Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])[CH:5]=[C:6]([O:20][CH2:21][CH3:22])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-])=O.C(O)(=O)C>C1COCC1.[Zn]>[NH2:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:6]([O:20][CH2:21][CH3:22])=[CH:5][C:4]([CH:23]2[C:32]3[C:31](=[O:33])[CH2:30][CH:29]([CH2:34][CH2:35][CH3:36])[CH2:28][C:27]=3[NH:26][C:25]([CH3:37])=[C:24]2[C:38]#[N:39])=[CH:3][C:2]=1[Br:1]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cc(F)ccc2[N+](=O)[O-])c(OCC)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cc(F)ccc2N)c(OCC)c1
Temperature: 50 °C

Procedure:
To a solution of the product of step b (3.8 g) in THF (110 ml) were added acetic acid (3.6 ml) and zinc dust (8.2 g). The suspension was heated for 1 h at 50° C. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate and washed with sat. NalCO3 and brine. The organic layer was separated, dried (Na2SO4) and concentrated. The remaining solid was stirred with a small amount of ethyl acetate to give the title compound as a pale yellow solid after filtration.
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8](O)[C:9]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)[Cl:20]>ClC(Cl)C>[Cl:20][C:8]1[C:9]2[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:7]=1
Reactant: O=S1(=O)CCCc2nc(C3CCCC3)nc(O)c21
Reactant: ClP(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=S1(=O)CCCc2nc(C3CCCC3)nc(Cl)c21
Temperature: 65 °C
Reaction time: 24 h
Yield: 21.6 %

Procedure:
To mixture of 2-cyclopentyl-4-hydroxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 5,5-dioxide (0.650 g, 2.42 mmol) in dichloroethane (10 mL) was added phosphorous trichloride (1.35 mL, 14.5 mmol). The mixture was stirred at 65° C. for 24 h. The reaction was quenched into a mixture of methylene chloride and a saturated solution of NaHCO3 and extracted with methylene chloride. The organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.150 g, 22%) as a tan solid. MW=286.78. 1H NMR (CDCl3, 500 MHz) δ 3.49-3.42 (m, 2H), 3.31 (p, J=8.0 Hz, 1H), 3.11 (t, J=6.2 Hz, 2H), 2.53-2.45 (m, 2H), 2.13-2.04 (m, 2H), 1.94-1.78 (m, 4H), 1.75-1.65 (m, 2H); APCI MS m/z 287 [M+H]+.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[NH2:9][C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18]>CN(C=O)C>[NH2:9][C:10]1[C:15]([O:16][CH3:3])=[CH:14][CH:13]=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cccc(O)c1N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccc(C(C)=O)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Under an atmosphere of nitrogen, methyl iodide (1.35 g, 10 mmol) and potassium carbonate (4.39 g, 320 mmol) were added to a solution of 2′-amino-3′-hydroxyacetophenone (960 mg, 6 mmol, TCI Europe) in DMF (6 ml). The reaction mixture was stirred for 1 h at r.t., during which time the color of the mixture changed from light brown to dark green. The mixture was then worked up by extraction with H2O/ethyl acetate, drying of the organic phase (Na2SO4), and evaporation of solvent. The title compound (960 mg, 92%) was isolated from the residue by column chromatography (silica gel, heptan/ethyl acetate=100/0-70/30).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH2:7][CH2:6]1)C.[CH2:15]([S:22][C:23](=[NH:25])[NH2:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([S:22][C:23]1[N:24]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[C:10]=2[N:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)SCc1ccccc1
Reactant: CCOC1=CCCC(=CN(C)C)C1=O
Solvent: CN(C)C=O
Product: CCOC1=CCCc2cnc(SCc3ccccc3)nc21
Temperature: 95 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 2.0 g (0.01 mol) of 6-[(dimethylamino)methylene]-2-ethoxycyclohex-2-en-1-one in 20 mL of dimethylformamide 2.6 g of S-benzylisothiourea (2 eq. mol.) were added. The reaction mixture was stirred at 95° C. for 4 hours. The solvent was then evaporated under reduced pressure and the crude purified by chromatography on a silica gel column (eluant dichloromethane/methanol 9/1) leading 1.5 g (50% yield) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)CNC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)CNC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 23.2 %

