Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][O:17][C:18](=[O:25])[CH:19](Cl)[C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:16][O:17][C:18](=[O:25])[CH:19]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1cccc(OC)c1)C(=O)OC
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-methoxyphenol (115 g) in acetone (1000 ml) was added K2CO3 (115 g). The suspension was stirred at 40° C. for 15 min. A solution of dimethylchloromalonate (133 ml) in acetone was added over a period of 45 min. The resulting brown suspension was stirred overnight at 70° C. Finally, the solvent was removed under reduced pressure and the residue was taken up in water (1000 ml) and extracted twice with DCM (500 ml). The combined organic layers were washed with water (500 ml), dried over Na2SO4, and evaporated to give crude dimethyl-(3-methoxyphenoxy)malonate (230 g) as an orange oil. The product was not purified any further.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23]O)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:50]1[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:50]4[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]4)=[N:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)nc3)no2)cc1F
Reactant: COC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(F)c4)n3)cn2)C1
Reaction time: 0.17 h
Yield: 59 %

Procedure:
{5-[5-(3-Fluoro-4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.16 g, 0.47 mmol) that was obtained in Example 23 (23H), carbon tetrabromide (0.23 g, 0.71 mmol), and triphenylphosphine (0.19 g, 0.71 mmol) were dissolved in dichloromethane (6 ml) at 0° C. and stirred at the same temperature for 10 minutes. After stirring, the reaction mixture was evaporated in vacuo, and the residue obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:6) to afford the reaction intermediate. Subsequently, to a solution of the reaction intermediate obtained in dichloromethane (7 ml) were added successively methyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.71 mmol) and N,N-diisopropylethylamine (0.25 ml, 1.4 mmol) with stirring, and the resulting mixture was stirred at room temperature for 13 hours. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (2 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:12) as the eluent to afford the title compound (0.12 g) in a yield of 59% as a white crystalline solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[C:12]([C:16]1([OH:39])[CH2:21][CH2:20][N:19]([C:22]([CH:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][CH2:27][C:26]3[CH:35]=[CH:36][CH:37]=[CH:38][C:25]2=3)=O)[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[C:12]([C:16]1([OH:39])[CH2:21][CH2:20][N:19]([CH2:22][CH:24]2[C:25]3[CH:38]=[CH:37][CH:36]=[CH:35][C:26]=3[CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=3)[CH2:18][CH2:17]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)C1(O)CCN(C(=O)C2c3ccccc3CCc3ccccc32)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)C1(O)CCN(CC2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a cooled solution of lithium aluminum hydride in tetrahydrofuran (35.3 parts by volume of 0.9 M) is added 0.85 parts by volume of concentrated sulfuric acid dropwise over 5 minutes. The resultant mixture is stirred at 0° C. for about 1 hour and then solution of 3 parts of 4-tert-butyl-1-[(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-carbonyl]-4-piperidinol in 50 parts by volume of tetrahydrofuran is added over a 5 minute period. The resultant mixture is allowed to warm to room temperature and stirred at that temperature for about 24 hours. Then, the mixture is cooled in an ice bath and quenched with the careful sequential addition of 1.2 part by volume of water, 1.2 part by volume of 15% sodium hydroxide, and 3.6 parts by volume of water. The resultant mixture is stirred for about 4 hours, the aluminum salts removed by filtration and washed well with ethyl ether. The filtrate is concentrated in vacuo to give 4-tert-butyl-1-[(10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)methyl]-4-piperidinol, as a colorless glass which crystallizes on standing. This compound is identical to that obtained in Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].CC(C)=O>[Zn].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cccc(Cl)c1N
Temperature: 23 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To a solution of 3-chloro-2-nitro-phenylamine (1.73 g, 10.0 mmol), NH4Cl (2.68 g, 50.0 mmol), acetone (40 mL) and water (10 mL), was added zinc powder portion-wise (three equal portions over 5 minutes) (3.26 g, 50.0 mmol) at 0° C. The mixture was stirred for 2 h then warmed to 23° C. The mixture was filtered through Celite® and the solvents were concentrated under reduced pressure. The mixture was re-dissolved in EtOAc/DCM and filtered a second time through Celite® and the solvents were evaporated. The crude mixture was diluted with EtOAc (100 mL), washed with brine (40 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-50% EtOAc/hexanes) to yield the titled compound (1.00 g, 70%). MS (ESI/CI): mass calcd. for C6H7ClN2, 142.0; m/z found, 143.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 6.86-6.78 (m, 1H), 6.65-6.58 (m, 2H), 3.74 (br s, 2H), 3.46 (br s, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:55][C:56]([F:67])([F:66])[C:57]1[CH:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15]([C:60]4[CH:61]=[CH:62][C:57]([C:56]([F:67])([F:66])[F:55])=[CH:58][CH:59]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(C(F)(F)F)cc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Yield: 55 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 36 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=1:2) to obtain the title compound (55%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24]C(=O)C2C=CC=CC=2)=[N:9]3)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.Cl.CON>C(O)C>[NH2:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:9]=1
Reactant: N#Cc1ccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Agent: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#Cc1ccc([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(N)=N3)s1
Temperature: 55 °C
Yield: 85.8 %

