Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[F:28][CH:29]([F:32])[CH2:30]I>CN(C)C=O>[F:28][CH:29]([F:32])[CH2:30][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1
Reactant: FC(F)CI
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NCC2CN(CC(F)F)CCO2)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
To a solution of EXAMPLE 415B (633 mg) in anhydrous N,N-dimethylformamide (10 mL) was added sodium carbonate (254 mg) and 2,2-difluoroethyl iodide (422 mg). After stirring at 110° C. for 48 hours, the mixture was concentrated. The residue was mixed with water (20 mL) and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 10% methanol in methylene chloride to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][C:9]=1F)(=[O:3])[NH2:2].NC1C=C2C(=CC=1)[C:33](=[O:37])[NH:32]NC2=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:12]([NH:11][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[C:33](=[O:37])[NH:32][NH:2][C:1]3=[O:3])[C:13]([OH:15])=[O:14])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Reactant: Nc1ccc2c(=O)[nH][nH]c(=O)c2c1
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2ccc3c(=O)[nH][nH]c(=O)c3c2)C(=O)O)cc1OC
Yield: 95 %

Procedure:
15A was prepared in a procedure similar to that of 13A using 6-amino-2,3-dihydrophthalazine-1,4-dione, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 95%. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H) 3.74 (s, 3H) 5.15 (d, J=7.03 Hz, 1H) 6.95 (d, 1H) 7.01-7.06 (m, 1H) 7.13 (d, J=2.20 Hz, 1H) 7.25 (d, J=7.03 Hz, 2H) 7.74 (s, 1H), LCMS: 344 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:19])[NH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O.Cl>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][N:14]1[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C:13]1=[O:19])[CH3:28]
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Reactant: CCOC(=O)CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)ccc(NC(=O)OCc2ccccc2)c1=O
Reaction time: 0.75 h
Yield: 55.5 %

Procedure:
The compound of Example 13 (1.80 g, 7.0 mmole) was added to a stirred suspension of sodium hydride (0.33 g, 8.4 mmole) in dry dimethylformamide (50 mL). After 45 minutes, ethyl iodoacetate (1.43 g, 6.7 mmole) was added, and the mixture was stirred overnight, diluted with 10% hydrochloric acid (300 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was washed with brine (twice), dried and evaporated. The resulting yellow, wary solid was chromatographed, eluting with 3% ethyl acetate in dichloromethane, to give the title compound (1.28 g, 53% yield). Rf =0.52 (silica gel, 5:95 methanol:dichloromethane). Fast atom bombardment mass spectrometry confirmed the theoretical molecular weight of 344.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.CO.[NH3:17]>>[Cl:1][C:2]1[CH:11]=[C:10]([NH2:17])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: COc1ccc2nc(Cl)cc(Cl)c2c1
Solvent: CO
Product: COc1ccc2nc(Cl)cc(N)c2c1
Temperature: 150 °C
Yield: 55 %

Procedure:
A suspension of 2,4-dichloro-6-methoxyquinoline (5.00 g, 22.0 mmol) in NH3 (g)/MeOH (saturated, 40 mL) was heated to 150° C. for 16 hours in a sealed tube. The solvent was removed in vacuo and the residue was diluted with MeOH (20 mL). The mixture was filtered off and the filtrate was concentrated to give the crude product, which was purified by column chromatography on silica gel (PE/EtOAc=2/1) to give 2-chloro-6-methoxyquinolin-4-amine (7.50 g, yield: 55%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:6]2=[CH:7][CH:8]=[CH:9][N:5]2[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[F:29][C:30]([F:36])([F:35])S([O-])(=O)=O.FC(F)(F)[S+]1C2C=CC=CC=2C2C=CC=CC1=2>C(#N)C>[CH3:1][N:2]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[C:6]2=[CH:7][CH:8]=[C:9]([C:30]([F:36])([F:35])[F:29])[N:5]2[CH2:4][CH2:3]1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CN1CCn2cccc2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: FC(F)(F)[s+]1c2ccccc2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Yield: 66 %

