Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[C:13]2=[C:14]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:16][N:12]2[CH2:11][CH2:10][NH:9]1)=[O:7])(=O)C.[OH-].[Na+]>C(O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[C:14]([C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[C:13]3[N:8]([C:6](=[O:7])[CH2:5][OH:4])[NH:9][CH2:10][CH2:11][N:12]3[N:16]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)OCC(=O)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CO)N1NCCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c21
Yield: 29.8 %

Procedure:
A mixture of 2-acetoxyacetyl-7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (75 mg, 0.190 mmol) and an aqueous sodium hydroxide solution (1N, 0.38 ml, 0.380 mmol) in ethanol (1.5 ml) was stirred for 30 minutes at ambient temperature. After dilution of an aqueous saturated ammonium chloride solution, the mixture was extracted with ethyl acetate. The extracts were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent:dichloromethane/methanol; 50/1~10/1), and the obtained amorphous product was crystallized from diisopropyl ether to give 7-(4-fluorophenyl)- 2-hydroxyacetyl-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (20 mg).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.[Br:11]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:11][C:7]1[C:6]2[N:1]=[CH:2][NH:3][C:4](=[O:10])[C:5]=2[S:9][CH:8]=1
Reactant: O=c1[nH]cnc2ccsc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)csc12
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 3H-thieno[3,2-d]pyrimid-4-one (82, 0.98 g, 6.4 mmol) in acetic acid (3.4 mL) was added a solution of bromine (1 mL) in acetic acid (3 mL). The reaction mixture was heated at reflux for 8 hours. The resulting suspension was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The solid product was collected by vacuum filtration to give 7-bromo-3H-thieno[3,2-d]pyrimid-4-one (0.94 g, 64% yield) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](Cl)=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: NCCCO
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCO)cccc2c1=O
Reaction time: 3 h

Procedure:
A solution of 7.6 ml of 3-aminopropanol in 50 ml of water was added dropwise over a period of 30 minutes to a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 g of potassium carbonate in 400 ml of acetone. The thick suspension was stirred for 3 hours at 20°-25° C. The solvents were removed in vacuo and the residue was taken up in 300 ml of water. After stirring for 1 hour, the precipitate was collected by suction filtration and washed with water. The crude product was purified by crystallization from 95% ethanol and 23.8 g of the title compound were obtained, m.p. 191°-193° C. An additional 4.7 g of the title compound was obtained by concentration in vacuo of the crystallization filtrate.
Reaction SMILES: [Na].Br[C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:17]#[N:18])[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:17]#[N:18])[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[CH3:20]
Reactant: N#CC1(c2ccc(Br)nc2)CCC(F)(F)CC1
Reactant: CCO
Agent: [Na]
Product: CCOc1ccc(C2(C#N)CCC(F)(F)CC2)cn1
Temperature: 70 °C
Yield: 49 %

Procedure:
Sodium metal (229 mg, 9.96 mmol) was added to ethanol (5 mL) at room temperature. To this solution was added 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (300 mg, 1.00 mmol) and the reaction was heated at 70° C. for 6 hours. After cooling to room temperature the volatiles were removed under reduced pressure. The residue was diluted with water and extracted with AcOEt (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford 1-(6-ethoxy-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (130 mg, 49%). LC-MS (m/z) 241.4 (MH+). 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=2.7 Hz, 1 H), 7.66 (dd, J=8.8, 2.7 Hz, 1 H), 6.78 (d, J=8.8, Hz, 1 H), 4.38 (q, J=7.1, Hz, 2 H), 2.07-2.42 (m, 8 H), 1.41 (t, J=7.1, Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:14]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:15]1
Reactant: OB(O)c1ccoc1
Reactant: Brc1cccc(N2CCNCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(-c2ccoc2)cc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixed solution of 1-(3-bromophenyl)-piperazine (100 mg, 0.415 mmol), 3-furylboronic acid (69.6 mg, 0.622 mmol), tetrakis(triphenylphosphine)palladium (57.5 mg, 0.050 mmol), 2N aqueous solution of sodium carbonate (1.66 ml, 3.32 mmol) in toluene (4.0 ml) was stirred at 95° C. for 14 hours under a nitrogen atmosphere. After cooling to room temperature, water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give the titled compound 45.4 mg (47.9%) as an oil.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH3:19])C1C=CC=CC=1>Br>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH3:19]
Reactant: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Agent: Br
Product: Cc1c(O)c(=O)ccn1CCO
Yield: 61.3 %

