Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][C:12]2=[O:15])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][CH:12]2[OH:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)CCC2
Temperature: 5 °C

Procedure:
In a mixture of 150 ml of methanol and 50 ml of tetrahydrofuran, 24.1 g of 7-methoxycarbonyl-3,4-dihydro-(2H)-1-naphthalenone was dissolved and 5 g of sodium borohydride was added by portions with ice cooling. The mixture was stirred at 5° C. for an hour and successively the solvent was distilled off under reduced pressure. The concentrated residue was adjusted to pH 2 by adding a 2N aqueous hydrochloric acid solution and extracted with chloroform. The chloroform layer was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude intermediate 7-methoxycarbonyl-1,2,3,4-tetrahydro-1-naphthol. The crude intermediate was dissolved in 150 ml of benzene, 5 g of Amberlyst 15 was added, a Dean-Stark Trap was mounted, and the mixture was refluxed by heating for 2 hours. After cooling, the reaction mixture was filtered and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography using a mixture, ethyl acetate: n-hexane=1:10, as a developer. 7-methoxycarbonyl-3,4-dihydronaphthalene thus obtained was 19.2 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15](Cl)[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccccc1N1CCN(CCCO)CC1
Temperature: 0 °C
Reaction time: 10 h
Yield: 76.8 %

Procedure:
46 g of 1-(2-methoxyphenyl)-piperazine and 24.5 g of trimethylene chlorohydrine are dissolved in 200 ml of ethanol, and 25 g of potassium carbonate are added to the solution. The mixture is refluxed for 30 hours, thereafter it is cooled to 0° C., diluted with 50 ml of ethyl ether, filtered, and the filtrate is evaporated. The residue is dissolved in 100 ml of 50° C. benzene, the solution is cooled to 0° C., and allowed to stand for 10 hours. The separated crystals are filtered off and dried. 46 g (77%) of 3-[4-(2-methoxyphenyl)-piperazin-1-yl]-1-hydroxy-propane are obtained; m.p.: 92°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH3:10][O:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:13](=[O:14])[C:12]([O:11][CH3:10])([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COC(C)(C)C(=O)O
Reactant: Nc1ccc(F)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(C)(C)C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
A stirred solution of 6.1 grams (42 mmole) of 3-chloro-4-fluoroaniline, 5.0 grams (42 mmole) of 2-methoxy-2-methylpropanoic acid, and 10.5 grams (55 mmole) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 120 mL of methylene chloride was cooled to about 0° C., and 7.4 grams (55 mmole) of 1-hydroxybenzotriazole was added. Upon completion of the addition the reaction was slowly warmed to ambient temperature, where it stirred for about 18 hours. After this time the reaction mixture was poured into water, and the resulting mixture was filtered through diatomaceous earth to remove any salts that had precipitated. The organic layer was separated from the aqueous layer, washed with an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a brown oil, which was passed through a silica gel scrub plug, yielding 5.0 grams of N-(3-chloro-4-fluorophenyl)-2-methoxy-2-methylpropionamide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH:7]([C:12]([F:15])([F:13])[F:14])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cnc2NC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)cnc2NC1C(F)(F)F
Temperature: 50 °C
Yield: 22.5 %

Procedure:
The ester from Step 4 (1.3 g, 4.4 mmol) and 2.5 N sodium hydroxide solution (3.5 mL, 9 mmol) were mixed in tetrahydrofuran (25 mL), methanol (10 mL), and water (25 mL). The mixture was heated at 50° C. for 4 hours, allowed to cool to room temperature, and was concentrated in vacuo to remove the tetrahydrofuran and methanol. The resulting aqueous solution was washed with diethyl ether (2×100 mL). The aqueous phase was acidified with 3 N HCl causing the precipitation of a yellow solid (1.1 g). The solid was triturated with ethanol-acetone and collected by vacuum filtration providing the title compound as a yellow solid (276 mg, 23%): mp 287.4–288.4° C. 1H NMR (acetone-d6/300 MHz) 11.50 (br s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.28 (br s, 1H), 5.42–5.30 (m, 1H). Anal. Calc'd for C10H6N2O2F3Cl: C, 43.11; H, 2.17; N, 10.05 Found: C, 42.88; H, 2.03; N, 10.06.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17](Br)=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])[CH3:2].[CH2:21]([N:25]1C=CN=C1)CCC>C1(C)C=CC=CC=1.[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([C:21]#[N:25])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])[CH3:2]
Reactant: CCCCn1ccnc1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2c(s1)CCOc1ccc(C#N)cc1-2