Procedure:
tert-Butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1.0 g, 3.27 mmol), potassium carbonate (497.7 mg, 3.60 mmol) and trifluoromethanesulfonate; 5-(trifluoromethyl)dibenzothiophen-5-ium (1.32 g, 3.27 mmol) were combined in acetonitrile (10 mL). The reaction mixture was heated at 60° C. for 16 h. The reaction was evaporated to dryness and the residue was dissolved in dichloromethane. The organics were washed with water and brine, dried over sodium sulfate and evaporated. The crude material was purified by silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to give tert-butyl 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (812 mg, 66%). ESI-MS m/z calc. 373.2, found 374.5 (M+1)+; Retention time: 1.21 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.52 (d, J=3.8 Hz, 1H), 5.91 (d, J=3.8 Hz, 1H), 3.98 (t, J=6.0 Hz, 2H), 3.93-3.76 (m, 2H), 3.32 (t, J=6.0 Hz, 2H), 3.26-3.08 (m, 2H), 2.36 (s, 3H), 2.11-1.99 (m, 2H), 1.81-1.65 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: Fc1ccc(CBr)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(Cc2ccc(F)cn2)c2cc([N+](=O)[O-])c(N)cc21
Yield: 49.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.3 g; 1.14 mmol) is alkylated using 2-bromomethyl-5-fluoro-pyridine (0.22 g; 0.46 mmol) and K2CO3 (0.4 g; 0.23 mmol) at 35° C. for 18 h. After aqueous work-up and purification by RP chromatography the pure material (87 mg) is de-acetylated in MeOH (6 ml) using DBU (16 μl) at reflux. After aqueous work-up 5-amino-1-(5-fluoro-pyridin-2-ylmethyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (75.0 mg) is obtained and used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:15][CH2:16][Cl:17])[P:5](Cl)([N:7]([CH2:11][CH2:12][Cl:13])[CH2:8][CH2:9][Cl:10])=[O:6].[OH:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][OH:24].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[Cl:17][CH2:16][CH2:15][N:4]([CH2:3][CH2:2][Cl:1])[P:5]([N:7]([CH2:11][CH2:12][Cl:13])[CH2:8][CH2:9][Cl:10])(=[O:6])[O:18][CH2:19][CH2:20][S:21][CH2:22][CH2:23][OH:24]
Reactant: OCCSCCO
Reactant: O=P(Cl)(N(CCCl)CCCl)N(CCCl)CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=P(OCCSCCO)(N(CCCl)CCCl)N(CCCl)CCCl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
N,N,N′,N′-Tetrakis(2-chloroethyl)phosphorodiamidoyl chloride, 636 mg (1.745 mmol), and bis(2-hydroxyethyl)sulfide, 1 mL (9.67 mmol), were dissolved in 8 mL anhydrous tetrahydrofuran and cooled to 0-5° C. in an ice-water bath. Potassium tert-butoxide, 1.8 mL of 1 M solution in tetrahydrofuran (1.8 mmol), was added over a 10 minute period, and the reaction mixture kept at 0-5° C. for another 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 18 hours. It was then diluted with ethyl acetate; and the ethyl acetate layer separated, washed with 1 M hydrochloric acid and brine, then dried over anhydrous magnesium sulfate, and the ethyl acetate removed under vacuum. The crude 5-hydroxy-3-thiapentyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate was purified by column chromatography (silica gel, eluting with 25% ethyl acetate/hexane and 100% ethyl acetate), and obtained as a colorless oil, 335 mg (42.6% yield), identified by HPLC and 1H and 31P NMR.
Reaction SMILES: [C:1]([C:9]1[CH:15]=[C:14]2[O:16][CH2:17][O:18][C:13]2=[CH:12][C:10]=1[NH2:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O:20]([C:22]#[N:23])[Na]>CC(O)=O>[CH2:17]1[O:18][C:13]2[CH:12]=[C:10]3[C:9]([C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:23][C:22](=[O:20])[NH:11]3)=[CH:15][C:14]=2[O:16]1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: N#CO[Na]
Solvent: CC(=O)O
Solvent: O
Product: O=c1nc(-c2ccccc2)c2cc3c(cc2[nH]1)OCO3
Temperature: 10 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of 2-benzoyl-4,5-(methylenedioxy)aniline (200 mg) in AcOH (10 mL) was added water (1 mL) and NaOCN (64 mg) at 10° C. The mixture was stirred at 10° C. for 1 h, then at rt for 2 h. Water (70 mL) was added to the mixture. The resulting yellow solid was collected by filtration, washed with water and 3:2 hexane/EtOAc, recrystallized from DMSO/water to yield the title compound as a yellow solid (104 mg, 47%), mp: 351-354° C. 1H NMR (DMSO-d6): 11.86 (s, 1H), 7.63-7.58 (m, 5H), 6.94 (s, 1H), 6.85 (s, 1H), 6.16 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[CH2:12]=[O:13].[OH-].[Na+].S(=O)(=O)(O)O>>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([CH2:12][OH:13])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:11]
Reactant: C=O
Reactant: COc1cccc(OC)c1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CO)cc(OC)c1O

