Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10]([O:18]C)=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[O:15][CH3:16])(C)(C)C>Cl.O.CCO>[NH2:7][CH2:8][C:9]1[C:10]([OH:18])=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1cc(C)nc(OC)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C)nc(O)c1CN
Yield: 63 %

Procedure:
tert-butyl((2,4-dimethoxy-6-methylpyridin-3-yl)methyl)carbamate (83 g, 294 mmol) was dissolved in 4 N HCl/H2O (830 ml). Then the mixture was refluxed for 4.5 h. (The reaction mixture was monitored by MS spectrum to make sure the methyl group at 2-position de-protect completely.) After the reaction completed, the mixture was concentrated under vacuum to give a brown oil. The oil was suspended in EtOH (300 ml) for 15 min to give a yellow precipitate. The precipitate was filtered, washed with ethanol (100 ml) and MTBE (100 ml) and dried under high vacuum to give 38 g of fraction 1 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (Purity 98% by LCMS, yield 63%) as a yellow powder. In the meantime, the filtration from fraction 1 was concentrated under vacuum and the residue was solidified by ethanol (100 ml). The precipitate was filtered, washed with ethanol (100 ml) and MTBE (100 ml) and dried under high vacuum to give 20 g of fraction 2 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (Purity 94% by LCMS, yield 33%) as a yellow powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)#[N:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C#N)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (25 mL) was added dropwise 4-cyanobenzoyl chloride (92 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 120 mg (61%) of the title compound as white crystals: mp 184-186° C.; [α]21D -47° (c 1.0, CHCL3); EIMS (70 eV) m/z (relative intensity) 374 (54, M+).
Reaction SMILES: [O-]CC.[Na+].[CH:5]1([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](=[O:28])[CH2:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[CH:18][C:13]=3[N:12]([CH3:29])[C:11]2=[O:30])[CH2:9][CH2:8][CH2:7][CH2:6]1.[N:31](OCCCC)=[O:32]>C(O)C.O>[CH:5]1([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19](=[O:28])[C:20]([C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[N:31][OH:32])=[CH:18][C:13]=3[N:12]([CH3:29])[C:11]2=[O:30])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CCCCON=O
Reactant: Cc1cccc(CC(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=NO)C(=O)c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium ethoxide (9.27 mL of a 21% solution in ethanol, 28.6 mmol) was added to ethanol (12 mL) at 0 deg C. After 5 minutes, 1-cyclopentyl-3-methyl-5-m-tolylacetyl-1,3-dihydro-benzoimidazol-2-one (prepared as described in the general procedure, 5 gm, 14.3 mmol) was added. n-Butyl nitrite (3.34 mL, 28.6 mmol) was then added dropwise over 5 minutes. When the addition was complete, the flask was covered with a septum and allowed to stand in the refrigerator overnight, after which time LCMS of an aliquot showed essentially complete reaction. The reaction mixture was diluted with 300 mL of water and allowed to stir at room temperature overnight. The resulting precipitate was filtered and dried in vacuo. The yellow solid was slurried with benzene for 2 hours and filtered to afford 4.0 gm of a pale tan solid. The title oxime is formed a ca. 10:1 mixture of isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[C:35](N(OC)C)=[O:36])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:44][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([C:35](=[O:36])[CH3:44])[CH:41]=[CH:42][CH:43]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide (0.10 g, 0.157 mmol) in anhydrous tetrahydrofuran (THF) (3.0 mL) at 0° C. was added a solution of methyl magnesium chloride (3.0 M in THF) (0.523 mL, 1.57 mmoL). The mixture was stirred for 3 hours, then quenched with saturated aqueous ammonium chloride solution (1 mL). Product was extracted with 10 mL of dichloromethane, washed with water (5 mL×2), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (40% dichloromethane in ethyl acetate) to afford 0.085 g (91%) of the title compound as a pale yellow solid. M.p.=124-127° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.17 (m, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.9 (d, J=7.6 Hz, 1H), 7.86-7.84 (m, 1H), 7.77-7.74 (m, 2H), 7.67-7.65 (m, 2H), 7.62 (t, J=8.0 Hz, 1H), 7.42 (d, J=4.8 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.38 (d, J=5.2 Hz, 1H), 3.93 (bs, 1H), 3.74-3.72 (m, 1H), 3.48-3.45 (m, 1H), 2.57 (s, 3H), 2.49-2.45 (m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.32 (m, 1H); LCMS: 594 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:23]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]([CH3:34])[N:26]=1)=[O:24]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[N:26]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(C(=O)c2cc(Cl)ccc2N)c2ccccc21
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cn1nc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c2ccccc21

