Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[C:32]1([CH:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:40][CH2:39][CH:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCC(c1ccccc1)c1ccccc1
Product: O=C(NCC(c1ccccc1)c1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2,2-diphenylethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=626.99 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH3:11])(=[O:9])=[O:8].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1COCC1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7](=[O:9])(=[O:8])[NH:10][CH3:11])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CNS(=O)(=O)CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNS(=O)(=O)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 10 h
Yield: 41 %

Procedure:
To a solution of 5-hydroxy-N-methylpentane-1-sulfonamide (Example 21; 6.4 mmol) and triethyl amine (19.2 mmol) in THF (15 ml) was added para toluenesulfonyl chloride (5.9 mmol) in THF (5 ml) at room temperature and the reaction mixture was stirred for 10 hours. The reaction mixture was washed by saturated NaHCO3 solution and then brine. The organic layer was dried over MgSO4, filtered off and concentrated. The residue was purified by flash column chromatography (SiO2; eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to give the pure title compound (0.9 gr; 41% yield.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)[CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C#N)cc2)cn1
Yield: 37 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (60 mg, 37%) which was obtained as a white solid. MS (ESI): m/e=327.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:18][S:19]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][N:23]=1)(=[O:21])=[O:20].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)[C:7]([CH2:9][N:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]([S:19]([CH3:18])(=[O:20])=[O:21])=[N:23]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Reactant: ClCc1nc2cc(Cl)ccc2n1C1CCOC1
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCOC2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-(tetrahydro-furan-3-yl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.Cl.O>C(Cl)Cl.CCOCC>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN1CCC(N)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 56.2 %

Procedure:
A mixture of 4-amino-1-methylpiperidine (4.82 g, 32.3 mmol) and 4-fluoronitrobenzene (4.56 g, 32.3 mmol) is heated at 100° C. on an oil bath over a period of 7 hours. After cooling, the reaction mixture is mixed with 2N hydrochloric acid (20 ml) and water (20 ml) and shaken with ether. The acidic layer is neutralized with conc. ammoniac solution and shaken with methylene chloride. The methylene chloride layer is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is crystallized from ether-petroleum ether to give 4-(4-nitroanilino)-1-methylpiperidine (4.27 g) as crystals melting at 153° to 155° C. The yield is 56%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.C(OC([N:28]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][C:36]3[CH:39]=[C:40]([C:43](O)=O)[CH:41]=[CH:42][C:35]=3[O:34]2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:43]([C:40]3[CH:39]=[C:36]4[C:35](=[CH:42][CH:41]=3)[O:34][C:31]3([CH2:30][CH2:29][NH:28][CH2:33][CH2:32]3)[CH2:38][CH2:37]4)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCc3cc(C(=O)O)ccc3O2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc5c(c4)CCC4(CCNCC4)O5)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 50 °C

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and N-tert-butoxycarbonyl-6-carboxy-3,4-dihydrospiro[2H-1-benzopyran-2,4′-piperidine] (75.4 mg, 0.228 mmol) were reacted. The crude reaction was concentrated, then taken up into 4N HCl/dioxane and heated at 50° C. for 4 hours. The reaction mixture was then concentrated and chromatographed on Gilson HPLC 0-45% CH3CN/H2O. The desired fractions were neutralized with conc. bicarb. Attempted extraction into DCM and EtOAc failed but a solid formed in the sep funnel and was filtered. This solid was 7 mg (6%) of the title compound. mp: >250° C., 1H NMR (300 MHz, DMSO-d6): 13.12 (s, 1H), 7.92 (s, 2H), 7.88 (d, 1H), 7.76 (s, 1H), 7.24 (s, 1H), 7.15 (d, J=8 Hz, 1H), 6.98 (d, J=8 Hz, 1H), 6.38 (s, 2H), 5.15 (t, J=8 Hz, 1H), 3.23 (m, 2H), 3.14 (m, 2H), 2.88 (m, 3H), 2.78 (s, 1H), 2.62 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.96-1.85 (m, 4H), 1.39 (d, J=8 Hz, 1H). MS: 505 (M+H), HPLC: 1.96 min (G method).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C.O>[CH2:22]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Cl:1])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
8-Chloro-3-methyl-3,7-dihydropurine-2,6-dione (868 mg) and potassium carbonate (628 mg) were suspended in N,N-dimethylformamide (10 ml), and allyl bromide was added dropwise thereto while cooling on ice. After stirring the reaction mixture at room temperature for 17 hours, the resulting white suspension was diluted with ethyl acetate (30 ml) and water (4 ml), and was filtered to give a white solid. The solid was washed with water and ethyl acetate to give 797 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][OH:38]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH2:37][OH:38])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: OCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4-(5,6-Dimethyl-[2,2′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 338) (80 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (89 mg) and 2-bromoethanol (0.05 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (77 mg, yield 88%).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:46]=[CH:45][CH:44]=[CH:43][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][C@@H:25]([S:40][S:41][CH3:42])[CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([OH:31])=[O:30])=[O:22])=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:46]=[CH:45][CH:44]=[CH:43][C:18]=1[CH2:19][O:20][C:21]([NH:23][CH2:24][C@@H:25]([S:40][S:41][CH3:42])[CH2:26][CH2:27][C@H:28]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:29]([O:31][CH2:2][C:1]#[N:4])=[O:30])=[O:22])=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)O)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Agent: N#CCBr
Solvent: CC#N
Product: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Reaction time: 1.25 h
Yield: 80.4 %