Procedure:
310 g of 2,6-dimethoxyphenol, 300 g of 38 wt% formalin, and 810 g of 10% wt% aqueous sodium hydroxide were reacted for 60 hours at 25° C. under a pressure of 0 kg/cm2 -G, the reaction mixture was and then neutralized with sulfuric acid, to obtain 80 g of 2,6-dimethoxy-4-(hydroxymethyl)phenol. (Yield: 22 mol%) 25 g of the obtained 2,6-dimethoxy-4-(hydroxymethyl)phenol was reacted in 320 ml of methanol in the presence of 0.375 wt% of platinum-alumina catalyst and hydrogen for 4 hours at 200° C. at 199 kg/cm2 -G, and 15 g of 2,6-dimethoxy-4-methylphenol was obtained. (Yield: 66 mol%) The yield on the basis of the amount of the raw material was 15 mol%.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:25])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].C([O-])(=O)C.[Na+].[CH2:32]=[C:33]1[O:37][C:35](=[O:36])[CH2:34]1.C(OCC)(=O)C>ClCCl>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:25][C:35](=[O:36])[CH2:34][C:33](=[O:37])[CH3:32])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: C=C1CC(=O)O1
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)=O

Procedure:
In 30 ml of dichloromethane is dissolved 0.8 g of 16β-ethyl-17β-glycoloyloxy-4-estren-3-one, and 0.24 g of anhydrous sodium acetate and 0.3 ml of diketene are added. The mixture is refluxed for 4 hours. After cooling, 100 ml of ethyl acetate is added and the mixture is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following serial passage of 400 ml of diisopropyl ether and 400 ml of diisopropyl ether-ethyl acetate (10:1), elution is carried out with 600 ml of isopropyl ether-ethyl acetate (2:3). The eluate is evaporated under reduced pressure to remove the solvent, giving 1.0 g of the above-identified compound as a light-yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][N+:3]=1[O-].[C:21]([O:24]C(=O)C)(=[O:23])[CH3:22]>C(O)C>[C:21]([O:24][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][N:3]=1)(=[O:23])[CH3:22]
Reactant: Cc1c(OCCOCc2ccccn2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)OCc1nccc(OCCOCc2ccccn2)c1C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising 0.60 g of 2,3-dimethyl-4-(2-pyridylmethoxyethoxy)pyridine N-oxide and acetic anhydride was stirred at 100° C. for 0.5 hour and cooled, followed by the addition of 40 ml of ethanol. The obtained mixture was stirred at a room temperature for 0.5 hour and distilled to remove the solvent. The residue was dried in a vacuum to obtain 0.47 g of crude 2-acetoxymethyl-3-methyl-4-(2-pyridylmethoxyethoxy)pyridine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:24][CH2:23]2)[C:9]([N+:36]([O-:38])=[O:37])=[C:8]([CH3:39])[NH:7][C:6]=1[NH2:40])=[O:4].FC(F)(F)S(O)(=O)=[O:44].ClC1C=CC=C(C(OO)=O)C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[CH2:24][CH2:23]2)=[O:44])[C:9]([N+:36]([O-:38])=[O:37])=[C:8]([CH3:39])[NH:7][C:6]=1[NH2:40])=[O:4]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1SCCCCN1CCN(c2ccccc2OC)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1=C(N)NC(C)=C([N+](=O)[O-])C1c1ccccc1S(=O)CCCCN1CCN(c2ccccc2OC)CC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a 4-neck 500 ml round-bottom flask fitted with an addition funnel, thermometer and mechanical stirrer under a nitrogen atmosphere, was added 5.00 g of 2-amino-1,4-dihydro-4-(2-{4-[4-(2-methoxyphenyl)-1-piperazinyl]-butylthio}phenyl)-6-methyl-5-nitro-3-pyridinecarboxylic