Procedure:
A mixture of 9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (500 mg), potassium ferrocyanide (dried, 104 mg), copper (I) iodide (27 mg) and 1-butylimidazole (0.37 mL) in toluene (3 mL) was reacted in the microwave at 160° C. for 4 h. The mixture was then partitioned between dichloromethane (30 mL) and water (20 mL). The organic layer was dried (MgSO4), reduced in vacuo and purified on silica to give 9-cyano-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2].O.O[Li].O>C1COCC1>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=3)[NH:13][CH:12]=2)[C:8]([C:37]#[N:38])=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(NC(C)C)ncc3C#N)c3cc(Nc4ccccc4)cnc32)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Nc1ncc(C#N)c(-c2c[nH]c3ncc(Nc4ccccc4)cc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
2-(isopropylamino)-4-(5-(phenylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (0.083 g, 0.158 mmol) was stirred in THF (7 mL) and water (1.5 mL) and treated with LiOH.H2O (0.066 g, 1.60 mmol, 10.0 Eq) and allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated and purified by column chromatography (50% EtOAc/Petroleum ether) to yield the product as a yellow solid (29 mg, 50%)
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=[C:8]([C:29]([O:31]C)=[O:30])[O:7][C@H:6]1[C:33]([O-:35])=O)(=[O:3])[CH3:2].Cl.[C:37]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][CH2:46][CH2:47][CH3:48])=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][C@H:5]1[C@H:6]([C:33](=[O:35])[N:45]([CH2:44][CH2:43][C:40]2[CH:39]=[CH:38][C:37]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[CH:42][CH:41]=2)[CH2:46][CH2:47][CH3:48])[O:7][C:8]([C:29]([OH:31])=[O:30])=[CH:9][C@@H:10]1[OH:11])(=[O:3])[CH3:2]
Reactant: CCCNCCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)C1=C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H](NC(C)=O)[C@H](C(=O)[O-])O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCN(CCc1ccc(-c2ccccc2)cc1)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](O)[C@H]1NC(C)=O
Temperature: 23 °C
Reaction time: 24 h
Yield: 85.2 %

Procedure:
To a solution of (2R,3R,4S)-3-acetylamino-4-(tert-butyldiphenylsilanyloxy)-3,4-dihydro-2H-pyran-2,6-dicarboxylic acid, 6-methyl ester (2.0 g), (2-biphenyl-4-yl-ethyl)propylamine hydrochloride (1.33 g) and diisopropyl ethylamine (2.52 ml) in anhydrous dimethylformamide (5 ml) was added 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (1.55 g). The reaction was stirred at 23° C. for 24 hours then diluted with ethyl acetate (200 ml) and washed with water (2×200 ml), dilute hydrochloric acid (100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml). The organic phase was dried over anhydrous magnesium sulphate and the solvent was removed in vacuo and the residue was chromatographed over silica (Merck 9385, 20 g) using medium pressure (ca 4 psi) and cyclohexane/ethyl acetate (10:1 v/v) as the eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a white solid (1.6 g). 1H NMR (250 MHz, D6 -DMSO rotamers) 8.16+8.12 (1H,2×d, J=10 Hz), 7.64 (8H, m), 7.53-7.30 (11H, m), 5.50 (1H, m), 5.11 (1H, m), 4.54+4.40 (1H, 2×m), 4.26 (1H, m), 3.71+3.65 (3H, 2×s), 3.6-3.1 (4H, m), 2.92 (1H, m), 2.82 (1H, m), 1.81+1.79 (3H, 2×s), 1.62 (1H, m), 1.52 (1H, m), 1.02 (9H, s), 0.91+0.82 (3H, 2×t, J=7 Hz). Mass analysis: C43H50N2O6Si. Required: C, 71.84; H, 7.01; N, 3.90. Found: C, 71.54; H, 7.33; N, 3.88.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[CH2:13][CH2:12][C:11]6[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=6[NH:9][C:8]5=[O:18])[CH2:5][CH2:6]4)[CH:21]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(N4CCc5ccccc5NC4=O)CC3)ncn2)cc2oc(=O)n(C)c12