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-aryl-benzenesulfonamides using 4-tert-butyl-benzenesulfonyl chloride and (2-Amino-5-chloro-phenyl)-(1-methyl-1H-indazol-3-yl)-methanone and purified by HPLC: MS: m/z 483 (M++1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:10]2[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)=[O:26])[CH:16]=3)[N:11]=2)[CH:6]=[CH:7][C:8]=1[OH:9])=O.[NH2:37]OS(O)(=O)=O.CO>O>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27][CH2:28][C:29]5[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)=[O:26])[CH:16]=4)[N:11]=3)=[CH:4][C:3]=2[CH:1]=[N:37]1
Reactant: NOS(=O)(=O)O
Reactant: COc1ccc(COC(=O)c2ccc3nc(-c4ccc(O)c(C=O)c4)c(N(C)C(C)C)nc3c2)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(COC(=O)c2ccc3nc(-c4ccc5oncc5c4)c(N(C)C(C)C)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.6 %

Procedure:
To a solution of (4-methoxyphenyl)methyl 2-(3-formyl-4-hydroxyphenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (190 mg, 0.39 mmol) in water (5 mL) was added aminooxysulfonic acid (83 mg, 0.48 mmol) and methanol (5 mL). The resulting solution was stirred overnight at 25° C. Then the reaction was quenched by the addition of water (200 mL) and extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 1% to 5% ethyl acetate in petroleum to afford (4-methoxyphenyl)methyl 2-(1,2-benzoxazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a yellow solid (50 mg, 26%).
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[Cl:8][C:9]1[CH:10]=[C:11]([O:33][CH2:34][CH:35]=[O:36])[CH:12]=[N:13][C:14]=1[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:26][C:27]1[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=1>O>[Cl:8][C:9]1[CH:10]=[C:11]([O:33][CH2:34][CH2:35][OH:36])[CH:12]=[N:13][C:14]=1[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][N:20]=[C:19]2[NH:26][C:27]1[CH:31]=[CH:30][N:29]([CH3:32])[N:28]=1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(OCC=O)cc4Cl)cc23)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ncc(OCCO)cc4Cl)cc23)n1
Reaction time: 0.25 h