acid methyl ester and 120 ml of dichloromethane, followed by 1.73 ml of trifluoromethanesulfonic acid. The reaction mixture was cooled to -10° C. with an ice/acetone bath, and 1.88 g of 80% m-chloroperbenzoic acid in 120 ml of dichloromethane was added dropwise, maintaining -5° to -10° C. The reaction was stirred for an additional 2 hr. at -10° C. after the addition was complete. The reaction mixture was poured into conc. sodium bicarbonate, and the reaction flask was rinsed with acetone. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to an orange oil. The product (Ex. No. 2, Table 1) was isolated after column chromatography on silica gel, eluting with 20% methanol in ethyl acetate as an orange foam, 2.8 g. 1H-NMR (CDCl3) δ 1.84-2.05(m,2H); 2.03-2.05(m,2H); 2.36(s,3H); 2.55(t,2H,J=7 Hz); 2.71(br s,4H); 3.00-3.18(br s,6H); 3.61(s,3H); 3.85(s,3H); 5.76(s,1H); 6.70(br s,2H); 6.83-7.03(m,4H); 7.28-7.41(m,4H); 7.82-7.86(m,1H). Mass spectrum: 584 (M+1).
Reaction SMILES: [C:1]([N:4]1[CH:9]=[C:8]([CH:10]=[CH2:11])[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:9][C@@H:8]([CH2:10][CH3:11])[CH2:7][CH2:6][C@H:5]1[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: C=CC1=CN(C(C)=O)[C@H](C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CC[C@H]1CC[C@@H](C(=O)OC(C)(C)C)N(C(C)=O)C1
Yield: 3.4 %

Procedure:
4.08 g (16.3 mmol) of the t-butyl (S)-N-acetyl-5-vinyl-1,2,3,4-tetrahydropyridine-2-carboxylate obtained in Synthesis Example 16 was dissolved in 150 mL of ethanol, followed by the addition of 4.0 g of 10% Pd/C. It was treated in a hydrogen atmosphere of 3 kg/cm2 by the use of medium pressure catalytic reaction equipment to conduct hydrogenation. The catalyst was removed by filtration and the filtrate was concentrated to give 140 mg of the title compound. Yield 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH:9]=[O:10])[CH:6]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.S([CH2:32][N+:33]#[C-:34])(C1C=CC(C)=CC=1)(=O)=O.COCCOC>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH:6]=[C:7]([C:9]2[O:10][CH:34]=[N:33][CH:32]=2)[N:8]=1
Reactant: COc1ccc(CCNc2cc(C=O)nc(OC)n2)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: O
Solvent: COCCOC
Product: COc1ccc(CCNc2cc(-c3cnco3)nc(OC)n2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 8.5 %

Procedure:
In a tube is combined 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carbaldehyde [120 mg, 0.42 mmol, Intermediate (59)], tosylmethylisocyanide (90 mg, 0.46 mmol), Ambersep 900 OH resin (800 mg), ethylene glycol dimethyl ether (3.5 mL) and water (3.5 mL). The tube is sealed and the mixture is heated to 90° C. and stirred for 18 hours. The mixture is allowed to cool to ambient temperature and filtered to remove the resin, and the resin is washed with MeOH (10 mL). The combined filtrate and washings are concentrated by rotary evaporator and the residue is subjected to flash column chromatography on silica gel eluting with 0 to 40% EtOAc in heptane gradient) to afford (2-methoxy-6-oxazol-5-yl-pyrimidin-4-yl)-[2-(4-methoxy-phenyl)-ethyl]-amine [11.6 mg, 8.5%, Example 45]. LCMS: RT=2.57 minutes, MS: 327 (M+H). IC50=7.8 nM
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Cc2cccnc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cc2cccnc2)cc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 19.4 %

