Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(O)=O.[Na+].[N:6]1([NH2:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>ClCCl>[CH2:20]([O:19][C:17](=[O:18])[NH:15][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:21]
Reactant: Nn1ccc2ccccc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1ccc2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of NaHCO3 (50 g, 0.7 mole) in 100 ml dichloromethane (DCM) was added a solution of 1H-indol-1-amine (36 g, 0.27 mole) in 200 ml DCM. After cooling to 0° C. with an ice bath, a solution of ethyl chloroformate (29 ml, 0.30 mole) in 50 ml DCM was added over a period of thirty minutes. After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil which was eluted on a silica gel column with DCM, via high performance liquid chromatography (HPLC) to give N-(1H-indol-1-yl) carbamic acid ethyl ester, 33.6 g (61%) as an oil. To a cold solution of N-(1H-indol-1-yl) carbamic acid ethyl ester (15 g, 0.07 mole) in 100 ml tetrahydrofuran, was added potassium t-butoxide (9 g, 0.08 mole), and the mixture stirred at 5° C. for one hour. To this was added 1-bromopropane (7.3 ml, 0.08 mole), and the mixture stirred at ambient temperature for five hours. The mixture was poured into 300 ml iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated, NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester as an oil, 16.5 g (91%). To a solution of N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester (16.5 g, 0.067 mole) in 35 ml ethylene glycol, was added a solution of NaOH (10 g, 0.25 mole) in 30 ml water. After stirring at 120° C. for four hours, the mixture was poured into 300 ml ice water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylamine, 9.0 g (78%) as an oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])(=[O:30])=[O:29])[CH:19]=1>>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:15][CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:4]([OH:3])=[O:16])=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]([F:38])=[CH:33][CH:34]=[CH:35][C:36]=2[F:37])(=[O:30])=[O:29])[CH:19]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(NC(Cc1ccc(Cl)cc1Cl)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
(S)-2-Amino-3-(2,4-dichloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(2,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 4-bromo-2-(2,6-difluoro-benzenesulfonylamino)-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford title compound. HPLC: RT=10.26 min. MS (ESI−): mass calcd. for C22H15BrCl2F2N2O5S, 608.2; m/z found, 607 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.36 (s, 1H), 7.87 (d, J=1.8, 1H), 7.52-7.44 (m, 1H), 7.39 (d, J=1.6, 1H), 7.27-7.25 (m, 1H), 7.25-7.22 (m, 1H), 7.18-7.15 (m, 1H), 6.97 (t, J=8.7, 2H), 6.79 (d, J=7.7, 1H), 5.05-5.00 (m, 1H), 3.50 (dd, J=14.2, 5.5, 1H), 3.29 (dd, J=14.2, 8.1, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19](=[O:27])OC4C=CC=CC=4)[CH:13]=3)[CH:9]=2)[N:4]([C:28]([NH:30][CH3:31])=[O:29])[CH:3]=1.[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][NH2:38])[CH3:33].CN(C)C=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:31][NH:30][C:28]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:39][CH3:40])[CH2:32][CH3:33])=[O:27])[CH:13]=3)=[CH:7][CH:6]=2)[C:2]([Cl:1])=[CH:3]1)=[O:29]
Reactant: CNC(=O)n1cc(Cl)c2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Reactant: CCN(CC)CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCCNC(=O)Nc1cc(Oc2ccc3c(c2)c(Cl)cn3C(=O)NC)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
Phenyl N-(4-(3-chloro-1-(methylamino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate (160 mg), 3-(diethylamino)propylamine (120 mg), N,N-dimethylformamide (5 ml) were mixed together and stirred at room temperature for 10 minutes. After the addition of aqueous sodium hydrogencarbonate, extraction was performed with ethyl acetate. The purification by silica gel column chromatography (Fuji Silysia NH, ethyl acetate and sequentially ethyl acetate:methanol=10:1) to yield the title compound as a white solid (86 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:7]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:29][O:28][C:5]1[CH:4]=[CH:3][C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:31]([F:42])([F:41])[F:30])[CH:37]=2)=[CH:7][C:6]=1[C:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cccc(C(F)(F)F)c2)cc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 120 °C