Procedure:
3-Benzyloxy-1-(2'-hydroxyethyl)-2-methylpyrid-4-one (2 g) is added to concentrated hydrobromic acid (10 ml) and the mixture is heated on a steam bath for 30 minutes. The resultant product is then recrystallised from water to yield 3-hydroxy-1(2'-hydroxyethyl)-2-methylpyrid-4-one as white crystals (0.8 g), m.p. 164°-165° C.; δmax (nujol) 1630, 3150, 3350 cm-1 ; δ(dbDMSO), 2.5 (s, 3H), 3.7 (t, 2H), 4.35 (t, 2H), 7.25 (3, 1H), 8.15 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:23]1OC(O)C[O:25][CH:24]1O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[OH:25][CH2:24][CH2:23][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:20])[F:21])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: OC1COC(O)CO1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCO)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
350 mg (1.15 mmol) of the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38 was dissolved in 11.5 ml of methanol, and thereafter, 1.15 ml of acetic acid and 552.5 mg (4.60 mmol) of glycolaldehyde dimer were added thereto. Thereafter, 722 mg (11.5 mmol) of sodium cyanoborohydride was added to the mixture under cooling on ice. The temperature of the mixture was increased to a room temperature, and the mixture was then stirred for 8 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1 to 12:1), so as to obtain 61.8 mg (15%) of 7-(2-hydroxyethylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow amorphous substance, as well as 369.3 mg (82%) of 7-[bis(2-hydroxyethyl)amino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a yellow foaming substance.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.I[C:15]1[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:18]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([N:31]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]2)[CH:22]=1)=[O:19]>>[CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[C:13][C:15]3[CH:16]=[C:17]([CH:37]=[CH:38][C:39]=3[CH3:40])[C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[C:23]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)[CH:22]=3)=[O:19])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(C#Cc4ccc(NC5CCC5)nn4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (as prepared above) in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 223-225° C.; 1H NMR (300 MHz, DMSO-d6) δ: 10.72 (1 H, s), 8.31 (1 H, s), 8.17-8.22 (2 H, m), 7.94-7.96 (1 H, dd, J=1.5 and 8.1 Hz), 7.75 (1 H, s), 7.47-7.61 (4 H, m), 6.77-6.80 (1 H, d, J=9.0 Hz), 4.42 (1 H, m), 2.56 (3 H, s), 2.33-2.35 (2 H, m), 2.19 (3 H, brs), 1.88-1.99 (2 H, m), 1.72-1.78 (2 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H26F3N6O: 531.2115. found: 531.2113.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:13]1[C:12]2([CH2:17][CH2:18][NH:19][CH:10]([CH2:9][NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:11]2)[CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cccc(NCC2CC3(CCCC3)CCN2C(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(NCC2CC3(CCCC3)CCN2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
(±)tert-butyl 7-(((6-methylpyridin-2-yl)amino)methyl)-8-azaspiro[4.5]decane-8-carboxylate (intermediate 73, 1.3 g, 3.62 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C., then trifluoroacetic acid (30 ml) was added. After 1 hour at 0° C. and 2 hours at room temperature the solution was evaporated, the residue re-dissolved in dichloromethane was washed with saturated NaHCO3 aqueous solution. The organic layers were dried (Na2SO4) and concentrated under vacuum to obtain 900 mg of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[NH2:18][CH2:19][CH2:20][OH:21].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO>[OH:21][CH2:20][CH2:19][NH:18][CH2:1][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C=O)cc(-n2cccc2)c1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(CNCCO)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 3-formyl-5-(pyrrol-1-yl)benzoate (1.66 g), 2-aminoethanol (0.88 ml) and molecular sieves 4A (1.7 g) in methanol (40 ml) was stirred for 6 hours at room temperature. Then, to the reaction mixture was added sodium borohydride (0.55 g). After stirring for 3 hours at room temperature, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(2-hydroxyethylaminomethyl)-5-(pyrrol-1-yl)benzoate (0.80 g).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[N:25]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([C:11]3[C:15]4[S:16][CH:17]=[CH:18][C:14]=4[O:13][N:12]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(OCCN2CCCC2)cc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, pyrrolidine and acetonitrile essentially as described above in example 40. Purity by LC/MS (APCI)=100%, [M+H]+=315.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH2:18]OS(C)(=O)=O)[C:10](=[O:17])[N:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:12]=2)=[CH:3][CH:2]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH2:18][N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[C:10](=[O:17])[N:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:12]=2)=[CH:3][CH:2]=1
Reactant: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 68.2 %

Procedure:
Following the procedure of Example 1(10), 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: OC(CCn1ccnc1)c1ccc(Br)cc1
Product: Clc1ccc(C(CCn2ccnc2)c2ccc(Br)cc2)cc1
Yield: 67 %

