Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].OS(O)(=O)=O.[N+:15]([O-])(O)=O>OS(O)(=O)=O.[OH-].[Na+].[Zn]>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][NH2:15])[CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccnc(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccnc(NN)c1
Temperature: 0 °C
Yield: 77 %

Procedure:
To a solution of 5 g (40.9 mmol) of 4-ethylpyridin-2-amine in 10 mL of concentrated H2SO4 at 0° C. are added 8 mL of an H2SO4/HNO3 mixture (1/1) at a temperature of between 0 and 10° C., and stirring is maintained for 1 hour at 0° C. The reaction medium is then poured onto 100 g of ice and the white precipitate obtained is filtered off and washed successively with 10 mL of water, 10 mL of Et2O and 10 mL of pentane. The solid obtained is taken up in 100 mL of 100N NaOH at 0° C., 7.76 g (187 mmol) of zinc powder are added and the reaction medium is then stirred for 3 hours at 0° C. The reaction medium is then filtered through Celite and the filtrate is extracted with EtOAc (3×200 mL). The organic phases are combined, dried over Na2SO4, filtered and then concentrated under reduced pressure. 4.3 g of 4-ethyl-2-hydrazinopyridine are obtained in the form of a red oil, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([Cl:11])=[CH:4][N:3]=1.Br[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][N:14]=2)[C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(Br)c(C)c1
Reactant: OB(O)c1cc(Cl)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc(-c2cc(Cl)ncc2Cl)c(C)c1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
A mixture of 2,5-dichloropyridin-4-ylboronic acid (75.6 g, 0.4 mol), 2-bromo-3,5-dimethylpyridine (56.2 g, 0.3 mol), Pd(dppf)Cl2 (13.5 g, 17 mmol) and K3PO4.3H2O (162 g, 0.6 mol) in dioxane (600 mL) and H2O (120 mL) was stirred at reflux under N2 atmosphere overnight. TLC (petroleum ether/EtOAc=10:1) showed that the reaction was complete. After cooling to room temperature, the mixture was filtered. Water (500 mL) was then added to the filtrate. The mixture was extracted with dichloromethane (500 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/EtOAc=50:1 to 30:1) to give title compound (20 g, 26%) as a yellow solid. 1H NMR (400 MHz, MeOD): δ 8.54 (s, 1H), 8.31 (s, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 2.41 (s, 3H), 2.15 (s, 3H); m/z for C12H10Cl2N2 253.1 (M+H)+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH2:13][CH2:14][O:15][CH3:16])[CH2:2]1.[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[NH:19]1>O.CO>[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[N:19]1[CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: CC1CCCC(C)N1
Reactant: COCCOc1ccccc1OCC1CO1
Solvent: CO
Solvent: O
Product: COCCOc1ccccc1OCC(O)CN1C(C)CCCC1C
Yield: 76.8 %

Procedure:
A mixture of 4.5 g of 1,2-epoxy-3-[2-(2-methoxyethoxy)phenoxy]-propane, 2.4 g of 2,6-dimethylpiperidine, 30 ml of methanol and 1 drop of water is refluxed for 8 hours. The methanol is then removed, and the residue is cooled. The precipitated colorless crystals are collected by filtration, and washed with petroleum benzine to give 5.2 g of 1-(2,6-dimethylpiperidino)-3-[2-(2-methoxyethoxy)phenoxy]-2-propanol, melting at 92°-94°C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])=[O:5])C.C(O)C>O1CCCC1>[C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15]([C:17]1[C:29](=[O:30])[N:25]2[CH2:26][CH2:27][O:28][C:23]3[C:24]2=[C:19]([CH:20]=[C:21]([O:31][CH3:32])[CH:22]=3)[C:18]=1[OH:33])=[O:16])([OH:5])=[O:3]
Reactant: CCOC(=O)C1Cc2ccccc2N1C(=O)c1c(O)c2cc(OC)cc3c2n(c1=O)CCO3
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c3c(c1)c(O)c(C(=O)N1c4ccccc4CC1C(=O)O)c(=O)n3CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 2,3-dihydro-6-(2-ethoxycarbonyl-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5Hpyrido[1,2,3-de]-1,4-benzoxazine (2.8 g), 1N-sodium 35 hydroxide (20 ml), ethanol (20 ml) and tetrahydrofuran (20 ml was stirred for 2 hours at room temperature. The solvent was evaporated. The residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid to give precipitates, which were collected and washed with ethanol to afford crystals of 2,3-dihydro-6-(2-carboxy-1-indolinylcarbonyl)-7- hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4 -benzoxazine (1.6 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:12][C:13](=[O:39])/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[O:25])=[CH:18][CH:17]=1)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:38][N:35]1[CH2:34][CH2:33][CH:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]3[CH:18]=[CH:17][C:16](/[CH:15]=[CH:14]/[C:13]([OH:39])=[O:12])=[CH:21][CH:20]=3)=[CH:31][CH:30]=2)[CH2:37][CH2:36]1
Reactant: CN1CCC(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)OC(C)(C)C)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 ml of trifluoroacetic acid were added to a solution of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid tert-butyl ester (270 mg, 0.63 mmol) in 10 ml of DCM. The solution was stirred at room temperature for 2 hours. The solvent was then removed until dryness and 300 mg of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid trifluoro acetate were obtained as a yellow solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:11])=[O:10])=[N:7][N:8]=1)[CH3:2].[OH:16]O.O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:5][C:6]([S:9]([CH2:12][CH2:13][CH2:14][CH3:15])(=[O:11])=[O:10])=[N:7][N:8]=1)=[O:16])[CH3:2]
Reactant: CCCCS(=O)(=O)c1nnc(SCC)s1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CCCCS(=O)(=O)c1nnc(S(=O)CC)s1

