaction mixture is cooled to room temperature and crystallized from ether to give the crude product, 7-chloro-2-(2',6'-dichloroanilino)-3,4-dihydro-4-methyl-5H-1,4-benzodiazepine-5-one, m.p. (230) 240° - 245°. Recrystallization from acetone-ether and from methanol-isopropanol gives white solid with m.p. 247° - 249.5°.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.COCCN(S(F)(F)[F:32])CCOC.C(=O)(O)[O-].[Na+]>O>[CH:1]([N:14]1[CH2:17][CH:16]([F:32])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 250 mL, round bottom flask was charged with 3.0 g (12.5 mmol) of 1-benzhydryl-3-hydroxyazetidine and 80 mL of dichloromethane. To the stirring solution at −78° C. was added 4.6 mL (25 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 3 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise (with caution) to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with 80 mL of dichloromethane. The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography using a Biotage® system (gradient, hexane to 80% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>C1COCC1>[OH:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([NH:32][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=2)[CH2:34][CH2:35]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 48 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol), trans-4-aminocyclohexanol hydrochloride (151 mg, 1 mmol), and triethylamine (0.28 mL, 2 mmol) were combined in THF (10 mL) and stirred under Ar at 50° for 2 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-20% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a pale yellow crystalline solid. mp 148-151°, LC MS m/z=463 (MH+) Retention time=2.0 min.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][NH:31][C:30](=[O:34])[CH2:29]4)=[CH:26][N:27]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Nc1ccc(N2CCNC(=O)C2)cn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNC(=O)C4)cn3)nc2n1C1CCCC1
Yield: 23 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.34 mmol) and 4-(6-amino-pyridin-3-yl)-piperazin-2-one (111 mg, 0.578 mmol) gave 7-cyclopentyl-2-[5-(3-oxo-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (35 mg, 35%). MS (ESI) m/z 449.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
5.55 g of 4-Fluoro-3-nitro-benzoic acid were dissolved in 50 ml of methanol, 6.4 ml of concentrated sulfuric acid were added and the reaction was heated to reflux for 3 h. The reaction was cooled, poured unto ice and the precipitated product was collected by suction and dried in vacuo. 5.40 g (90%) of 4-fluoro-3-nitro-benzoic acid methyl ester were obtained.
Reaction SMILES: [CH2:1]=[CH2:2].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:9])[CH3:2]
Reactant: Cc1ccccc1
Reactant: C=C
Solvent: CC(=O)O
Product: CCc1ccccc1C
Reaction time: 16 h

Procedure:
The catalyst from Example II is then soaked in glacial acetic acid for 15 minutes at ambient temperature. The catalyst is then dried and calcined at 500° C. for 16 hours. Using the same reaction conditions as in Example II, toluene is reacted with ethylene in the presence of such an acetic acid-treated catalyst. Ethylation of toluene gives 7.1% conversion of toluene to produce an ethyltoluene product which contains 92.3% of the para-ethyltoluene isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[CH:5]2.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(N(CC)CC)C>[CH2:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([NH:1][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[CH:10][CH:9]=2)[CH3:12]
Reactant: CCc1cc2cc(N)ccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1

Procedure:
The above compound could be synthesized by treating 5-amino-2-ethylindole with p-toluenesulfonyl chloride in the presence of triethylamine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OC)=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[N:14]=2)[CH:3]=1.[NH3:21].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:21])=[O:9])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[N:14]=2)[CH:3]=1
Reactant: COC(=O)c1nnc(Cl)cc1Nc1ccc(Cl)c(C)n1
Reactant: N
Solvent: CO
Product: Cc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 116 %

Procedure:
A pressure tube was charged with methyl 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxylate (600 mg, 1.92 mmol) and an ammonia solution in methanol (7M, 20 mL, 140 mmol). The reaction mixture was heated to 50° C. and was stirred for 18 h. The mixture was cooled and concentrated in vacuo to give 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (665 mg crude, 116%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 11.69 (br. s., 1H), 9.18 (s, 1H), 8.20 (br. s., 1H), 7.61 (d, J=8.59 Hz, 1H), 6.77 (d, J=8.59 Hz, 1H), 5.71 (br. s., 1H), 2.65 (s, 3H). LC-MS 298 [M+H]+. This material was used directly in the next step without further purification.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:36]([OH:38])=O)=[C:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:30]=2)=[CH:22][CH:21]=1.[C:39]([O:43][C:44]([N:46]1[CH2:49][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].CN1CCOCC1>C1COCC1>[C:39]([O:43][C:44]([N:46]1[CH2:47][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH:57][C:36]([C:28]3[S:27][C:26]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=4)=[N:30][C:29]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:38])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:49]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)Nc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)c(OC)c1
Temperature: 5 °C
Yield: 89.8 %

Procedure:
Mix 1-propanephosphonic acid cyclic anhydride (50% in EtOAc) (528.7 g, 831.3 mmol) and THF (1110 mL) and chill to 5° C. Add 2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carboxylic acid (185.0 g, 593.43 mmol) followed by 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (192.2 g, 914.4 mmol). Charge N-methylmorpholine (99 mL, 1247 mmol) dropwise over 15 min and remove the ice bath immediately after the addition. Heat the reaction to 65° C. for 16 h and quench with water (555 mL). Dilute with EtOAc (1110 mL) and partition the layers. Wash with saturated sodium bicarbonate (555 mL) and with brine (555 mL). Distill the organic solvent until <5% THF remains and then back-add with ethyl acetate as needed to a total of 740 mL solvent at the end of the distillation. Add heptane (230 mL) at 75° C. and seed with authentic product at 55° C. Allow to cool to room temperature, filter, and rinse twice with heptane-EtOAc (2×100 mL, 1:1). Dry in a vacuum oven at 40° C. to obtain 313.5 g (90%) of the title compound as an orange-brown solid. ES/MS m/z (35Cl) 586 [M−1]−.