Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[H][H]>[C].[Pd].CO>[CH2:5]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COc1cc(C(OC(C)=O)c2ccccc2)ccn1
Agent: [Pd]
Solvent: CO
Product: COc1cc(Cc2ccccc2)ccn1
Yield: 84.2 %

Procedure:
5 g of 10% palladium carbon and 500 ml of methanol were added to 112 g of 4-(α-acetoxybenzyl)-2-methoxypyridine, followed by conducting hydrocracking in a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated. Then, the residue was neutralized by an aqueous saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed, to give 73 g of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:12])[CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][CH:21]([SH:23])[CH3:22].ClCCl>C(O)C.O>[CH2:1]([O:8][C:9](=[O:12])[CH2:10][CH2:11][S:23][CH:21]([CH3:22])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CC(C)S
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)SCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To benzylacrylate (100 mg, 0.617 mmol) in ethanol (2 mL) are added triethylamine (95 uL, 0.679 mmol) and 2-propanethiol (58 uL, 0.617 mmol). After stirring at rt during 2 h, the solvent is evaporated to give a residue which is treated with dichloromethane and water. The organic phase is dried and evaporated to afford a colorless oil before purification by preparative HPLC (Column Waters C18 ODB 5 μm 19×50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Cl:12][C:10]1[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:34](=[O:35])[CH2:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:25]([O:24][CH3:23])=[O:26])[CH:28]=2)[CH:11]=1
Reactant: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1N
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CC(=O)Nc2cc(Cl)c(-c3ccc4c(ccn4C)c3)cc2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of methyl 2-amino-4-chloro-5-(1-methyl-1H-indol-5-yl)benzoate (Intermediate 45) (150 mg, 0.477 mmol) in dichloromethane (10 mL) was added {3-[(methyloxy) carbonyl]phenyl}acetic acid (Akos, 97 mg, 0.500 mmol), HATU (236 mg, 0.620 mmol) and triethylamine (0.073 mL, 0.524 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was washed with water and brine, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography using cyclohexane to cyclohexane/ethyl acetate 80:20 as eluant gave the title compound methyl 4-chloro-2-(2-(3-(methoxycarbonyl)phenyl)acetamido)-5-(1-methyl-1H-indol-5-yl)benzoate (205 mg, 0.418 mmol, 88% yield) as a white amorphous solid. LCMS: (M+H)+=491; Rt=4.19 min.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:16]C)=[N:10][C:11]([O:14]C)=[N:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1.[ClH:18]>O1CCOCC1>[ClH:18].[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:9](=[O:16])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ncc(-c2cccc(F)n2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2cccc(F)n2)c(=O)[nH]1
Yield: 84 %

Procedure:
5-(6-Fluoro-pyridin-2-yl)-2,4-dimethoxy-pyrimidine (Prep74, 230 mg, 0.98 mmol) was dissolved in a solution of 4N HCl in dioxane (4 ml). After refluxing the reaction mixture for 1 hour, the solvent was removed under vacuum to give 200 mg of the title compound (84% yield)
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[O:24][C:23]([C:25]([NH:27][C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[O:26])=[N:22][N:21]=1.[C:40](O)(=[O:43])[CH2:41][OH:42].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]1[O:24][C:23]([C:25]([NH:27][C:28]2[CH:29]=[N:30][C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:41](=[O:42])[CH2:40][OH:43])[CH2:36][CH2:35]3)=[CH:32][CH:33]=2)=[O:26])=[N:22][N:21]=1
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nnc(Nc2ccccc2F)o1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(N2CCN(C(=O)CO)CC2)nc1)c1nnc(Nc2ccccc2F)o1
Reaction time: 16 h
Yield: 65 %