Procedure:
With cooling with ice, sodium borohydride (9 mg, 0.25 mmol) was added to a tetrahydrofuran (3 ml)/water (0.3 ml) mixed solution containing {[5-chloro-6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}acetaldehyde obtained in Example 1, and the reaction solution was stirred for 15 minutes. Saturated saline water was added to the reaction solution, extracted with chloroform/methanol (9:1), the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:4 to 100:5) and reversed-phase liquid chromatography (YMC CombiPrep Pro C18 AS-360-CC), and the obtained solid was recrystallized from ethyl acetate to obtain the entitled compound (19 mg) as a white solid.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][C:10]1[N:14]=[C:13]([CH3:15])[N:12]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18](/[CH:23]=[CH:24]/[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:17]=2)[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[N:14]=[C:13]([CH3:15])[N:12]([C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C@@H:23]3[CH2:2][C@H:24]3[C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:17]=2)[N:11]=1
Reactant: Cc1nc(/C=C/c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc([C@@H]2C[C@H]2c2ccc3ccccc3n2)cc(-n2nc(C)nc2C)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of trimethylsulfoxonium iodide (59.0 mg, 0.268 mmol, 1.3 eq.) in anhydrous DMSO (1.5 mL) was added sodium hydride (5.4 mg, 0.227 mmol, 1.1 eq.) and the reaction was heated to 50° C. for 30 minutes. The reaction was then cooled to room temperature and a solution of (E)-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)vinyl)quinoline (1-4) (70.0 mg, 0.205 mmol, 1.0 eq.) in DMSO (1.5 mL) was added. The reaction was stirred at room temperature for 1 hour, poured into water (5.0 mL) and extracted using ethyl acetate (3×5.0 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (10-40% ethyl acetate in hexanes) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropyl)quinoline (1-5) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.03 (br d, 1H, J=8.5 Hz), 7.98 (br d, 1H, J=8.4 Hz), 7.75 (br dd, 1H, J=8.0, 1.0 Hz), 7.67 (ddd, 1H, J=8.5, 7.0, 1.5 Hz), 7.60 (br s, 1H), 7.46 (ddd, 1H, J=8.0, 7.0, 1.0 Hz), 7.33 (d, 1H, J=8.5 Hz), 2.96-2.83 (m, 2H), 2.89 (s, 3H), 2.68 (s, 3H), 2.06-1.94 (m, 2H). LRMS m/z (M+H+) 357 found, 357 required. m.p. 140-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:28])([F:27])[C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:21]3([C:20]([F:28])([F:27])[F:19])[CH2:23][CH2:22]3)=[O:25])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)C1(C(F)(F)F)CC1
Product: C[C@]1(c2cc(NC(=O)C3(C(F)(F)F)CC3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 1-trifluoromethyl-cyclopropanecarboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=396.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8](Cl)=[O:9].[C:12]1([C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[OH:1][C:2]1[C:3](=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:24][C@H:21]1[CH2:20][CH2:19][C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)=[O:9]
Reactant: O=C(Cl)c1cc[nH]c(=O)c1O
Reactant: N[C@H]1CC[C@@H](c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@@H](c2ccccc2)CC1)c1cc[nH]c(=O)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-hydroxy-2-oxo-1,2-dihydropyridine-4-carbonyl chloride (Intermediate 17) (38.1 mg, 0.219 mmol) and cis-4-phenylcyclohexanamine (Intermediate 14) (50 mg, 0.29 mmol) in DCM (1 mL) was added Et3N (0.061 mL, 0.44 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was partitioned between H2O and DCM. The DCM layer was dried over Na2SO4 and filtered through a silica gel plug. The solvent was removed under reduced pressure to give Example 36A which was used without further purification.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([OH:11])[CH2:9][OH:10].[CH:12](O)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>S(=O)(=O)(O)O.CCOCC>[CH:12]([O:10][CH2:9][CH2:8][OH:11])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCO
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: OCCOC(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
8 ml of toluene and 2 drops of concentrated sulfuric acid were added to 621 mg (10.0 mmol) of ethylene glycol, and they were heated to 90° C. 737 mg (4.0 mmol) of benzhydrol was added dropwise to the obtained mixture for the duration of 50 minutes. 30 minutes after, 621 mg (10.0 mmol) of ethylene glycol was added thereto and they were stirred under heating for 40 minutes. Ether was added to the reaction mixture, and the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate solution, water and finally saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([CH3:16])[CH3:15]>>[CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([CH3:16])[CH3:15]
Reactant: C1CNCCN1
Reactant: CC(C)c1ccccc1Br
Product: CC(C)c1ccccc1N1CCNCC1

Procedure:
The title compound was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 1-bromo-2-isopropyl-benzene. LRMS (ESI+): 205.4 (M+1)
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([I:16])[CH:10]=3)=[CH:4][N:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1I
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Yield: 75.2 %

Procedure:
A solution of 6-chloro-N-(3-iodo-4-methyl-phenyl)-nicotinamide (360 mg, 0.97 mmol), ethyl isonipecotate (460 mg, 2.91 mmol), diisopropylethyl amine (0.51 mL, 2.91 mmol) and a catalytic amount of DMAP in dioxane (15 mL) was heated at 120° C. in a sealed tube until consumption of the limiting reagent, as judged by TLC. The reaction mixture was then cooled and partitioned between EtOAc and water. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified with a silica gel column and 0-50% EtOAc in hexanes gradient to afford the product (360 mg, Yield 75%). HRMS m/z calcd for C21H24N3O3I [M+H]+: 494.0935. Found: 494.0935.
Reaction SMILES: O[CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1.C(Cl)Cl.COCCN(CCOC)S(F)(F)[F:19].C(O)C>>[F:19][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: C=C1CC(C#N)(CO)C1
Solvent: CCO
Solvent: ClCCl
Product: C=C1CC(C#N)(CF)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-(hydroxymethyl)-3-methylenecyclobutanecarbonitrile (0.252 g, 0.00205 mol) in methylene chloride (20 mL, 0.3 mol) in a plastic bottle was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (1.13 mL, 0.00614 mol) followed by ethanol (20 μL, 0.0004 mol). The reaction was stirred at rt overnight, then quenched with aq. sodium bicarbonate, and extracted with dichloromethane. The extracts were combined and washed with water, brine, and dried over magnesium sulfate, and evaporated to dryness. The residue was used directly in next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.Cl.Cl.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]1>>[CH2:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([NH:12][CH2:11][C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=[CH:2][CH:3]=3)=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCN1CCC(N)CC1
Reactant: O=C(O)c1ccc(NCc2ccnc3ccccc23)cc1
Agent: Cl
Product: CCCCN1CCC(NC(=O)c2ccc(NCc3ccnc4ccccc34)cc2)CC1