Procedure:
To N-[(4aR,7aR)-7a-(5-cyanothiophen-2-yl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (442 mg, 0.951 mmol) in ethanol (19 mL) is added pyridine (752.6 mg, 9.5 mmol) and O-methylhydroxylamine HCl (794.6 mg, 9.5 mmol). The mixture is heated to 55° C. under an atmosphere of nitrogen for 12 hours. The mixture is concentrated, dissolved in dichloromethane and concentrated again. The residue is dissolved in ethyl acetate and water and washed with saturated aqueous NaHCO3. The phases are separated and the aqueous phase extracted with ethyl acetate (30 mL). The organic phases are combined, dried over Na2SO4, filtered, and concentrated. The residue is purified with silica gel chromatography eluting with a 70:30 to 0:100 hexane/ethyl acetate gradient. The isolated product is repurified with silica gel chromatography eluting with 70:30 dichloromethane/ethyl acetate for 20 minutes and then a gradient to 0:100 to give the title product (294 mg, 86%). ES/MS (m/e): 361 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:22]#[N:23])([C:14]2[C:19](F)=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[OH-].[Na+].O>C1COCC1.O1CCOCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:14]3[C:19](=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=3)[NH:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ncc(Cl)cc2F)CC1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1cc(Cl)cnc12
Yield: 38 %