Procedure:
The title compound (21 mg, 19%) was prepared from (4-{[(2-methylpropyl)amino]carbonyl}phenyl)boronic acid (44 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3 and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H, J=8.6 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.9 Hz), 6.17 (t, 1H, J=5.8 Hz), 4.97-4.84 (m, 1H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.34-3.27 (m, 2H), 2.83-2.73 (m, 2H), 2.05-1.95 (m, 1H), 1.95-1.89 (m, 1H), 1.90-1.80 (m, 2H), 1.35-1.26 (m, 2H), 1.24 (d, 6H, J=6.2 Hz), 0.99 (d, 6H, J=6.7 Hz); LRMS (ESI), m/z 453 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([CH:23]=[CH:24][C:25]#[N:26])[CH:17]=[CH:16]2>C(O)C.C(Cl)(Cl)Cl.[OH-].[Pd+2].[OH-].[C]>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([CH2:23][CH2:24][C:25]#[N:26])[CH:17]=[CH:16]2
Reactant: N#CC=Cc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N#CCCc1ccc2cc(CN3C(=O)c4ccccc4C3=O)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.6 %

Procedure:
The compound (574.4 mg) obtained in Example 119-6 was dissolved in ethanol (20 ml) and chloroform (10 ml). Then, the solution was added with 20% palladium hydroxide-carbon (172.3 mg) and then stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction, the solution was filtrated through Celite and the solvent was then distilled off under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (101.9 mg) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH:19]2[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>>[CH3:24][C:21]1([CH3:25])[O:20][CH:19]([CH2:18][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8]([C:5]2[CH:6]=[N:7][C:2]([NH:27][NH2:28])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:23][O:22]1
Reactant: CC1(C)OCC(CN(c2ccccc2)S(=O)(=O)c2ccc(Cl)nc2)O1
Reactant: NN
Solvent: O
Product: CC1(C)OCC(CN(c2ccccc2)S(=O)(=O)c2ccc(NN)nc2)O1
Yield: 99 %

Procedure:
According to process 5.2, starting with 0.54 g of 6-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-N-phenylpyridine-3-sulfonamide and 30 μL of hydrazine hydrate, 0.53 g of N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-hydrazinyl-N-phenylpyridine-3-sulfonamide is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]/[CH:10]=[C:11](\[CH3:23])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:6]=[C:5]([CH3:24])[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9]/[CH:10]=[C:11](\[CH3:23])/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]2[O:33][C:19]2([CH3:20])[CH3:21])[CH:6]=[C:5]([CH3:24])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)cc(C/C=C(\C)CC/C=C(\C)CCC=C(C)C)c1
Solvent: ClCCl
Product: COc1cc(C)cc(C/C=C(\C)CC/C=C(\C)CCC2OC2(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To a solution of 24 (488.2 mg, 1.5 mmol) in 12 mL of dry CH2Cl2 at 0° C. was added a solution of MCPBA (403.4 mg, 1.80 mmol in 4 mL of CH2Cl2), the reaction mixture was stirred at 0° C. for 1 hr and then quenched with saturated aqueous NaHCO3 (50 mL). Et2O (3×50 mL) was then added, and the organic layer was washed with saturated aqueous NaHCO3, water, and brine, and dried with MgSO4 and concentrated to give a crude product. The crude product was passed through a silica gel column (hexanes/EtOAc 80:1, 40:1, 20:1) to give the pure epoxide 25 (104 mg: yield 20%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:27]([O-:29])=[O:28])=[C:20]([N:22]([CH3:26])[C:23](=[O:25])[O-:24])[CH:21]=2)=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:32](Br)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:11]1[CH:31]=[CH:30][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:27]([O-:29])=[O:28])=[C:20]([N:22]([CH3:26])[C:23](=[O:24])[O:25][C:3]([CH3:6])([CH3:5])[CH3:4])[CH:21]=2)=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCCCCCBr
Reactant: CN(C(=O)[O-])c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 168.8 %