Procedure:
N,N-Diisopropylethylamine (34 μL, 0.197 mmol) and subsequently bromoacetonitrile (62 μL, 0.896 mmol) were added to a solution of (2S,5S)-6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoic acid (Compound tk15) (89.5 mg, 0.179 mmol) in acetonitrile (0.3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1.25 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (2S,5S)-cyanomethyl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk16) (77.5 mg, 80%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:13][NH:12][C:11](=[O:25])[CH2:10]2)[CH:6]=[CH:5][N:4]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(#N)C>CCOCC.CCOC(C)=O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([OH:25])[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CSc1nccc(C2CC(=O)NN=C2c2cccc(C(F)(F)F)c2)n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: CSc1nccc(-c2cc(O)nnc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 90 °C

Procedure:
Compound 6 (1.92 g, 5.26 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (4.78 g, 21.0 mmol), and acetonitrile (30 mL) were combined under argon and heated at 90° C. for 1 h. The solution was cooled and the solvent was removed in vacuo. The crude product was purified by flash column chromatography (methylene chloride:methanol:ammonium hydroxide 95:5:0.5) to give a solid. Trituration with.Et2O EtOAc gave Compound 69: 1.60 g (4.4 mmol, 83%)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[C:5]([CH3:19])([CH3:18])[C:4](=[O:20])[C:3]=1[C:21]([NH:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:22]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)[C:5]([CH3:18])([CH3:19])[C:4](=[O:20])[C:3]=1[C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(-c3cccnc3)ccc2C(C)(C)C1=O
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(-c3cccnc3)ccc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A suspension of 1,1-dimethylethyl N-((4-hydroxy-1,1-dimethyl-2-oxo-6-(pyridin-3-yl)-naphthalen-3-yl)carbonyl)glycinate (109 mg, 258 μmol) and silica gel (230-400 mesh, EMD Chemicals) (78 mg, 1290 μmol) in toluene (5 mL) was heated to 110° C. After 2 hours, the reaction was cooled to 23° C., filtered and washed with DCM (25 mL). The washings were discarded. The residue was subsequently washed with a 10% MeOH/DCM solution (1000 mL). The filtrate was then concentrated in vacuo affording 91 mg of the title compound. MS m/e=367.2 (M+H)+. Calculated for C20H18N2O5 366.12.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.O>C(OCC)(=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Cl:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][O:5][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: CC(C)(CO)CCl
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CCl)COC1CCCCO1
Reaction time: 19 h
Yield: 72 %

Procedure:
To a solution of 3-chloro-2,2-dimethylpropanol (5.0 g) and 2,3-dihydropyran (4.12 g) in ethyl acetate (20 ml) was added camphor sulfonic acid (57 mg), and the mixture was stirred for 19 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with O.1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and distilled under reduced pressure (2 mmHg, 108° C.) to give colorless oil of 2-(3-chloro-2,2-dimethylpropoxy)tetrahydropyran (6.07 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[C:9]([O:18][CH3:19])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:9]([O:18][CH3:19])[CH:8]=1
Reactant: COc1cc(Br)ccc1NC(=O)CCl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(Br)ccc1NC(=O)CN1CCCC1
Temperature: 80 °C
Yield: 99.3 %