Yield: 43.7 %

Procedure:
A vial was charged with 1-(5-CHLORO-2-METHOXYPHENYL)-N-(PYRIMIDIN-4-YL)ISOQUINOLINE-6-SULFONAMIDE (Example 146; 64.66 mg, 0.151 mmol) (3-(trifluoromethyl)phenyl)boronic acid (57.5 mg, 0.303 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.11 mg, 7.57 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.47 mg, 0.015 mmol), and potassium phosphate (96 mg, 0.454 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (689 μl) and water (68.9 μl) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 120° C. The mixture was extracted with EtOAc (4×), and the combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 3.5% MeOH/DCM) to give 1-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (35.6 mg, 0.066 mmol, 43.8% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=13.02 (br. s., 1H), 8.76-8.64 (m, 2H), 8.57 (s, 1H), 8.25 (d, J=5.8 Hz, 1H), 8.12 (d, J=5.7 Hz, 1H), 8.04-7.90 (m, 4H), 7.83-7.72 (m, 2H), 7.70-7.62 (m, 2H), 7.35 (d, J=8.7 Hz, 1H), 7.03 (d, J=6.0 Hz, 1H), 3.71 (s, 3H). m/z (ESI) 537.2 (M+H)+.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:12]([NH:15][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH2:13][CH3:14]
Reactant: O=C1CCc2ccccc2C1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3,4-dihydro-1-H-naphthalen-2-one (5 g, 34 mmol) in 1,2-dichloroethane (250 mL), propyl amine (2.8 mL, 34 mmol) was added, followed by addition of sodium triacetoxyborohydride (22 g, 102 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 hours, at which time it was concentrated in vacuo. The remaining solid was partitioned between 1M sodium hydroxide and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was acidified with 1 M HCl in ether and 6.3 g of propyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine was collected as a pale pink precipitate.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH:15]=[O:16].[CH2:17](Br)[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:17][CH3:18])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[CH:15]=[O:16]
Reactant: Nc1c(C=O)c(-c2ccccc2)n[nH]c1=O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccccc2)c(C=O)c(N)c1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 5-amino-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde (Dal Piaz, V., Ciciani, G, Giovannoni, M. P., Heterocycles, 1991, 32, 1173-9) (258 mg, 1.2 mmol), ethyl bromide (294 mg, 2.7 mmol) and anhydrous potassium carbonate (240 mg, 2.4 mmol) in anhydrous DMF (5 mL) was stirred at 85° C. for 2 h. Cold water (25 mL) was added and the precipitate was collected by filtration to yield the title product (90%).
Reaction SMILES: N([CH:4](OC)[O:5]C)(C)C.[CH3:9][C:10]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[O:24][CH3:25]>CC(N(C)C)=O.C(Cl)(Cl)Cl>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:10]=1[CH2:9][CH:4]=[O:5])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc(OC)c(C)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(OC)c(CC=O)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
13.3 ml of Me2NCH(OMe)2 was added to a solution of 4.78 g of ethyl 4-methyl-3-(methoxy)-5-nitrobenzoate in 10 ml of dimethylacetamide and the mixture was heated at 80° C. in a sealed tube for 40 minutes. The mixture was diluted with CHCl3, washed with water, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography to give 4.02 g of the intended compound as a pale tan solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1.[OH-].[Na+].O>C(O)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][N:26]1[CH2:25][CH:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: BrCCc1ccc2ccccc2c1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1
Yield: 90 %

Procedure:
A mixture of 12.5 g of 2-(2-bromoethyl)naphthalene, 14 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 4.34 g of sodium hydroxide, 135 ml of water and 95 ml of 95% ethanol is heated for 5 hours under reflux, and the reaction mixture is then left to cool overnight to room temperature. The mixture is cooled to below 25° C., and then is filtered, the product thus isolated is washed with water and then dried in vacuo at 50° C. 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine base is thus obtained in a yield of 90% calculated on the starting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:24]=1)([CH3:3])[CH3:2].O.[Li+].[OH-].Cl>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:24]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cccc(C(=O)O)c3)ncnc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 149.2 %