Procedure:
EDAC (60 mg, 0.31 mmol) was added to a stirred mixture of 5-[(2-fluorophenyl)amino]-N-(6-piperazin-1-ylpyridin-3-yl)-1,3,4-oxadiazole-2-carboxamide (Intermediate 41, 100 mg, 0.26 mmol), glycolic acid (20 mg (0.26 mmol) and HOBt (42 mg, 0.31 mmol) in 3 mL of DMF and stirring was continued for 16 h. Water (10 mL) was added and the resultant precipitate was collected by filtration, washed with water then ether and dried in vacuo to give the title compound (75 mg, 65%) as a solid; 1H NMR δ 10.94 (1H, s), 10.70 (1H, s), 8.50 (1H, s), 8.05 (1H, t), 7.90 (1H, d), 7.35-7.20 (2H, m), 7.20-7.10 (1H, m), 6.90 (1H, d), 4.60 (1H, t), 4.10 (2H, d), 3.60-3.4 (8H, m); MS m/e MH+ 442.
Reaction SMILES: [CH2:1]([O:9][CH2:10][C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]=[CH:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OO)(=[O:20])C.O>C(Cl)Cl>[CH2:1]([O:9][CH2:10][C:11]12[CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]1[CH:12]2[O:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OO
Reactant: CCCCCCCCOCC12C=CC(CC1)C2
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCOCC12CCC(C1)C1OC12

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 14.3 g (0.056 mol) of 4-n-octyloxymethyl-bicyclo[2.2.1]hept-2-ene, and 80 mL of methylene choride. Peracetic acid (15.6 g, 35 wt. % in acetic acid; 0.072 mol) in methylene chloride (70 mL) was added dropwise to the above mixture over 20 min. in an ice bath. After the above mixture was reacted at room termperature for 3 hrs., 100 mL of water was added to the above reaction mixture, the organic layer was washed with saturated sodium carbonate solution (2×100 mL), then with water (2×100 mL), and dried with sodium sulfate. The solvent was evaporated and the residue was vacuum distilled to give pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[C:9](=[O:16])[C:8]=2[CH:17]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[CH:9]([OH:16])[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: CC1C(=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1C(O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
A suspension of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (40 g, 0.170 mol) in methanol (400 ml) was treated with sodium borohydride (6.4 g, 0.170 mol) at room temperature. After stirring for two hours the solvent was evaporated under reduced pressure, and the residue treated with a mixture of water and dichloromethane. After stirring the organic phase was separated and evaporated under reduced pressure to give 42.2 g of 6-nitro-2,2,3-trimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran, as an oil, 1H NMR (CDCl3): δ1.05 (d, 3H), 1.4 (s, 3H), 1.45 (s, 3H), 2.0-2.2 (m, 2H), 4.4 and 4.9 (multiplets cis and trans, 1H), 6.85 (m, 1H), 8.05 (m, 1H), 8.4 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1.C([Li])(C)(C)C.[CH:21](=[O:23])[CH3:22]>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH:21]([OH:23])[CH3:22])=[CH:7][C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:9][CH:10]=1
Reactant: CC=O
Reactant: COCOc1ccc(CC(C)(C)C)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCOc1cnc(CC(C)(C)C)cc1C(C)O
Temperature: -78 °C