Procedure:
Add pyrrolidine (7.5 mL, 90 mmol) to a mixture of N-(4-bromo-2-methoxy-phenyl)-2-chloro-acetamide (5.0 g, 18 mmol) and potassium carbonate (4.96 g, 36 mmol) in acetonitrile (180 mL). Heat the mixture at 80° C. for 4 h. Cool the mixture to RT and filter with CH2Cl2 (300 mL). Wash the filtrate with brine (400 mL), back extract the aqueous twice with CH2Cl2 (300 mL). Wash the combined organic layer with water (250 mL). Dry the organic portion over Na2SO4, filter, and concentrate. Dry the resulting solid on house vacuum overnight to give 5.6 g (99%) of the title compound. LC-ES/MS m/z (81Br) 314.0 [M+].
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=3[CH2:12][N:11]([S:21]([CH3:24])(=[O:23])=[O:22])[C@H:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:9]2)[N:4]=[CH:3]1.[C:32]1([C:38](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[C:32]1([C:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:2]2[CH:6]=[C:5]([CH2:7][N:8]3[C:14]4[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=4[CH2:12][N:11]([S:21]([CH3:24])(=[O:22])=[O:23])[C@H:10]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:9]3)[N:4]=[CH:3]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Solvent: CC#N
Product: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C[C@H]1Cc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 1.2 g (2.85 mmol) of the free base of Example 225 in 20 ml of acetonitrile, at rt and under argon, was added 1.2 ml (8.55 mmol) of TEA, followed by 1.2 g (4.3 mmol) of triphenylmethyl chloride. Stirring was continued overnight. The resulting cloudy solution was evaporated to dryness and the residue subjected to flash chromatography on a 100 cc column of silica gel (50% ethyl acetate-hexane) to afford 1.2 g (64%) of Cmpd A as a viscous white foam.
Reaction SMILES: ClC1C=C(N(C)CC(O)=O)C=CC=1Cl.[Br:15][C:16]1[C:17]([Br:31])=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=O)[C:20]=2[CH:30]=1.C1(C2C=CC=CC=2)C=CC(C(NC)CN2CCCC2)=CC=1.[C:53]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:58]=[CH:57][C:56]([CH:59]([NH:67][CH3:68])[CH2:60][N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)=[CH:55][CH:54]=1>>[C:53]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:54]=[CH:55][C:56]([CH:59]([N:67]([CH3:68])[C:27](=[O:29])[CH2:26][N:21]2[C:20]3[CH:30]=[C:16]([Br:15])[C:17]([Br:31])=[CH:18][C:19]=3[O:24][CH2:23][C:22]2=[O:25])[CH2:60][N:61]2[CH2:62][CH2:63][O:64][CH2:65][CH2:66]2)=[CH:57][CH:58]=1
Reactant: O=C(O)CN1C(=O)COc2cc(Br)c(Br)cc21
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Product: CN(C(=O)CN1C(=O)COc2cc(Br)c(Br)cc21)C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Yield: 58 %

Procedure:
The title compound was prepared according to the procedure described in example 11 replacing N-(3,4-dichlorophenyl)-N-methylglycine with (6,7-dibromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid, and [1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine with the product from step b) above to give the title compound (52 mg, 58%). MS (ES) m/e 643 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.CN1[C:41](=[O:42])[CH2:40][CH2:39]C1.C(Cl)(=O)C=C>C(Cl)Cl>[O:22]([C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH:40]=[CH2:39])[CH:7]=[CH:6][CH:5]=3)[CH:14]=2)[CH:21]=[CH:20][CH:19]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Reactant: CN1CCCC1=O
Agent: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Reaction time: 3 h

