Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]([CH2:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[CH2:13][C:10]4[O:9][C:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[N:12][N:11]=4)=[CH:20][CH:21]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Cc1nnc(Cc2ccccc2)o1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cc4nnc(Cc5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-benzyl-5-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-[1,3,4]oxadiazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:33][C:34]([CH3:39])([CH3:38])[C:35](=[S:37])[NH2:36].O>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:37][C:35]([C:34]([CH3:39])([CH3:38])[CH3:33])=[N:36][C:9]=2[C:11]2[C:12]([F:24])=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)C(N)=S
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (30 g, 85.9 mmol) (Intermediate 20) in DMA (300 mL), NBS (15.3 g, 85.9 mmol) was added. The reaction mixture was stirred at rt for 1 h. Then 2,2-dimethylpropanethioamide (11.0 g, 94.5 mmol) was added at 0° C. The mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with EtOAc (200 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the title compound. (11 g, 35.4% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J=5.27 Hz, 1H), 8.12-8.19 (m, 1H), 7.12-7.25 (m, 2H), 6.80-6.88 (m, 2H), 5.85-5.98 (m, 1H), 5.20-5.37 (m, 2H), 4.61-4.67 (m, 2H). MS (ES+): 447 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11]Cl)=[N:5][N:4]=[N:3]1.SN1NC[C:18](=[O:21])[C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=2[NH:15]1.[OH-].[Na+]>CO>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][S:7][C:6]2[NH:5][NH:4][C:18](=[O:21])[C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=3[N:15]=2)=[N:5][N:4]=[N:3]1
Reactant: O=C1CNN(S)Nc2ccccc21
Reactant: Cn1nnnc1SCCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nnnc1SCCCCSC1=Nc2ccccc2C(=O)NN1
Yield: 136.5 %

Procedure:
1-Methyl-5-(4-chlorobutyl)thio-1,2,3,4-tetrazole (2.00 g) and 2-mercapto-3H,4H-benzotriazepin-5-one (2.2 g) are dissolved in methanol (50 ml), and thereto is added sodium hydroxide (4.8 g), and the mixture is refluxed at 2.5 hours. After the solvent is distilled off, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with 5% aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is recrystallized from methanol to give 1-methyl-5-[4-(3H,4H-1,3,4-benzotriazepin-5-on-2-yl)thiobutyl]thio-1,2,3,4-tetrazole (2.4 g) as colorless prisms, m.p. 94°-95° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7]Br)=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[O-:13][CH2:14][CH3:15].[Na+].C(O)C.O.Cl>C(O)C>[Br:1][C:2]1[O:6][C:5]([CH2:7][O:13][CH2:14][CH3:15])=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: CC[O-]
Reactant: COC(=O)c1cc(Br)oc1CBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOCc1oc(Br)cc1C(=O)OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of methyl 5-bromo-2-(bromomethyl)furan-3-carboxylate (4.5 g) in ethanol (50 mL) was added 20% sodium ethoxide-ethanol solution (7.8 g) at 0° C., and the mixture was stirred at 0° C. for 2 hr and at room temperature overnight. The reaction was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (2.8 g, 67%) as an oil.
Reaction SMILES: C([C:5]1[CH:33]=[CH:32][C:8]([N:9](O[SiH](C)C)[C:10]2[CH:15]=[C:14]([N:16]([CH2:25][C:26]#[N:27])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)(C)(C)C.[F-].[O:35]1CCCC1>>[OH:35][C:5]1[CH:33]=[CH:32][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][C:26]#[N:27])[C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[Br:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(N(CC#N)c2cc(N(O[SiH](C)C)c3ccc(C(C)(C)C)cc3)ncn2)c(Br)c1
Reactant: C1CCOC1
Agent: [F-]
Product: Cc1ccc(N(CC#N)c2cc(Nc3ccc(O)cc3)ncn2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 4-(4-tertbutyldimethylsilyloxyanilino)-6-(N-cyanomethyl-2-bromo-4-methylanilino)pyrimidine (Reference Example 2, 890 mg) in tetrahydrofuran (1 ml) was added N,N,N,N-tetraburylammonium fluoride (1M solution in tetrahydrofuran, 2 ml). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was evaporated and the residue partitioned between EtOAc and water. The organic layer was separated and dried (MgSO4), evaporated and purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 95:4:1 to give the title compound (510 mg, 73%) as a solid. M/z 410 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=2)([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1ccc(Br)cc1F
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Yield: 38.7 %