Procedure:
To a solution of 5-(methoxymethoxy)-2-neopentylpyridine (16.5 g, 79 mmol) and in THF (200 mL)-78° C. is added tert-butyllithium (46 ml, 79 mmol) (1.7 M in pentane) over 2 min via cannula. The reaction was stirred at −78° C. 30 min, and acetaldehyde (11 ml, 197 mmol) was added. The reaction was stirred at −78° C. 10 min, then the reaction was warmed to rt and stirred 3 h. The reaction was quenched by addition of saturated aqueous NH4Cl (400 mL), extracted with EtOAc (3×200 mL), the combined organic layers washed with saturated NaCl (10 mL), dried (Na2SO4), and concentrated to give a orange oil, which was purified by chromatography on an ISCO (330 g SiO2, 10%-50% EtOAc/Hexane) gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol as a clear, light yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][C:15]=2[N+:23]([O-])=O)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:12]2[CH:26]=[CH:27][C:9]([OH:8])=[CH:10][CH:11]=2)=[C:15]([CH:16]=1)[NH2:23])[CH3:22]
Reactant: CCOc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(Oc2ccc(O)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of 4-[4-(benzyloxy)phenoxy]-3-nitrophenetole (4.26 g, 11.7 mmol) in a mixture of ethanol (70 ml) and tetrahydrofuran (50 ml) was added 10% palladium-carbon (430 mg), followed by stirring under a hydrogen gas atmosphere at room temperature overnight. After removal of the insoluble matter by filtration, the solvent was evaporated under reduced pressure. The resulting crude crystals were recrystallized from a mixture of ethyl acetate and hexane (1:9) to give the title compound (2.63 g).
Reaction SMILES: I/C=C/C1C(=O)CCCC=1C.I/[CH:13]=[CH:14]/[C:15]1[C:16](=[O:23])[CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH:20]=1.[C:24]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1)#[CH:25]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[CH3:21][C:19]1([CH3:22])[CH2:18][CH2:17][C:16](=[O:23])[C:15](/[CH:14]=[CH:13]/[C:25]#[C:24][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)=[CH:20]1
Reactant: C#Cc1ccc(C(=O)OCC)cc1
Reactant: CC1(C)C=C(/C=C/I)C(=O)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC1=C(/C=C/I)C(=O)CCC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C/C=C/C2=CC(C)(C)CCC2=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of (E)-2-(2-iodoethenyl)-3-methyl-2-cyclohexen-1-one (Compound 19, 0.22 g, 0.797 mmol), ethyl 4-ethynylbenzoate (0.167 g, 0.956 mmol) and triethylamine (9.5 mL) was purged with argon for 10 minutes, and then treated with bis(triphenylphosphine)palladium (II) chloride (28 mg, 0.04 mmol) and copper (I) iodide (8 mg, 0.04 mmol). The solution was stirred 40° C. for 3 hours, and concentrated under a water aspirator vacuum. The residue was dissolved in ethyl acetate and washed with saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic fractions were washed with water, and brine, and dried (MgSO4). The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (88:12, hexane:ethyl acetate) to give the title compound as a yellow crystaline solid.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32].[Cl:36][C:37]1[N:42]=[C:41](Cl)[C:40]([F:44])=[CH:39][N:38]=1>>[Cl:36][C:37]1[N:42]=[C:41]([NH:27][C:28]2[CH:35]=[CH:34][CH:33]=[C:30]([C:31]#[N:32])[CH:29]=2)[C:40]([F:44])=[CH:39][N:38]=1
Reactant: N#Cc1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: N#Cc1cccc(Nc2nc(Cl)ncc2F)c1
Yield: 85.8 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 3-aminobenzonitrile (142 mg, 1.2 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (128 mg, 86%) as a white solid. The reaction of 2-chloro-N4-(3-cyanophenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.2 mmol) and 3-aminophenol (66 mg, 0.6 mmol) gave N4-(3-cyanophenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 62%). 1H NMR (acetone-d6): δ 6.48 (ddd, J=0.9, 2.4 and 7.8 Hz, 1H), 7.10 (t, J=8.1 Hz, 1H), 7.18 (ddd, J=1.2, 2.1 and 8.1 Hz, 1H), 7.33 (t, J=2.1 Hz, 1H), 7.45 (dt, J=1.2 and 7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 8.08 (d, J=3.3 Hz, 1H), 8.14 (ddd, J=1.5, 2.7 and 8.4 Hz, 1H), 8.39 (t, J=2.1 Hz, 1H), 8.58 (s, 1H, NH), 8.84 (s, 1H, NH); 19F NMR (282 MHz, acetone-d6): δ −167.41; LCMS: ret. time: 17.75 min.; purity: 92.39%; MS (m/e): 322.59 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=2[C:11]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22].C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:12]=2[C:11]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: Cc1cc(O)ccc1-c1sc2cc(O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Yield: 27.5 %

Procedure:
By the method described in Example 2, the product of Example 15 (1.0 g, 1.94 mmol), ethanethiol (0.71 mL, 9.75 mmol), and aluminum chloride (1.81 g, 13.57 mmol) were stirred in anhydrous CH2Cl2 (40 mL). Purification by chromatography (silica gel, 5-10% MeOH in CH2Cl2), provided 260 mg (27%) of the title product as a dark yellow foam: 1H NMR d 1.47 (m, 2H), 1.61 (m, 4H), 2.13 (s, 3H), 2.55 (m, 4H), 2.77 (t, J=5.5 Hz, 2H), 4.09 (t, J=5.5 Hz, 2H), 4.87 (s, 2H), 6.45 (m, 2H), 6.77 (d, J=8.7 Hz, 2H), 6.87 (dd, J=2.2, 8.8 Hz, 1H), 7.01 (d, J=9.1 Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H); MS (FD) m/e 488 (MH+); HRMS (FAB) m/e calc'd. for C29H30N1O4S1 : 488.1896, found: 488.1911.
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O.[I-].[Na+]>[CH2:1]1[CH:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][N:2]1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 82 %