Procedure:
98 mg (0.40 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.12 g (0.40 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.14 mL (0.80 mmol) DIPEA were stirred in 3 mL DMF for 2 h at RT. The mixture was diluted with methanol, and the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:47](=[O:48])[N:12]2[C:13]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:14]([NH:17]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:15][S:16][C@H:11]12)=[O:8].C(Cl)Cl.CO.[H][H]>[Pd].C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:47](=[O:48])[N:12]2[C:13]([C:31]([O:33][CH:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:32])=[C:14]([NH2:17])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(NC(=O)OCc3ccc([N+](=O)[O-])cc3)CS[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: NC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Yield: 97.8 %

Procedure:
A solution of 0.178 g. (0.26 mmole) of benzhydryl 7-(2-thienylacetamido)-3-(4-nitrobenzyloxycarbonylamino)-3-cephem-4-carboxylate in 3 ml. of methylene chloride was combined with 70 ml. of methanol and 0.178 g. of 5 percent palladium on carbon (prereduced with hydrogen at 50 psi for 15 minutes) in 30 ml. of 3A ethanol. The alcoholic mixture was reduced with hydrogen at 50 psi for 3.5 hours. The catalyst was filtered and washed with hot 3A ethanol. The filtrate and washings were combined and evaporated in vacuo to dryness. A methylene chloride solution of the residue thereby obtained was filtered through a celite filter pad. Evaporation in vacuo to dryness provided 128 mg. (97.8 percent) of the title product as a yellow froth: ir (CHCl3) 1720 cm-1 (β-lactam); nmr (CDCl3) δ3.7 (ABq, C2--H), 3.92 (s, 1, side chain CH2), 5.01 (d, 1, J=4.0 Hz, C6--H), 5.32 (q, 1, J = 4.0 Hz, and 8.0 Hz, C7 --H), and 6.3 (NH).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.[CH:86]1([NH2:92])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1>>[CH:86]1([NH:92][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:4])[CH3:5])[CH:31]=3)[CH:36]=2)=[O:41])[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: NC1CCCCC1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CCCCC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.83 g) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cyclohexylamine (0.18 mL) in a similar manner as described in Example 24-(i) to give the titled compound (598 mg) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=1)([O-])=O>[Pd].C(O)C>[N:11]1([CH2:10][CH2:9][N:7]2[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cnn(CCN2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnn(CCN2CCCC2)c1
Reaction time: 2 h

Procedure:
A mixture of 4-nitro-1H-pyrazole (5.00 g, 44.22 mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (8.86 g, 52.42 mmol), acetonitrile (50 mL) and potassium carbonate (19.00 g, 137.50 mmol) was heated at 80° C. under an argon atmosphere for 16 hours. The reaction mixture was evaporated in vacuo and partitioned between water and dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. 4-Nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole was isolated as an orange solid (8.50 g, 91%). MP=39-41° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.29 (s, 1H), 8.06 (s, 1H), 4.27 (t, J=6.22 Hz, 2H), 2.95 (t, J=6.17 Hz, 2H), 2.55 (s, 4H), 1.80 (s, 4H). MS=211 (MH)+. 219b) A mixture of 4-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole (4.40 g, 20.9 mmol), ethanol (100 mL) and 10% palladium on carbon (0.41 g, 30.7 mmol) was hydrogenated in a Paar shaker at 30 psi under hydrogen for 2 h. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated in vacuo. 1-(2-Pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine was isolated as an orange oil, which became a dark gummy material upon standing at room temperature (3.10 g, 82%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.15 (s, 1H), 7.08 (s, 1H), 4.14 (t, J=7.00 Hz, 2H), 2.88 (t, J=6.97 Hz, 4H), 2.52 (s, 4H), 1.765 (s, 4H). MS=181 (MH)+. 219 c) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine was synthesized from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.487 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.105 g, 0.585 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. The isolated pure product was treated with 2N hydrogen chloride in dioxane. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine hydrochloride was isolated as a light green solid (70 mg, 30%). MP=Softened at 155-161° C. then melted at 234-236° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.47 (s, 1H), 9.57 (s, 1H), 8.80 (d, J=6.44 Hz, 1H), 8.45 (d, J=8.20 Hz, 2H), 8.105 (d, J=8.20 Hz, 2H), 7.99 (d, J=7.09 Hz, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.17 (t, J=6.88 Hz, 1H), 4.55 (t, J=5.88 Hz, 2H), 3.655 (d, J=5.44 Hz, 2H), 3.48 (brs, 2H), 3.32 (s, 3H), 2.99 (brs, 2H), 2.00 (brs, 2H), 1.86 (brs, 2H). MS=452 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:4]3[CH:3]=[C:2]([NH:1][S:25]([C:22]4[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=4)(=[O:27])=[O:26])[CH:7]=[CH:6][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(-n2ncc3c(N)ncnc32)c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
Title compound 11B, 1-(3-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (40 mg, 1.1 eq, 0.18 mmol), 4-chlorobenzenesulphonylchloride (34 mg, 1.0 eq, 0.16 mmol) and diisopropylethylamine (28 μl, 1.0 eq, 0.16 mmol) were added to DMF (1 ml) and the mixture was stirred for 18 hours at room temperature under an inert atmosphere. Methanol was then added (1 ml) and the solvents were removed in vacuo. The resultant oil was purified by semi-preparative HPLC to yield the title compound as a white solid (45 mg, 0.11 mmol, 70%). LCMS: [M+H]+=401, Rt=1.80 min, 100% purity.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.O.[NH2:15][NH2:16].O>CCO>[N:11]1[C:10]2[C:5]([C:3]([NH:15][NH2:16])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:13][CH:12]=1
Reactant: COC(=O)c1cccc2[nH]cnc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cccc2[nH]cnc12
Temperature: 25 °C