Procedure:
A solution of 53.29 g of 2-Ethylthio-5-butylsulfonyl-1,3,4-thiadiazole in 500 ml acetic acid is mixed with 23 g of 30 percent hydrogen peroxide. The reaction takes place over night upon standing at room temperature. Then one liter water is added to the reaction solution, the separated oil is extracted with dichloromethane, the extract is freed from acetic acid by extraction with soda ash solution, the dichloromethane phase is dried with magnesium sulfate and the solvent is distilled off completely, finally in vacuo. The remaining residue is recrystallized from isopropylether/isopropanol.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:23][CH2:22]1
Reactant: NCC1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(CN)CC3)nc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 634.5 %

Procedure:
A mixture of 0.52 g (0.19 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8 -naphthyridine-3-carboxylic acid, 150 mL acetonitrile, and 0.66 g (5.76 mmole) 4-aminomethylpiperidine [J. Med. Chem., 9 441 (1966)] was stirred at room temperature for four days. The reaction was filtered and the precipitate dissolved in 500 mL of aqueous ammonium hydroxide at pH 10.5. The solution was filtered and the solvent was removed at reduced pressure. The precipitate was washed with 5 mL of water, then ether until dry to give 0.42 g of 7-[4-(aminomethyl)-1-piperidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4 -oxo-1,8-naphthyridine-3-carboxylic acid, mp 203°-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[N:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[N:29][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:33]([C:31]3[CH:32]=[N:27][CH:28]=[N:29][CH:30]=3)=[O:34])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Reactant: O=C(O)c1cncnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cncnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (100 mg, 0.22 mol) was dissolved in DMF (5 mL), and pyrimidine-5-carboxylic acid (41 mg, 0.33 mmol) was added. PYBOP (173 mg, 0.33 mmol) and diisopropylethylamine (0.16 mL, 0.89 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the precipitate was isolated by vacuum filtration to give the title compound (12 mg, 11%): HPLC MS RT=1.07 min, MH+=466.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.48 (2H, s), 9.39 (1H, s), 8.05 (1H, d), 7.47 (1H, d), 4.59 (2H, m), 4.35 (2H, br t), 4.26 (2H, m), 4.02 (3H, s), 4.00 (2H, m), 3.67 (2H, br t), 3.52 (2H, m), 3.33 (2H, m), 3.16 (2H, m), 2.27 (2H, m).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[S:7][CH:8]=1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.Cl>O.CN(C)C=O>[CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CC(C)CCNc1nc(C(C)C)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(CCC(C)C)c3nc(C(C)C)cs3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A mixture of 4-isopropyl-N-(3-methylbutyl)-1,3-thiazol-2-amine (313 mg), sodium hydride (60% oil, 50 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (318 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was dried using Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by preparative HPLC (gradient cycle A) to give the title compound (150 mg, yield 28%) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([N:6]=[C:7]([Cl:9])[CH3:8])[CH2:4][CH3:5].[Cl:10][CH2:11][CH:12]([N:15]=[C:16](Cl)[CH3:17])[CH2:13][CH3:14].O.[CH3:20][CH2:21][CH:22]([NH2:25])[CH2:23][OH:24].[OH:26]CC(NC(=O)C)CC>C(O)C.CO.C(O)(=O)C>[CH3:20][CH2:21][CH:22]([NH2:25])[CH2:23][OH:24].[Cl:1][CH2:2][CH:3]([N:6]=[C:7]([Cl:9])[CH3:8])[CH2:4][CH3:5].[Cl:10][CH2:11][CH:12]([NH:15][C:16](=[O:26])[CH3:17])[CH2:13][CH3:14]
Reactant: CCC(CO)NC(C)=O
Agent: CCC(CCl)N=C(C)Cl
Agent: CCC(N)CO
Solvent: CO
Solvent: CC(=O)O
Solvent: CCO
Product: CCC(CCl)NC(C)=O
Reaction time: 2 h