Procedure:
A mixture of 5-chloro-4′-cyano-3-fluoro-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (0.05 g) and lithium tri-tert-butoxyaluminohydride (0.57 ml), 1M solution in THF) in 1-4-dioxane (0.75 ml) was refluxed under nitrogen for 4 hrs. After cooling, 1 N NaOH and H2O and ethyl acetate were added slowly to the mixture at 0° C. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with saturated sodium bicarbonate, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography [SiO2; hexane-ethyl acetate-triethylamine (75:25:1)] to give 18 mg g (38%) of 6-chloro-4-aza-spiro[indoline-3,4′-piperidine]-1′-carboxylic acid tert-butylester; MS (ES+) 324 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:17]([O:15][C:14](=[O:16])[C@H:6]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])[NH2:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCO
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCOC(=O)[C@@H](N)CCCNC(=N)N
Temperature: 90 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
One millimole thionyl chloride was added to a stirred suspension of one millimole L-arginine free base in 50 mL of octanol under nitrogen. The mixture was heated to 90° C, and the temperature was maintained with stirring for 2 hours. The mixture was cooled to 60° C, one more equivalent of thionyl chloride was added, and the mixture was stirred at 60° C. for an additional 2 hours, at which time the reaction was seen to be complete by TLC (performed as described in Example 33). Excess thionyl chloride was allowed to evaporate. Then, the solution was cooled to room temperature, and 250 ml diethyl ether was added. Washing of the resultant soft white precipitate with saturated sodium bicarbonate solution gave a white solid. Filtration of this suspension and washing of the filtrate with saturated sodium bicarbonate solution (3× with 20 ml), water (3× with 20 ml), acetone (3× with 20 ml) and diethyl ether (3× with 20 ml) gave arginine octyl ester. The yield was 85%. FAB mass spectrometry gave the expected parameters for arginine octyl ester.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:14]([N:17]2[CH:22]3[CH2:23][CH2:24][CH2:25][CH:18]2[CH2:19][N:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:21]3)(=[O:16])=[O:15])[CH2:6]1)=[O:4].[Li+].[OH-].O1CCCC1.FC(F)(F)C1C=CC(C2CCNCC=2)=CC=1>CO>[F:36][C:33]([F:34])([F:35])[O:32][C:29]1[CH:28]=[CH:27][C:26]([N:20]2[CH2:21][CH:22]3[N:17]([S:14]([C:11]4[CH:10]=[CH:9][CH:8]=[C:7]5[C:12]=4[CH2:13][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]5)(=[O:16])=[O:15])[CH:18]([CH2:25][CH2:24][CH2:23]3)[CH2:19]2)=[CH:31][CH:30]=1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Agent: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3C4CCCC3CN(c3ccc(OC(F)(F)F)cc3)C4)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid methyl ester (13 mg, 0.025 mmol), 1N LiOH (2 mL), tetrahydrofuran (8 mL), and methanol (2 mL) was stirred at rt for 3 h. The reaction was poured into 1N HCl (40 mL) and extracted with ethyl acetate (40 mL×2). The combined organic extracts were dried, filtered, and concentrated to give 4-[3-(4-trifluoromethoxy-phenyl)-3,9-diaza-bicyclo [3.3.1]nonane-9-sulfonyl]-indan-2-carboxylic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.19 (d, 2H), 6.92 (d, 2H), 4.04-3.97 (m, 2H), 3.74-3.67 (m, 2H), 3.44-3.30 (m, 3H), 3.26-3.10 (m, 2H), 2.96-2.86 (m, 2H), 2.26-2.15 (m, 1H), 1.86-1.72 (m, 4H), 1.51-1.43 (m, 1H); MS (ESI): 511.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(Br)(Br)Br.CC(=O)OCC>C(Cl)Cl>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:2]=1[Br:1]
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)ccc1Br
Yield: 84.5 %

Procedure:
To a solution of compound methyl 2-bromo-5-methoxybenzoate (100 g, 410 mmol) in DCM (2000 mL) was added and BBr3 (1N, 150 mL) at −78° C. under N2 The mixture was stirred at 0° C. under N2 for 24 hr. The reaction was quenched with MeOH (500 mL), concentrated to dryness, diluted with H2O (50 mL), and extracted with ethyl acetate (800 mL*3), The organic phase was washed with saturated sodium bicarbonate solution 50 mL, dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography eluted with PE:EA=1:1 to give title product (80 g, 85% yield) as yellow oil. LCMS (10-80 AB—2MIN.M): Rt=0.820, purity=85%, M+1=231.
Reaction SMILES: [N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=O)=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:26]=C=NC2CCCCC2)CCCCC1.N.ClCCl.C(=O)([O-])O.[Na+]>ClCCl>[N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([NH2:26])=[O:19])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)Cc1ccc2c(c1)CCc1cccnc1O2
Yield: 37.6 %