Procedure:
The product from Example 7A (1.0 g, 3.26 mmol) was dissolved in THF (12.0 mL) and water (12.0 mL) and LiOH (390 mg, 16.29 mmol) was added and the reaction was stirred at room temperature overnight. Reaction was neutralised with 1 N HCl and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated to give the title compound (1.5 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[NH:10][CH2:9][C@@H:8]3[CH2:14][O:15][CH2:16][CH2:17][N:7]3[C:6]=2[N:5]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].O>CN(C=O)C>[Cl:3][C:4]1[N:13]=[CH:12][C:11]2[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C@@H:8]3[CH2:14][O:15][CH2:16][CH2:17][N:7]3[C:6]=2[N:5]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
Sodium hydride (60% in oil, 19.41 mg, 0.485 mmol) was added to a solution of (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 100 mg, 0.441 mmol) in DMF (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes, after which tert-butyl bromoacetate (0.078 mL, 0.529 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 20-80% EtOAc/hexane gradient) to afford the title compound as an off-white solid (101 mg, 67.2%). 1H NMR (400 MHz, CDCl3) δ 1.44-1.49 (m, 9H), 3.01-3.11 (m, 1H), 3.15-3.29 (m, 2H), 3.37 (dd, J=11.37, 8.84 Hz, 1H), 3.58 (td, J=11.94, 2.91 Hz, 1H), 3.64-3.76 (m, 2H), 3.88-4.07 (m, 3H), 4.53 (dd, J=13.89, 2.02 Hz, 1H), 7.22 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O3, 341.13. found 341.2
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:11])[O:4][C:5]([CH3:10])([CH3:9])[O:6][C:7]=1[CH3:8].[N+:12]([C:15]1[CH:20]=CC(O)=C[CH:16]=1)([O-:14])=[O:13]>C1(C)C(C)=CC=CC=1>[Cl:1][CH:2]([C:7]([CH3:8])=[O:6])[C:3]([O:4][C:5]1[CH:10]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:9]=1)=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC1=C(Cl)C(=O)OC(C)(C)O1
Solvent: Cc1ccccc1C
Product: CC(=O)C(Cl)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 135 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
A solution of 5-chloro-2,2,6-trimethyl-4H-1,3-dioxin-4-one (8.8 g, 50 mmol) and 4-nitrophenol (7.65 g, 55 mmol) in 5 ml of xylene under continuous nitrogen purge was immersed in an oil bath preheated to 110° C. The reaction was then heated to 135° C. and then stirred an additional 15 minutes. The pale brown reaction was cooled to 20° C. and the precipitated product washed with ether/hexanes to afford 10.9 g (84%) of the title compound as flaky, white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][CH:19]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH2:18]3)[CH:14]=[C:13]([NH:30][C:31]3[CH:36]=[N:35][CH:34]=[CH:33][N:32]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:22][CH2:21][CH:19]1[CH2:18][N:17]([C:15]2[N:16]=[C:11]([NH:10][C@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH3:9])[N:12]=[C:13]([NH:30][C:31]3[CH:36]=[N:35][CH:34]=[CH:33][N:32]=3)[CH:14]=2)[CH2:20]1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CNC(=O)OC(C)(C)C)C2)n1)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
80 mg of t-butyl (S)-(1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-yl)methylcarbamate was dissolved in 4 ml of dichloromethane, and 0.8 ml of trifluoroacetic acid was added thereto, and the mixture solution was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 63 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[CH3:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[S:3][C:4]=1[CH3:8]
Reactant: C1CNCCN1
Reactant: Cc1nc(I)sc1C
Product: Cc1nc(N2CCNCC2)sc1C
Yield: 25 %

Procedure:
Prepared in analogy to example 2 (b) from 2-iodo-4,5-dimethyl-thiazole and piperazine. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow crystalline solid (yield 25%). MS (m/e): 198.3 (M+H+, 100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH:23]=3)[CH2:20][C:19](=[O:35])[NH:18][C:9]=2[CH:10]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-ethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M163) (111 mg, 0.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (62 mg, 72%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)(=[O:13])=[O:12])=[O:9])=[N:4][C:3]=1[CH3:21].C[S-].[Na+].[CH3:25][OH:26]>>[CH3:25][O:26][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)(=[O:13])=[O:12])=[O:9])=[N:4][C:3]=1[CH3:21]