Procedure:
To a solution of 1-bromo-3,4-difluorobenzene (4 g, 20.7 mmol) in dry diethyl ether (25 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 8.3 mL, 20.7 mmol). The mixture was stirred at −78° C. for 1 h after which a solution of 1-benzylpyrrolidin-3-one (3.62 g, 20.7 mmol) in dry diethyl ether (15 mL) was added drop wise. The mixture was stirred at −78° C. for 15 min and at ambient temperature for 1 h after which aqueous saturated ammonium chloride solution (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification twice by flash chromatography on silica gel (isooctane/ethyl acetate, 4:1 to 1:1 and 3:2 isocratic) gave the title compound (2.32 g). MS m/z (relative intensity, 70 eV) 289 (M+, 4), 198 (23), 133 (29), 132 (23), 91 (bp). The enantiomers were separated by chiral HPLC (Kromasil 5-Cellucoat, heptane/2-propanol/diethyl amine, 99:1:0.1). Yield: enantiomer E1, 0.81 g, enantiomer E2 0.835 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:30]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC2CC2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.65 g, 5.4 mmol) in dry CCl4 (60 mL), NBS (0.96 g, 5.4 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5 g) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[O:24]1[CH2:27][CH:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][C:35]=3[NH2:40])[CH2:30][CH2:29]2)[CH2:25]1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:40][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:34]=2[N:31]2[CH2:30][CH2:29][N:28]([CH:26]3[CH2:25][O:24][CH2:27]3)[CH2:33][CH2:32]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccccc21
Reactant: Nc1cnccc1N1CCN(C2COC2)CC1
Solvent: CN1CCCC1=O
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cnccc1N1CCN(C2COC2)CC1
Temperature: 100 °C

Procedure:
To a suspension of benzotriazol-1-yl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (prepared according to methods similar to the one depicted in Preparation 2a) (5 g, 15.62 mmol) in NMP (78.27 mL) was added 4-[4-(oxetan-3-yl)piperazin-1-yl]pyridin-3-amine (prepared according to methods similar to the one depicted in Preparation N-1, described below) (3.660 g, 15.62 mmol) and the resulting mixture heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and then passed through a pre-wetted SCX cartridge (2×50 g cartridge) and the cartridge was washed with methanol. The product was eluted with 2M ammonia in methanol and the eluent was concentrated in vacuo to leave a dark solid that was purified by column chromatography on silica using the ISCO column companion, eluting with DCM and 90:10:1 DCM:MeOH:NH3 (0-100% gradient, 40 g column) Product fractions were combined and concentrated in vacuo to leave the product as a yellow solid which was then recrystallised from methanol to leave pure product as a yellow solid. MS (ES+) 413.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Reactant: OB(O)c1ccccc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(-c2ccccc2)cc1F

Procedure:
In analogy to example 57.1, (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2) was reacted with phenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-biphenyl-4-yl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].Cl[CH2:21][C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:6]=2[C:5](=[O:18])[N:4]([CH2:21][C:22](=[O:24])[CH3:23])[C:3]1=[O:19]
Reactant: CC(=O)CCl
Reactant: CC(=O)CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCCCn1cnc2c1c(=O)n(CC(C)=O)c(=O)n2C