Procedure:
To a stirred solution of N4-(3-aminophenyl)-N6-(3-phenoxyphenyl)pyrimidine-4,6-diamine (40 mg, 0.1 mmol), Et3N (0.03 mL, 0.2 mmol) and NMP (0.4 mL) in CH2Cl2 (2 mL), at 0° C., was added acryloyl chloride (6) (29 mg, 0.3 mmol). The reaction mixture was allowed to come to rt and stirred at this temperature for 3 h. It was washed with 10% NaHCO3 solution (2 mL), water (2 mL), brine (2 mL) and dried over Na2SO4. Filtration followed by concentration under reduced pressure offered a residue which was purified by column chromatography (SiO2, 230-400, chloroform/methanol, 9/1) to gave N-(3-(6-(3-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (I-75) as a light brown solid. 1H NMR (DMSO-d6) 5 ppm: 5.73 (dd, J=1.72 & 10 Hz, 1H), 6.18 (s, 1H), 6.24 (dd, J=1.92 & 17 Hz, 1H), 6.45 (dd, J=10.04 & 16.88 Hz, 1H), 6.54-6.57 (m, 1H), 7.01-7.05 (m, 2H), 7.11-7.15 (dd, J=0.88 & 7.48 Hz, 1H), 7.19-7.32 (s, 4H), 7.35-7.41 (m, 4H), 7.89 (s, 1H), 8.26 (s, 1H), 9.2 (s, 1H), 9.25 (s, 1H), 10.26 (s, 1H); LCMS: m/e 423.8 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([OH:16])[CH2:6]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>CS(C)=O>[CH3:3][N:4]([CH3:17])[C@@H:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[C@H:7]([O:16][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH2:6]1
Reactant: Fc1ccc(Cl)cc1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(Cl)cc2)C1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
0.6 ml of dimethylsulfoxide were added at room temperature to 60 mg of sodium hydride in a 50% oil dispersion and the mixture was heated to 50° C. for 20 minutes and was then cooled to 20° C. 205 mg of cis 7-dimethylamino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol were added thereto and after stirring the mixture for 15 minutes, 0.13 ml of p-chloro-fluorobenzene was added thereto. The mixture stood for one hour at 20° C. and was heated at 50° C. for 90 minutes and for 3 hours at 100° C. The mixture was cooled to 20° C. and was extracted with 30 ml of methylene chloride. The organic phase was washed with water, dried and evaporated to dryness to obtain 300 mg of raw product which was chromatographed over silica gel. Elution with a 7-3 chloroform-methanol mixture and evaporation of the solvent yielded 250 mg of cis N,N-dimethyl-5-[4-chlorophenoxy]-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-amine in the form of an oil.
Reaction SMILES: [OH-].[Na+].CO.C1(C)C=CC=CC=1.C([S:15][CH2:16][C:17]([N:19]([CH3:26])[CH:20]([CH3:25])[CH2:21][N+:22]([O-])=[O:23])=[O:18])(=O)C>O>[N:22](=[C:21]1[CH:20]([CH3:25])[N:19]([CH3:26])[C:17](=[O:18])[CH2:16][S:15]1)[OH:23]
Reactant: CC(=O)SCC(=O)N(C)C(C)C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1C(=NO)SCC(=O)N1C
Reaction time: 0.08 h
Yield: 29.2 %

Procedure:
A solution of 5.6 g of sodium hydroxide, 100 ml of methanol and 100 ml of toluene was charged into a flask and stirred vigorously while adding 23 g of 2-(acetylthio)-N-methyl-N-(1-nitro-2-propyl)acetamide, over a 5 minute period at 30°-40° C. The reaction mixture was stirred at 40° C for 8 hours, then stirred overnight at room temperature. The mixture was stripped of solvents under reduced pressure. The solid residue was dissolved in 200 ml of water. The mixture was filtered and the filtrate was acidified with hydrochloric acid. The solid which precipitated was filtered, washed with water and dried at room temperature. The solid product was recrystallized from isopropanol to yield 5.0 g of 2-oximino-3,4-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 205° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH2:4][CH2:3][CH:2]1[C:14]([O:16]CC)=[O:15].[OH-].[K+]>CCO>[CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH2:4][CH2:3][CH:2]1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C1CCc2sc3ccccc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCc2sc3ccccc3c2C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of ethyl 1,2,3,4-tetrahydrodibenzo[b,d]thiophene-2-carboxylate (1.15 g, 4.42 mmol) in EtOH (50 mL) was added KOH (0.4 g, 7.07 mmol). The reaction was stirred at 40° C. for 3 hours. After cooling to room temperature, the mixture was extracted with ether. The ether layer was washed with aqueous Na2CO3. The combined aqueous layers were acidified to pH 2 with conc. HCl and extracted with EtOAc. The EtOAc layer was washed with brine, then was dried over MgSO4 and concentrated to dryness to afford the 0.77 g (75%) of the title compound as a white solid: mp 202-203° C., MS (−) 231 (M−H)−.