Reactant: CO
Reactant: Cc1cccc(S(=O)(=O)NC(=O)Nc2nc(C)c(Br)s2)c1
Agent: C[S-]
Agent: [Na+]
Product: COc1sc(NC(=O)NS(=O)(=O)c2cccc(C)c2)nc1C

Procedure:
N-[(5-Bromo-4-methyl-1,3-thiazol-2-yl)carbamoyl]-3-methylbenzenesulfonamide (41 mg, 0.11 mmol) was treated with sodium methanethiolate (31 mg, 0.42 mmol) in methanol (3.1 ml) at 80° C. for 4 days. After purification on preparative HPLC, 9 mg of the title compound were unexpectedly obtained as a white, amorph, freeze-dried solid. MS (ES): m/e 340.1 (M−H)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH2:34]([C:38]1[O:42][N:41]=[C:40]([C:43](O)=[O:44])[CH:39]=1)[CH:35]([CH3:37])[CH3:36].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C>>[CH2:34]([C:38]1[O:42][N:41]=[C:40]([C:43]([N:29]2[CH2:28][CH2:27][CH:26]([N:23]3[C:19]4=[N:20][CH:21]=[N:22][C:17]([O:16][C:15]5[CH:14]=[CH:13][C:12]([S:9]([CH3:8])(=[O:11])=[O:10])=[CH:33][CH:32]=5)=[C:18]4[CH:25]=[N:24]3)[CH2:31][CH2:30]2)=[O:44])[CH:39]=1)[CH:35]([CH3:37])[CH3:36]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: CC(C)Cc1cc(C(=O)O)no1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cc(C(=O)N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)no1
Yield: 11.7 %

Procedure:
(5-Isobutyl-isoxazol-3-yl)-{4-[4-(4-methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-methanone (8 mg, 12%) was prepared as a white solid using the conditions described in Example 152, by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27, 63 mg, 0.13 mmol) with 5-isobutyl-isoxazole-3-carboxylic acid (Matrix Scientific, Columbia, S.C., USA; 26 mg, 0.15 mmol) in the presence of TSTU (O—(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; 78 mg, 0.26 mmol) and diisopropylethylamine (0.14 mL, 0.8 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:24]1[O:33][C:32]2[C:26](=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[O:25]1.CC(O)CCC.Cl>C(O)(C)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:32]2[O:33][CH2:24][O:25][C:26]=12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1cccc2c1OCO2
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 106.3 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.1 g), 2,3-methylenedioxyaniline (0.048 g), pentan-2-ol (5 ml) and a solution of hydrogen chloride in isopropanol (6M, 4 drops) was stirred and heated to 100° C. for 5 hours. The resultant mixture was cooled to ambient temperature and the precipitate was isolated by filtration, washed with pentan-2-ol and dried under vacuum. There was thus obtained the title compound (0.138 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd6 and CF3COOD) 2.35 (m, 2H), 2.5 (m, 2H), 3.15 (m, 2H), 3.3 (m, 2H), 3.55 (d, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.1 (s, 2H), 7.0 (m, 3H), 7.4 (s, 1H), 8.2 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 439; Elemental Analysis: Found C, 52.8; H, 5.56; N, 10.68; C23H26N4O52HCl0.5H2O requires C, 53.08; H, 5.62; N, 10.77%.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[N:6]([C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:19])[CH:16]=2)[N:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10]1)=[N+:7]=[N-:8]>FC(F)(F)C(O)=O>[N:6]([C@@H:9]1[CH2:18][C:17]2[C:12](=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=[C:15]([Br:19])[CH:16]=2)[N:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10]1)=[N+:7]=[N-:8]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2cc(Br)ccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2cc(Br)cc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of sodium nitrate (30 mg, 0.40 mmol) in trifluoroacetic acid (5 mL) was added bromo azide 13 (100 mg, 0.32 mmol). The resulting solution was stirred at 25° C. for 30 min and then concentrated under reduced pressure. The crude product was then dissolved in EtOAc (50 mL) and the organic portion washed sequentially with saturated aqueous sodium hydrogen carbonate (10 mL), NaOH (1 M solution, 10 mL), and water (10 mL), dried with anhydrous Na2SO4, and then concentrated under reduced pressure. It was purified by column chromatography with petroleum ether/EtOAc (6:4 v/v) to give nitro compound 14 (108 mg) as a thick liquid.