Procedure:
This compound was prepared by alkylation of 3-methyl-7-(5-oxohexyl)-xanthine with chloroacetone in dimethylformamide in the presence of potassium carbonate at 100° C. for 1.5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]1([N:29]2[C:33]([NH:34][C:35](=O)[O:36]C3C=CC=CC=3)=[CH:32][C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:33]2[N:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:30]=[C:31]([C:44]([CH3:50])([CH3:49])[C:45]([F:48])([F:47])[F:46])[CH:32]=2)=[O:36])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-ylcarbamate (104 mg, 0.3 mmol) described in the previous step. The reaction mixture was stirred at rt overnight, then concentrated under reduced pressure. The crude was purified by silica gel chromatography (hexane/ethyl acetate 25-100%) and triturated in diethyl ether to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(1-phenyl-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)urea (103 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.56 (s, 6H), 4.02 (s, 6H), 6.55 (s, 1H), 6.94 (d, J=9 Hz, 1H), 7.17 (d, J=9 Hz, 1H), 7.34-7.57 (m, 9H), 8.55-8.59 (m, 2H), 9.28 (s, 1H); LC-MS (ESI) m/z 593 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:30]1([CH3:39])[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:39][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[O:38])=[CH:32][CH:31]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 93 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 15 ml of methylene chloride is added dropwise a solution of p-tolyl isocyanate in 10 ml of methylene chloride under nitrogen at room temperature. After complete addition, the resultant suspension is stirred at room temperature for 2 hours. This suspension is then filtered and the white residue is washed with methylene chloride and dried. This is re-crystallized from methanol/methylene chloride to give 2.5 g (93%) of white crystalline 1-[[(4-methylphenyl)amino]carbonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 280°-282° C.
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH:9](Br)[CH:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:5]1[CH2:6][CH2:7]2)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[CH2:14]([N:13]1[CH:5]2[CH2:6][CH2:7][CH:8]1[CH:9]1[NH:1][CH:4]2[CH2:11][CH2:10]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=NC1CCC(Br)C2CCC1N2Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2C3CCC2C2CCC3N2)cc1
Temperature: 25 °C
Yield: 91 %

Procedure:
3.44 grams of the azide (1.1A) obtained in Ex. 1.1 are dissolved in 26 ml of anhydrous THF. To this solution 2.96 grams of triphenylphosphine, dissolved in 10 ml of anhydrous THE are added. The mixture is heated at reflux for 5 hours. At the end it is cooled at room temperature and 0.5 ml of water are added. It is further heated at reflux for 14 hours and then cooled at room temperature. The precipitate is filtered under vacuum and washed with THF, suspended in 50 ml of a CH2Cl2/H2O (1/1 v/v) mixture and treated with a 10% by weight K2CO3 aqueous solution up to pH 8. The organic phase is separated, dehydrated with sodium sulphate, filtered and evaporated under vacuum. 2.13 g of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane are recovered. Yield: 91%. 1H-NMR (CDCl3) δ 1.45-1.55 (m, 2H); 1.80-1.90 (m, 4H); 2.00-2.15 (m, 2H); 2.78-2.88 (m, 2H); 3.02-3.12 (m, 2H); 3.31 (s, 2H); 7.20-7.45 (m, 5H). Anal, calc. for C15H20N2: C, 78.90; H, 8.83; N, 12.27. Found: C, 78.71; H, 8.80; N, 12.25.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].S(=O)(=O)(O)O.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([C:23](O)=[O:24])[C:17]=1[Cl:26]>O>[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([C:23]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:24])[C:17]=1[Cl:26]
Reactant: CCCCC(CC)CO
Reactant: Nc1cc(Cl)nc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(CC)COC(=O)c1nc(Cl)cc(N)c1Cl

Procedure:
To a solution of 2-ethylhexanol (10 mL) and sulfuric acid (1 mL) was added 4-amino-3,6-dichloro-pyridine-2-carboxylic acid (0.0097 mol, 2.0 g). After heating the reaction to reflux overnight, the reaction mixture was cooled, poured into water (75 mL), and extracted with ethyl acetate (75 mL). The organic phase was washed with sodium bicarbonate (75 mL), dried (Na2SO4), and concentrated. The resulting solid was recrystallized out of dichloromethane and hexane and filtered to give 2-ethylhexyl 4-amino-3,6-dichloropyridine-2-carboxylate (0.0074 mol, 2.36 g) as a crystalline solid (mp 55° C.). 1H NMR (CDCl3): δ 0.9 (7 H, m), 1.3 (7 H, m), 1.7 (1 H, m), 4.3 (2 H, d), 5.1 (2 H, bs), 6.7 (1 H, s).
Reaction SMILES: C(CC1C=CC(OC)=C([N:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([N:23]([C:33]4[CH:37]=[CH:36][O:35][N:34]=4)CC4C=CC(OC)=CC=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:38])C=1)#N.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:35]1[CH:36]=[CH:37][C:33]([NH:23][S:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:10][C:11](=[O:38])[CH:12]=[CH:13]3)(=[O:22])=[O:21])=[N:34]1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(CC#N)ccc3OC)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2[nH]1
Yield: 15.1 %