Procedure:
A mixture of 0.70 g of the phenol compound (prepared as described in Example 9), 0.30 g of sodium hydride (content 63%) and 14 ml of N,N-dimethylformamide was stirred at 100° C. for 20 minutes, and stirred with 0.64 g of ethyl bromoacetate at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and extracted with diethyl ether. The extract was washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 0.5% V/V solution of ethanol in chloroform as eluent to give 0.166 g of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:17]([O:19]C)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CN(C)C(=O)OC(C)(C)C)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC1(C(=O)O)CCOCC1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 97.7 %

Procedure:
Methyl 4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}tetrahydro-2H-pyran-4-carboxylate (2.81 mmol) was dissolved in methanol (7.3 mL) and water (5.9 mL) and treated with 10 M sodium hydroxide (1.40 mL, 14.0 mmol). The solution was heated at 60° C. overnight. The reaction was cooled to room temperature, and volatiles were removed on a rotovap. The remaining solution was diluted with water and washed with ethyl acetate (2 times). The water layer was cooled with an ice bath and then acidified with a mixture of 1 N aqueous HCl (28.1 mL) and saturated sodium chloride (28.1 mL). The product was extracted with ethyl acetate (3 times), and the organic solution was dried over anhydrous sodium sulfate and filtered. Concentration of the organic solution gave the title compound (750 mg, 97% yield) which was used crude in the next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][S:11]([C:14]3[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.FC1C=C(OC)C=C(F)C=1CN.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:45][C:46]1[CH:75]=[C:74]([O:76][CH3:77])[CH:73]=[C:72]([F:78])[C:47]=1[CH2:48][N:49]1C2N=CC=CC=2S(=O)(=O)N(C2C=CC(OC)=C(OC)C=2)[C:50]1=[O:71].FC1C=CC2N(C(C3C=CC=CC=3F)C)C(=O)N(C3C=CC=C(SC)C=3)S(=O)(=O)C=2C=1>O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:50](=[O:71])[N:49]([CH2:48][C:47]4[C:72]([F:78])=[CH:73][C:74]([O:76][CH3:77])=[CH:75][C:46]=4[F:45])[C:15]4[N:16]=[CH:17][CH:18]=[CH:19][C:14]=4[S:11]3(=[O:13])=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Reactant: O=S(=O)(Nc1ccc2ncsc2c1)c1cccnc1Cl
Agent: COc1cc(F)c(CN)c(F)c1
Agent: CSc1cccc(N2C(=O)N(C(C)c3ccccc3F)c3ccc(F)cc3S2(=O)=O)c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(F)c(CN2C(=O)N(c3ccc4ncsc4c3)S(=O)(=O)c3cccnc32)c(F)c1

Procedure:
The title compound (60 mg, 0.12 mmol) was prepared in two steps from N-(1,3-benzothiazol-6-yl)-2-chloropyridine-3-sulfonamide (IntC9) (300 mg, 0.92 mmol) and 2,6-difluoro-4-methoxybenzylamine (176 mg, 1.01 mmol) at 140° C. in a sealed tube; followed by triphosgene (288 mg, 0.97 mmol) in 1,4-dioxane (5 mL) at 110° C. for 16 h using the methods of (95) then (63).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:28].C(N(CC)CC)C>ClCCl>[CH2:30]([O:29][C:27](=[O:28])[NH:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a stirred solution of [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethyl-phenyl)methanone (100 mg, 0.285 mmol) in dichloromethane (5 mL) was added n-butyl chloroformate (0.285 mmol) in the presence of triethylamine (0.313 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 24 h and then quenched with water (10 mL). The organic phase was washed with water, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford the desired product as a white solid (0.095 g, 74% yield). 1H NMR (500 MHz, CDCl3) δ 8.10, 7.73, 7.63, 7.55, 7.36, 7.04, 4.19, 3.96-4.02, 3.89-3.95, 3.61-3.66, 3.52-3.56, 3.32, 1.64-1.70, 1.38-1.46, 0.95.