Procedure:
Hydrolysis of N-[1-(chloromethyl)propyl]acetimidoyl chloride is highly pH dependent. It has now been found that a simple hydrolysis procedure is effective. On refluxing with water N-[1-(chloromethyl)propyl]acetimidoyl chloride is transformed into a mixture of dl-2-amino-1-butanol (77%), dl-2-amino-1-butanol acetate hydrochloride (17%), the N-[1-(hydroxymethyl)propyl]acetamide (7%) and acetic acid within one hour. The product ratios appear to represent equilibrium compositions because additional heating (14 hrs.) does not materially change their distribution. If, however, the hydrolysis is carried out with aqueous methanol or ethanol, it is complete within 2 hours and the acetyl component of the product can be removed as methyl or ethyl acetate by distillation. This procedure not only decreases hydrolysis time, it also avoids the accumulation of salts in the reaction mixture, gives essentially quantitative yields of dl-2-amino-1-butanol fron N-[1-(chloromethyl)propyl]acetimidoyl chloride through N-[1-(chloromethyl)propyl]acetamide, and facilitates product work-up. Methyl acetate boils at 57° C., and is readily distilled off.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][N:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:4][CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][N:7]=1
Reactant: CC(C)N
Reactant: O=Cc1ccnc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)NCc1ccnc(Br)c1
Temperature: 25 °C

Procedure:
After a mixture of isopropylamine (2.8 mL), 2-bromopyridine-4-carboxaldehyde (3.00 g), and chloroform (60 mL) was stirred at room temperature, sodium triacetoxyborohydride (10.00 g) was added thereto and the mixture was stirred for 21 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was then stirred for a while and extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=88:12-0:100) and (NH silica gel cartridge, hexane:ethyl acetate=90:10-0:100) to afford the title compound (2.64 g).
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]1=[O:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][C:22]3=[O:31])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=c1ccc2ccccc2n1CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc2ccccc2n1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
3-(1-piperazinyl)-1,2-benzisothiazole (0.44 g, 2.0 mmoles), 1-(4-bromobutyl)-2(1H)-quinolinone (0.56 g, 2.0 mmoles) and potassium carbonate (0.33 g, 2.4 mmoles) were suspended in 4 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 hours. Insolubles were removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column to give 0.68 g (yield 80%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][C:15]1[N:16]=[N:17][NH:18][N:19]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59])[CH2:54][CH2:55][CH3:56]>CN(C=O)C.C(Cl)Cl>[CH2:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][N:63]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][C:15]2[N:16]=[N:17][NH:18][N:19]=2)[CH2:62][CH2:61]1)=[O:59])[CH2:54][CH2:55][CH3:56]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1nn[nH]n1)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 500 mg (S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyric acid in 20 ml DMF were added 701 mg HATU, 457 μl DIPEA and 343 mg 1-butoxycarbonyl-piperazine. After 3 h the solution was concentrated, the residue obtained diluted with DCM and subsequently washed with aqueous LiCl (4%) and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. Yield: 730 mg.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:16]([N:18]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH:19]1[C:27](=[O:41])[NH:28][CH:29]([CH:33]([C:35](=[O:40])[NH:36][CH:37]1[CH2:39][CH2:38]1)[OH:34])[CH2:30][CH2:31][CH3:32])=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH:37]1([NH:36][C:35]([CH:33]([OH:34])[CH:29]([NH:28][C:27]([CH:19]2[CH2:20][CH:21]3[CH:26]([CH2:25][CH2:24][CH2:23][CH2:22]3)[N:18]2[C:16](=[O:17])[CH:11]([NH2:10])[C:12]([CH3:14])([CH3:13])[CH3:15])=[O:41])[CH2:30][CH2:31][CH3:32])=[O:40])[CH2:38][CH2:39]1
Reactant: CCCC(NC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C)C(O)C(=O)NC1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC(NC(=O)C1CC2CCCCC2N1C(=O)C(N)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 10.9 %