Procedure:
To a suspension of sodium hydride (55 wt. %, 1.26 g) in anhydrous N,N-dimethylformamide (100 ml) was added N-[5-(4-t-butoxycarbonylaminophenoxy)-2-nitrophenyl]-N-methylcarbamate (12.1 g). The mixture was stirred at ambient temperature for several minutes. To the mixture was added hexyl bromide (6.5 g) under ice cooling and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 1.0 hour. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by chromatography on a silica gel column using toluene/diisopropyl ether=100/7 as the eluant to give the title compound (13.8 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[O:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])C2=CC=CC=C2C1=O)=[O:5])[CH3:2].[OH2:47].NN>C(O)C>[C:39]([O:20][C:19]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[O:29][CH2:28]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:47])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reactant: O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 159.7 %

Procedure:
A mixture of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.46 g), hydrazine hydrate (0.18 g) and ethanol (10 ml) is allowed to stand overnight at room temperature. The mixture is concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (50 ml×4). Water (50 ml) and sodium bicarbonate (0.5 g) are added to the organic extract, and to the resulting mixture is added dropwise di-tert-butyl dicarbonate (0.24 g) with stirring. After stirring for 30 minutes at room temperature, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluent to yield tert-butyl 3(S)-[9-tert-butoxycarbonylamino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.
Reaction SMILES: O[C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:15]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:16]2[CH:15]=[C:14]([C:13]3[O:26][C:2]4[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][C:11]=4[N:12]=3)[CH:19]=[CH:18][CH:17]=2)[CH:21]=1
Reactant: COC(=O)c1cccc(NC(=O)c2cccc(-c3cccnc3)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc2nc(-c3cccc(-c4cccnc4)c3)oc12
Yield: 15.7 %

Procedure:
Methyl 2-hydroxy-3-(3-(pyridin-3-yl)benzamido)benzoate (0.9 g, 2.5 mmol) and 4-methylbenzenesulfonic acid monohydrate (1 g, 5 mmol) were added to toluene (20 mL) and the mixture was stirred under reflux for 2 days. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1 to 10:1). 130 mg of methyl 2-(3-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxylate as a solid was obtained. Yield: 15%. LC-MS (ESI) m/z: 331 (M+1)+.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19](O)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:5][CH:4]=1.[CH3:24][N:25]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][C:15]([C:19]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([CH2:32][N:25]([CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH3:24])=[CH:34][CH:35]=4)=[O:20])=[CH:14][C:13]=3[CH:22]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCO3)cc1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
To a solution of 7-(4-dimethylaminophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.11 g) and triethylamine (0.2 ml) in dimethylformamide (15 ml) was added diethyl cyano-phosphate (0.11 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-dimethylaminophenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 149) (0.07 g) as pale brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]([F:18])([F:17])[F:19])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)(F)F)CC2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3-n3cccn3)n2)ccc2c1CCC(NCC(F)(F)F)CC2
Yield: 63 %

Procedure:
In an analogous procedure to Example 651, part c, 1-Methoxy-N*7*-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine to yield -Chloro-N*2*-[1-methoxy-7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine (60.59 mg, 63% yield) as a red glass. 1H-NMR (CDCl3) δ 10.17 (s, 1H), 8.52 (d, J=8.3 Hz, 1H), 8.05 (m, 2H), 7.82 (d, J=18.2 Hz, 2H), 7.41 (m, 3H), 7.21 (m, 1H), 6.82 (d, J=8.2 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 6.51 (m, 2H), 3.71 (s, 3H), 3.23 (m, 3H), 2.87 (m, 1H), 2.62 (m, 2H), 2.45 (m, 1H), 2.09 (m, 2H), 1.29 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]2[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=12.[CH3:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[NH2:28][C:27]1[CH:26]=[CH:25][C:24]([CH3:23])=[C:30]([C:2]2[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]3[N:10]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[F:22])[C:11](=[O:14])[NH:12][CH2:13][C:3]=23)[CH:29]=1
Reactant: CSc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(-c2cc(N)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Temperature: 95 °C