Procedure:
The title compound was prepared from 4-[(4-quinolinylmethyl)amino]benzoic acid and 4-amino-1-butylpiperidine bishydrochloride by the procedure described in Example 18, m.p. 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[C:6](Cl)=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([S:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5][S:4][N:3]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: Sc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=c1c(Cl)nsnc1Sc1ccccc1
Reaction time: 2 h

Procedure:
A mixture of 3.66 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one, 30 ml of ethyl ether, and 2.02 g of triethylamine is stirred at 0°-5° C. while a solution of 2.20 g of thiophenol in 20 ml of ethyl ether is added dropwise to it. This mixture is stirred 2 hours longer while it is allowed to return to ambient temperature. Then it is filtered to remove triethylamine hydrochloride, and the filtrate is concentrated on a rotary evaporator. The solid residue is recrystallized from hexane to yield yellow prisms, mp 100°-2°.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[I:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]O)[CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[I:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[CH:23][CH:22]=1
Reactant: OCCN1CCOCC1
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Ic1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.4 %

Procedure:
40% DEAD/toluene (2.5 mL) was added to a THF (30 mL) solution of 4-iodophenol (1.0 g), 2-morpholinoethanol (0.72 g) and triphenylphosphine (1.4 g) under ice cooling, and the mixture was stirred for 17 hours at room temperature. After the solvents were distilled off, the resulting residue was purified by NH type silica gel chromatography (gradient elution with hexane/ethyl acetate=90/0→60/40) to obtain 4-[2-(4-iodophenoxy)ethyl]morpholine (colorless oil) (1.4 g, 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10](F)=[C:9]([CH:14]=O)[C:8]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20]>COCCOC>[C:1]([O:5][C:6]([C:7]1[C:8]([Br:16])=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:20][N:19]=[CH:14]2)=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1ccc(F)c(C=O)c1Br
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc2[nH]ncc2c1Br
Yield: 100 %

Procedure:
A bi-phasic solution of 2-bromo-4-fluoro-3-formyl-benzoic acid tert-butyl ester (4.25 g, 14 mmol), DME (25 mL) and hydrazine hydrate (15 mL) was heated at 90° C. for 1 hour. After cooling, the products were partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a tan solid (4.1 g, 100%). LCMS (method B) RT=3.63 min, [M+CH3CN+H]+=338/340, [M−H]−=295/297.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:20]([O:19][C:13](=[O:18])[CH2:14][C:15]1([CH3:17])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: Oc1ccccc1-n1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)Oc2ccccc2-n2cccc21

Procedure:
A solution of the compound of formula 2, N-(2-hydroxyphenyl)pyrrole (5 g), described in Example 1, ethyl acetoacetate (4.3 g) and p-toluenesulfonic acid (0.5 g) in benzene (1,500 ml) is stirred and heated at reflux with a Dean-Stark water trap for 3 hr. Ethyl acetoacetate (1.0 g) is added and the reaction mixture kept under the refluxing condition overnight. After being cooled, the mixture is washed with a 5% solution of sodium bicarbonate and then water. The benzene solution is dried (MgSO4), filtered and evaporated. The crude product is purified by chromatography on a column of silica gel. Elution with chloroform gives 4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-acetic acid ethyl ester (3; R1 and R2 = H,R3 = CH3, n = 1, X = 0 and A = COOC2H5), νmaxCHCl3 1,725, 1,600, 1,505, 1,345, 1,080, 1,031 cm-1.