Procedure:
0.546 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine, 0.437 g of ethyl bromoacetate; 0.692 g of sodium carbonate and 0.016 g of sodium iodide were added to 20 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 16 hours. At the end of this time, the mixture was diluted with water and then extracted with ethyl acetate. The solvent was then removed by evaporation under reduced pressure. The resulting residue was then subjected to column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.602 g (yield 82%) of the title compound as a pale yellow oil. The hydrochloride of this compound, melting at 187°-190° C., may be prepared by similar means to Those described in Example 17.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.O.[CH3:39][N:40](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:39]([C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1)#[N:40]
Reactant: CN(C)C=O
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 60 °C
Yield: 60 %

Procedure:
N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (3.54 g, 6.23 mmol), zinc cyanide (0.805 g, 6.86 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.720 g, 0.623 mmol) were stirred in N,N-dimethylformamide (DMF) (27.1 ml) overnight at 80° C. The reaction mixture was added dropwise into water to give a solid. The solids were filtered and dried in a vacuum oven overnight. DCM and MeOH (5:1) were added to solid and heat at 60° C. The mixture was cooled and filtered to obtain N-{3-[5-(2-cyano-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (2.06, 60%). MS (ESI): 559 [M+H]+.
Reaction SMILES: [CH3:1][N:2](C=O)[CH3:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:29]=[C:28](F)[CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].N1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[Cl-].[Na+].O>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:29]=[C:28]([N:2]([CH3:3])[CH3:1])[CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)c1ccc(F)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1COCCN1
Solvent: O
Product: COC(=O)c1ccc(N(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Yield: 59 %

Procedure:
The 4-dimethylamino compound was obtained in the following preparation in which the dimethylamino group was derived from in situ decomposition of the solvent DMF: A mixture of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-fluorobenzoate (6.45 g, 18.25 mmol), morpholine (8 g, 91.26 mmol), Cs2CO3 (11.8 g, 36.5 mmol), and DMF (10 mL) was heated 3 days at 110° C. The reaction mixture was poured into brine (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (3×200 mL), dried over MgSO4, and concentrated to an oil which was purified by chromatography on silica using 25% EtOAc in hexanes to give 4.1 g (59%) of product as a white solid.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[OH-].[Na+].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18](I)[CH:17]=[C:16]([Cl:21])[CH:15]=1.[CH3:23][S:24]([O-:26])=[O:25].[Na+].C(=O)(O)[O-].[Na+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[C:18]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:17]=[C:16]([Cl:21])[CH:15]=1
Reactant: COC(=O)c1cc(Cl)cc(I)c1
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of L-proline (1.553 g, 13.49 mmol, CAS RN 147-85-3) in dimethylsulfoxide (80 mL) was added sodium hydroxide (0.54 g, 13.49 mmol) and the reaction mixture was stirred at 25° C. for 30 min. Then copper(I) iodide (2.568 g, 13.49 mmol), 3-chloro-5-iodo-benzoic acid methyl ester (5.0 g, 16.86 mmol, CAS RN 289039-85-6) and sodium methanesulfinate (13.77 g, 134.9 mmol, CAS RN 20277-69-4) were added to the reaction mixture and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was allowed to cool down, poured on saturated aqueous sodium bicarbonate solution (500 mL) and ethyl acetate (500 mL) and filtered through celite. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (200 mL each). The combined organic layers were washed with cold water (200 mL) and brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography over silica gel (100-200 mesh) with a gradient of ethyl acetate:n-hexane (1:10 to 2:10) to get the desired compound as a colorless solid (2.31 g, 55%). MS (EI): m/z=248 ([M]).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1.O>CC(N(C)C)=O>[Cl:21][C:22]1[N:27]=[C:26]([NH:13][C@H:10]2[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc(Cl)n2)C1
Reaction time: 24 h
Yield: 89.7 %

Procedure:
(S)-(−)-1-Boc-3-aminopyrrolidine (0.375 g, 2.014 mmol) and triethylamine (0.561 mL, 4.028 mmol) were added to a solution of 2,4-dichloropyrimidine (0.300 g, 2.014 mmol) in DMA (12 mL) at 0° C. After 24 hours at room temperature, water (150 mL) was added and the aqueous phase was extracted with ethyl acetate (3×40 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography (5% methanol in dichloromethane) to give the title compound as an oil (0.540 g, 90%).