Procedure:
To 5-chloro-1-(2,6-difluorophenyl)-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.342 g, 1 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.256 g, 1.1 mmol) in dioxane (40 mL), was added a solution of K2CO3 (0.417 g, 3 mmol) in water (10 mL). Argon was vigorously bubbled through the mixture for 5 minutes and then tetrakis(triphenyl-phosphine)palladium(0) (0.078 g, 0.05 mmol) was added. The mixture was heated in a 95° C. oil bath for 17 hours. The solvent was pumped off in vacuo, and the residue partitioned between ethyl acetate and water. The phases separated and the organic phase washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was flash chromatographed on silica gel (20 grams) eluted with 0-10% MeOH/CH2Cl2 to give the title product as a white solid. mp 122-125° C. LC-MS m/z 414 (M+H)+, 1.58 min (ret. time).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH2:13][CH:14]([OH:16])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:6]([CH2:13][CH:14]([O:16][S:1](=[O:4])(=[O:3])[NH2:2])[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(O)COc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: CC(COc1ccccc1)OS(N)(=O)=O

Procedure:
The title compound was prepared by procedures of Example 22 from sulfamoyl chloride and 3-phenoxy-2-propanol through the partitioning and final evaporation to give an oil as residue. The oil was purified by chromatography using a 4.5 cm×100 cm glass column packed with 500 g of silica gel and methylene chloride as eluting agent. Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give a 37% yield of an oil which solidified on standing, mp 57°-60° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[C:16]=[S:17]>>[OH:4][CH2:3][CH:2]([NH:1][C:16]([NH:15][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[CH:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:31][CH:30]=3)[N:25]=2)=[CH:20][CH:19]=1)=[S:17])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1
Reactant: NC(CO)c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-(trifluoromethyl)phenyl)ethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.54 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.66 (d, J=8.7 Hz, 2H), 7.43 (d, J=6.3 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.2 Hz, 2H), 6.88-6.69 (m, 4H), 6.61-6.50 (m, 2H), 5.27-5.07 (m, 1H), 3.48-3.40 (m, 1H), 3.40-3.24 (m, 1H); ESIMS m/z 552 ([M+H]+).
Reaction SMILES: I[CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCCC1CCNCC1
Solvent: CC#N
Product: CCCCC1CCN(C[C@H](C)CN2C(=O)COc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.5 %

Procedure:
A 4 ml vial was charged with crude (R)-4-(3-iodo-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one (108LM46-43) (0.312 g) and 4-butyl-piperidine (0.210 g, 1.49 mmol) in dry MeCN (½ ml) and shaken at 60° C. for 3 days. The reaction mixture was quenched with water (1 ml), and the product extracted into EtOAc (2×1 ml). The combined organic layers were added a cation exchange column. The column was washed with MeOH (2 column volumes) then the product was eluded of the column using 8% ammonium hydroxide in MeOH (2 column volumes). The product was purified by flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM53-50) (0.193 g, 17% -3 steps). 1H NMR (CDCl3) δ 7.18 (d, J=7.8 Hz, 1H), 7.03-6.96 (m, 3H), 4.58 (ABq, J=14.3 Hz, J=33.9 Hz, CH2), 4.05-3.90 (m, 2H), 2.88 (bd, J=10.4 Hz, 1H), 2.71 (bd, J=10.4 Hz, 1H), 2.25-2.01 (m, 3H), 2.00-1.92 (m, 1H), 1.83-1.75 (m, 1H), 1.68-1.56 (m, 2H), 1.33-112 (m, 9H), 0.95-0.85 (m, 6H); 13C NMR (CDCl3) δ 164.9, 145.7, 128.9, 123.8, 122.7, 117.2, 115.8, 67.8, 64.2, 55.8, 54.4, 45.4, 36.6, 36.1, 33.0, 32.8, 29.3, 23.2, 17.1, 14.4; HPLC-MS (ammonium acetate) [M+H]+=345.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]4[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=4)=[CH:28][CH:27]=3)[CH2:11][CH2:12]2)=[O:17])=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCOc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 11.5 %

Procedure:
4-[4-(2-Aminoethoxy)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.63 g, 1.4 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.53 g, 1.3 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.125 g, 0.15 mmol).