Procedure:
Amide 93 (10.10 g, 1.0 eq) in EtOH (10 mL) was treated with 10% Pd/C (100 mg) and hydrogen gas was bubbled into the black suspension until starting material was consumed (monitored by TLC). Catalyst was removed by filtration and the filtrate concentrated in vacuo to give 852 mg (100% yield) of 1-(2-amino-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid [1-(cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-amide 94 as a white solid with consistent NMR data. 1H NMR (CDCl3) δ 4.40 (m, 1H), 4.20 (m, 1H), 4.10 (d, 1H), 3.95 (m, 1H), 2.70 (m, 1H), 2.40 (m, 2H), 2.0 (m, 2H), 1.60-1.80 (m, 6H), 1.50 (m, 2H), 1.30 (m, 3H), 1.20 (m, 1H), 1.00 (s, 9H), 0.90 (m, 3H), 0.75 (m, 2H), 0.55 (m, 2H)ppm.
Reaction SMILES: Cl[CH:2]([C:12](=O)[CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([Cl:11])[CH:5]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([NH:29][C:30]([NH2:32])=[S:31])[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>C(O)C>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[CH2:3][C:2]1[S:31][C:30]([NH:29][C:19]2[CH:20]=[CH:21][C:22]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:17]([O:16][CH3:15])[CH:18]=2)=[N:32][C:12]=1[CH3:13]
Reactant: CC(=O)C(Cl)Cc1ccc(C)c(Cl)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3ccc(C)c(Cl)c3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from crude 2-chloro-1-(3-chloro-4-methyl-phenyl)-butan-3-one and 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 56 mg (64%) of the title compound as a brown solid. MS ISP (m/e): 439.3/440.3/441.2/442.2 (100/69/50/34) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.18-7.15 (m, 3H), 7.13 (s, 1H), 6.98 (d, 1H), 6.88 (d, 1H), 6.85 (s, 1H), 3.91 (s, 2H), 3.83 (s, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(F)c1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A mixture of 3-fluorophenol (3.36 g, 30.0 mmol), ethyl 2-bromo-2-methylpropanoate (8.78 g, 45.0 mmol) and K2CO3 (6.22 g, 45.0 mmol) in acetone (50 mL) was refluxed overnight. The mixture was cooled to rt and 60 mL of water was added. The resulting mixture was extracted with DCM (40 mL×2). The combined organic phases were washed with brine (40 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=4:1) to give the title compound as colorless liquid (3.20 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of 3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AP) (0.31 g, 0.00071 mol) and benzoyl chloride (0.105 g, 0.00075 mol) in anhydrous dichloromethane (10 mL) N-ethyl-N,N-diisopropylamine (0.11 g, 0.00085 moL) was added dropwise over a 5 min. period. The stirring under nitrogen was continued for an additional 4 hours, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (30 mL) and water (25 mL). The organic phase was dried with magnesium sulfate and concentrated under the reduced pressure to yield a yellow oil which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (94:5:1) as a mobile phase to give trans-N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}benzamide as a white solid (0.250 g, 0.00045 mol). It was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.155 g, 0.00133 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give trans—N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl }-2-methoxyphenyl}benzamide dimaleate as a white solid (0.196 g, 0.000254 mol):
Reaction SMILES: C([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C>CCO.N.O.[Ni]>[NH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[N:9]=[C:8]([NH:7][C:6](=[O:5])[OH:22])[CH:13]=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: NCc1ccc(-c2cccc(NC(=O)O)n2)cc1
Reaction time: 6 h

Procedure:
A suspension of [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 24 mmol), Raney Ni (1.0 g) in EtOH (500 mL) and NH3.H2O (10 mL) was hydrogenated under H2 (50 psi.) at 50° C. for 6 h. The catalyst was filtered off and the filtrate was concentrated to dryness to give [6-(4-aminomethyl-phenyl)-pyridin-2-yl]-carbamic acid ten-butyl ester, which was used directly in next step. 1H NMR (300 MHz, CDCl3) δ 7.83-7.92 (m, 3 H), 7.70 (t, J=7.8 Hz, 1 H), 7.33-7.40 (m, 4 H), 3.92 (brs, 2 H), 1.53 (s, 9 H).