Procedure:
Benzimidazole ester 3 (1.65 g, 9.36 mmol), hydrazine monohydrate (10 mL), and water (3 mL) were refluxed in EtOH (60 mL) for 24 hs. Reaction mixture was cooled to room temperature and solid formed was filtered, washed with EtOH and dried to give 1.13 g (68%) of pure 4: 1H NMR (DMSO-d6) δ 12.31 (br.s, 1H), 10.59 (s, 1H), 8.44 (s, 1H), 7.86 (d, 1H, J=6.5 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.34 (t, 1H, J=8.0 Hz), 4.68 (s, 2H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.O.C(O)C.C([O-])(=O)C.[Na+]>C(O)C.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH:18][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)=[CH:13][CH:12]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1C=C(NNc2ccc(F)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
The title compound was prepared by a modification of a published procedure (Brueckner R. et al., European Patent EP 1 424 337 A1 (2004)). To a stirred solution of cyclohexane-1,3-dione (10 g, 0.089 mol) in ethanol (50 mL) and water (150 mL) was added portionwise under nitrogen over 15 minutes 4-fluorophenyl hydrazine hydrochloride (14.5 g, 0.089 mol). After 10 minutes 120 mL of 3:1 (v/v) water/ethanol was added in three portions. Solid sodium acetate (7.2 g) was then added portionwise over 45 minutes. The mixture was stirred for another 30 minutes at room temperature. The brown solid was collected, washed with 2×30 mL of 3:1 (v/v) water/ethanol and water, and dried in vacuo overnight to provide the title compound (16.48 g). MS (ES): [M+H]+ @m/z 221.1.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[C:24]([F:32])[CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:35][CH:34]=[CH:33][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[C:24]([F:32])[CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=4)=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: NCc1ccc(F)cc1
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NCc3ccc(F)cc3)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.4 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added [(4-fluorophenyl)methyl]amine (1.01 mL, 8.89 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure and purified via SiO2. This lead to a yellow solid containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a 10% ammonium chloride solution, saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide (67 mg, 0.104 mmol) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 3.06-3.18 (m, 4 H), 3.76 (s, 3 H), 4.16 (t, J=8.29 Hz, 2 H), 4.51 (d, J=5.86 Hz, 2 H), 6.17 (d, J=1.19 Hz, 1 H), 6.81-7.01 (m, 3 H), 7.13 (t, J=8.84 Hz, 2 H), 7.38 (dd, J=8.29, 5.72 Hz, 2 H), 7.78 (s, 1 H), 8.43 (d, J=11.90 Hz, 1 H), 8.51 (s, 1 H), 9.14-9.25 (m, 1 H), 10.38 (s, 1 H), 11.32 (br. s., 1 H). (ESIMS (M+H)+=645)