Procedure:
To a mixture of Xantphos (0.049 g, 0.084 mmol), Pd2(dba)3 (0.077 g, 0.084 mmol) and 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.838 mmol) in N,N-dimethylformamide (0.838 ml) was added (trimethylsilyl)acetonitrile (0.138 ml, 1.006 mmol) followed by zinc difluoride (0.061 g, 0.587 mmol). The flask was sealed under an atmosphere of nitrogen and heated at 100° C. overnight. The reaction was diluted with water and extracted with DCM (×2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was taken up in DCM and purified via MPLC, eluting with 0-100% ethyl acetate in heptanes with a 5% DCM additive, followed by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 95% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.092 g, 0.165 mmol, 19.72% yield) as a light-yellow solid. 1-(5-(cyanomethyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (92 mg) was taken up in 2.5 mL of DCM and 2.5 mL of TFA and was heated under microwave irradiation for 1 h at 70° C. until complete deprotection. The reaction mixture was concentrated in vacuo. The crude material was purified by reverse-phase preparative HPLC (XBridge Prep C18 column, 10 micron OBD, 19×100 mm), 0.1% TFA in CH3CN/H2O, gradient 25% to 70% over 12 min to provide 1-(5-(cyanomethyl)-2-methoxyphenyl))-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.011 g, 0.025 mmol, 3.01% yield) as a white solid. MS (ESI, pos. ion) m/z: [M+1] 437.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.68 (s, 3 H) 4.03 (s, 2 H) 6.44 (d, J=1.76 Hz, 1 H) 6.71 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.64 Hz, 1 H) 7.30 (d, J=2.28 Hz, 1 H) 7.34 (d, J=8.60 Hz, 1 H) 7.55 (dd, J=8.60, 2.28 Hz, 1 H) 7.84 (dd, J=8.97, 2.23 Hz, 1 H) 8.22 (d, J=9.74 Hz, 1 H) 8.36 (d, J=2.18 Hz, 1 H) 8.73 (d, J=1.87 Hz, 1 H) 11.64 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.2 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (45.6 g, 200 mmol) in dioxane (400 mL) was added N-cyclopentylamine (20.4 g, 240 mmol) at room temperature. The mixture thus obtained was stirred at room temperature for 6 h. The reaction mixture was then diluted with ethyl acetate and washed with brine and dried over MgSO4. The solvent was evaporated to give the title compound as a light yellow solid (56 g, 100%) which was used in next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.23 (1H, s), 7.37 (1H, d, J=7.3 Hz), 4.31 (1H, m), 1.92 (2H, m), 1.71 (2H, m), 1.53-1.59 (4H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 276.0, Calculated 275.9.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:7]1)=[N+:2]=[N-:3].[CH:30]12CC(C=C1)C=[CH:31]2>O1CCOCC1>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C@@H:8]3[CH2:9][CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:1]4[CH:31]=[CH:30][N:3]=[N:2]4)[CH2:7]3)[CH2:14][CH2:15]2)=[O:20])[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: [N-]=[N+]=NCCN1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCn3ccnn3)C2)CC1
Temperature: 180 °C

Procedure:
4-{[(3R)-1-(2-Azidoethyl)piperidin-3-yl]methyl}-N-(3,4-dichlorophenyl)piperazine-1-carboxamide (100 mg, 0.23 μmmol) was dissolved in 1,4-dioxane (4 ml). Bicyclo(2.2.1)hepta-2,5-diene (0.5 ml) was added and the mixture heated in the microwave at 180° C. for 20 minutes. The reaction mixture was poured onto a bond elute column (SiO2, 20 g) and the product eluted with a gradient of dichloromethane through to 20% methanolic ammonia/dichloromethane to yield the title compound as a white solid (80.1 mg)
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:17]>C1COCC1>[F:1][C:2]1[CH:12]=[C:11]([NH2:17])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 2,4-difluoro-5-nitro-benzoate (5.0 g, 21 mmol), 5.2 mL conc. NH3 and THF (25 mL) is stirred for 30 min in an ice bath and overnight at rt. The mixture is concentrated and diluted with water. The precipitate is filtered, washed with water and dried at 55° C. to furnish the crude sub-title compound.