Procedure:
A mixture of 40 mg of (5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetic acid, 60 mg of dicyclohexylcarbodiimide and 2 ml of dry dichloromethane was stirred under ice cooling. To the resulting mixture was added 8 ml of a saturated liquid ammonia-dichloromethane solution, and the mixture was stirred for 3 hours. After the completion of the reaction, this was basified with a saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a light yellow oil, which was chromatographed over 4 g of silica gel and eluted with chloroform/ethyl acetate (10/1-8/2) to obtain crystals. These were recrystallized from ethyl acetate to yield 15 mg (yield: 40%) of (5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetamide as light yellow needle crystals having a melting point of 164°-165° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](OCC3C=CC=CC=3)=O)=[CH:20][C:19]=2[F:35])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:41][CH2:42][C@@H:43]1[O:45]C1)(=[O:40])CCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][C@H:42]([CH2:43][OH:45])[O:41][C:36]3=[O:40])=[CH:20][C:19]=2[F:35])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(NC2CCN(C(=O)OCc3ccccc3)CC2)c(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(Nc2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 6.6 g (15 mmol) 4-(4-benzyloxycarbonylamino-2-fluoro-phenylamino)-piperidine-1-carboxylic acid benzyl ester in 50 ml THF at −78° C. was added dropwise 12.12 ml nBuli 1.6 M (19.5 mmol). The mixture was further stirred at this temperature for 10 min. The resulting yellow solution was allowed to reach −40° C. over 10 min. 3.0 ml (21 mmol) of (R)-glycidyl butyrate was then added and the solution was allowed to reach slowly RT and further stirred for 16 h. The reaction was quenched with a saturated ammonium chloride solution, diluted with 400 ml of EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by chromatography using a CH2Cl2/MeOH 5% mixture.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C@@H:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[C:18]4=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]4[C:16]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[N+:37]([O-])=O)=[CH:26][CH:25]=4)=[N:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.C(O)(=O)C>C(O)C.[Pd]>[NH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:17]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:23])[N:14]([C@H:11]3[CH2:12][CH2:13][C@@H:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)[N:15]=2)=[CH:29][CH:28]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5[N+](=O)[O-])cc4)c4c(N)ncnc43)CC2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccccc5N)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A mixture of cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2nitrophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.059 g, 0.091 mmol, 1 equiv), glacial acetic acid (0.03 mL, 0.5 mmol, 5 equiv), and 10% Pd-C (0.024 g, 0.4 wt/wt equiv) in ethanol (1 mL) was stirred at room temperature under a positive pressure of H2 for 16 h. Solids were removed by filtration with the aid of CH2Cl2 (10 mL) and the filtrate was concentrated to afford a yellow oil. The residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 10%-60% acetonitrile-0.1M ammonium acetate over 20 min, 21 mL/min). The acetonitrile was removed in vacuo and the aqueous mixture was lyopholyzed to afford cis-3-[4-(2-aminophenoxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid (0.018 g, 0.036 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.22 (1H, s), 7.59 (2H, d, J=8.6 Hz), 7.05 (2H, d, J=8.7 Hz), 6.85-6.98 (3H, m), 6.58-6.61 (1H, m), 4.93 (2H, bs), 4.78-4.80 (1H, m), 2.20-2.50 (11H, m), 2.14 (3H, s), 2.05-2.09 (2H, m), 1.55-1.70 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.00 min. MS: MH+ 499.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8](N)[S:9][C:5]=2[CH:4]=1.[C:13]([Cu])#[N:14]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([C:13]#[N:14])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(N)sc2c1
Reactant: N#C[Cu]
Product: COc1ccc2nc(C#N)sc2c1
Yield: 22.1 %

Procedure:
6-methoxybenzo[d]thiazol-2-amine (9 g, 50 mmol) was reacted with CuCN (8.96 g, 100 mmol) according to the procedure as described in Example 61, Step A to give the title compound as a white solid (2.1 g, 22%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.[NH:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[NH2:7]>CCCC(C)C>[C:1]1(=[N:7][NH:6][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCC1
Solvent: CCCC(C)C
Product: CC(C)(C)OC(=O)NN=C1CCC1
Temperature: 25 °C

Procedure:
A mixture of cyclobutanone (16.96 ml, 227 mmol) and tert-butyl hydrazinecarboxylate (30 g, 227 mmol) in isohexane (378 mL), under nitrogen was stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The resulting suspension was filtered, rinsing the solid with iso-hexane (×2). The solid was dried under vacuum at 30° C. to afford the title compound;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1>O.CN(C)C=O.C(#N)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 45.3 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.1 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-chlorophenyl)-1,8-naphthyridine (1.8 g). The product obtained by precipitation in water (2.2 g; m.p. 210° C.) is dissolved in a boiling mixture of dimethylformamide (20 cc) and acetonitrile (100 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Chlorophenyl)1,8-naphthyridin-2-yl]-3-bromobenzamide (1.4 g), m.p. 220°-224° C., is obtained.