Procedure:
Chlorobenzene (5 ml) was reacted with 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol (0.41 mg, 1.46 mmol) following the procedure set out in Example 42B to give the title compound (0.37 g, 67% yield). LC/MS: (PS-A2) Rt 2.40 [M+H]+ 375.16, 377.17.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[C:17]([NH:19][C:20](N)=[O:21])=[O:18].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:20]([NH:19][C:17](=[O:18])[C:16]1[CH:23]=[CH:24][CH:25]=[C:14]([C:13]([F:12])([F:26])[F:27])[CH:15]=1)=[O:21])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: NC(=O)NC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NC(=O)c1cccc(C(F)(F)F)c1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared from 3-amino quinuclidine dihydrochloride (1.0 g, 5 mmol), 3-trifluoromethylbenzoylurea (1.16 g, 5 mmol) and diisopropylethylamine (1.29 g, 10 mmol) in pyridine (20 ml), by refluxing under nitrogen overnight. The solvent was evaporated and the residue worked-up as in Example 1. The product (1.18 g) was converted to oxalate salt, mp 197°-200° C.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O[N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27].C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C@H:2]([C:7]([O:9][N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Z-Leu-OH (15.92 g) and N-hydroxysuccinimide (6.9 g) were dissolved in dioxane and cooled to 0° C. To the cooled solution, DCC was added and stirred at 0° C. for 0.5 h, then room temp overnight. After filtering off the byproduct urea, the filtrate was concentrated to give crude Z-Leu-OSu as an oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5]([C:14]2[C:15]([F:39])=[C:16]([N:21](COCCOC)[S:22]([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=2[F:20])=[N:4]1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C([NH2:55])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:55][C:12]1[CH:13]=[C:8]([C:6]2[C:5]([C:14]3[C:15]([F:39])=[C:16]([NH:21][S:22]([C:25]4[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=4[F:32])(=[O:24])=[O:23])[CH:17]=[CH:18][C:19]=3[F:20])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=2)[CH:9]=[CH:10][N:11]=1
Reactant: CC(C)(C)N
Reactant: CCn1cc(-c2ccncc2)c(-c2c(F)ccc(N(COCCOC)S(=O)(=O)c3cc(F)ccc3F)c2F)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1cc(-c2ccnc(N)c2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
N-[3-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzenesulfonamide (123 mg, 0.217 mmol) was dissolved in dry DCM, mCPBA (75 mg, 2 eq) was added and the reaction mixture was stirred at room temperature for 3 hours. A further addition of mCPBA was made (50 mg) and the mixture was stirred for 2 more hours. It was then diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude intermediate N-oxide (130 mg) was dissolved in dry trifluoromethylbenzene (1.5 mL), the solution was cooled to 0° C. and t-butyl amine (0.118 mL 1.12 mmol, 5 eq) was added. Tosylanhydride (150 mg, 0.448 mmol, 2 eq) was then added in portions. After 1 h stirring at 0° C., further additions of t-butyl amine (0.03 mL, 1.25 eq) and tosylanhydride (40 mg, 0.5 eq) were made and the reaction mixture was stirred at 0° C. for 30 more minutes. Trifluoroacetic acid (1.5 mL) was then added and the mixture was hated to 70° C. and stirred at this temperature for 1.5 h. The solvent was evaporated and the residue taken up with DCM and water. The aqueous phase was neutralized with 32% aq. NaOHand extracted 3 times with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (DCM/MeOH 95:5) to give 46 mg of N-{3-[4-(2-amino-pyridin-4-yl)-1-ethyl-1H-pyrazol-3-yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)=[C:5]([N+:27]([O-])=O)[CH:4]=1>C(O)C.[Pd]>[NH2:27][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:26])[C:11]1[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=1
Reactant: COc1ccc(NC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(NC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(N)c1
Yield: 56.9 %

Procedure:
To a solution of N-(4-methoxy-2-nitrophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (1.50 g) in ethanol (10 ml) was added a catalytic amount of 10% palladium/carbon to perform catalytic reduction under a pressure of 1-2.5 arms at room temperature for 5 hrs. After filtering the catalyst and distilling off the solvent, crystallization of the residue from hexane-ethyl acetate afforded N-(2-amino-4-methoxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide (0.79 g, 57%).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:34][C:35]([F:46])([F:45])[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43]N)=[CH:39][CH:38]=1>>[CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:41]4[C:40](=[CH:39][CH:38]=[C:37]([O:36][C:35]([F:46])([F:45])[F:34])[CH:42]=4)[NH:43][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:16][CH2:17]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl}propanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 592.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Br:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](Br)[C:27]=1[CH3:33]>ClCCl>[Br:25][C:26]1[C:27]([CH3:33])=[C:28]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Reactant: Cc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 150 °C
Yield: 63.9 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO and 2,6-dibromotoluene (395 mg, 1.58 mmol) were added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (30 mg, 0.16 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was washed with brine. The combined aqueous layers were washed with dichloromethane. The combined dichloromethane layers were dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (181 mg, 0.504 mmol). MS (ESI) 361.1 (M+H)+.