Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=2)[CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][C:37]([F:40])([F:39])[F:38]>CN(C)C=O>[F:38][C:37]([F:40])([F:39])[CH2:36][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:24]=[CH:25][CH:26]=2)[CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cc3)c2)CC1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(OCC(F)(F)F)cc3)c2)CC1
Reaction time: 8 h
Yield: 27.4 %

Procedure:
A solution of tert-butyl 4-(3-(4-hydroxyphenoxy)benzylidene)piperidine-1-carboxylate (150 mg, 0.393 mmol) in dimethylformamide (5 mL) was treated with potassium carbonate (218 mg, 1.572 mmol), 18-crown ether (210 mg, 0.786 mmol) and 2-iodo-1,1,1 trifluoroethane (105 mg, 0.491 mmol). The mixture was stirred overnight at a temperature below 50° C. The reaction mixture was washed with water and organic part extracted with ether (2×50 mL). The organic fractions were dried over sodium sulfate and evaporated. The crude material was purified by column chromatography (10-20% ethyl acetate/hexanes) to give the title compound (50 mg, 27%). 1H-NMR (500 MHz, CDCl3): δ ppm 7.26 (m, 1H), 7.00 (d, J=6 Hz, 2H), 6.94 (m, 3H), 6.80 (m, 2H), 6.29 (s, 1H), 4.36 (m, 2H), 3.49 (s, 2H), 3.38 (s, 2H), 2.42 (s, 2H), 2.30 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([C:18](O)(C)[CH3:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18]=[CH2:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(O)c1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=Cc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Yield: 97.8 %

Procedure:
To a solution of 2-(2-(3,5-diphenylpyridazin-4-yl)oxazol-4-yl)propan-2-ol (80 mg, 0.22 mmol) in toluene (4 mL), p-toluenesulfonic acid (20 mg) was added and the reaction mixture was refluxed for 2 h. After completion of starting material, reaction was quenched with solid K2CO3. Solvent was removed under reduced pressure to obtain the crude product that was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-Hexane) to furnish 2-(3, 5-diphenylpyridazin-4-yl)-4-vinyloxazole (70 mg, 92%) as a gummy liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N
Reactant: O=C=Nc1ccccc1
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3NC(=O)Nc1ccccc1

Procedure:
N-(6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea was prepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenyl isocyanate in a similar manner as described above to give a white solid (82% yield). 1H-NMR (DMSO-d6): δ 10.57 (s, 1H), 8.27 (s, 1H), 7.42-7.34 (m, 2H), 7.20 (m, 2H), 7.17-7.11 (m, 2H), 6.87 (m, 1H), 6.82 (m, 1H), 6.51 (d, 1H), 4.92 (m, 1H), 2.58 (m, 2H), 2.32 (s, 3H), 1.97 (m, 1H), 1.87-1.70 (m, 3H); MS m/z 318 (M−1).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:11][C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][C:10]([CH2:12][NH:14][CH:15]([CH3:17])[CH3:16])([NH:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)NC(=O)C1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)NCC1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
To a solution of the 1-(diphenylmethyl)-N-(1-methylethyl)-3-[(phenylmethyl)amino]azetidine-3-carboxamide (0.40 g, 0.97 mmol) in tetrahydrofuran (10 mL) at room was added a solution of lithium aluminum hydride in tetrahydrofuran (1M, 2.90 mL, 2.90 mmol), and the resulting mixture was stirred at 50° C. for 3 h. The reaction mixture was cooled to room temperature, quenched with 20% aqueous hydroxide solution (1 mL), diluted with ether (50 mL) and filtered. The filtrate was washed with brine solution (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, eluting with 5% methanol-dichloromethane) to give 1-(diphenylmethyl)-3-{[(1-methylethyl)amino]methyl}-N-(phenylmethyl)azetidin-3-amine (0.35 g, 90% yield), 1H NMR (400 MHz, CDCl3): 7.42-7.14 (m, 15H), 4.34 (s, 1H), 3.66 (s, 2H), 3.22-3.18 (d, 2H), 2.97 (s, 2H), 2.90-2.86 (d, 2H), 2.68-2.62 (p, 1H), 1.09-1.07 (d, 6H); MS (EI) for C27H33N3: 400 (MH+).
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:35])[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.Cl.CONC>CN(C=O)C>[CH3:4][O:8][N:9]([CH3:10])[C:32]([CH:29]1[CH2:30][CH2:31][C:26]([F:35])([F:25])[CH2:27][CH2:28]1)=[O:33]
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
2.78 g HATU were added to a solution of 1 g 4,4-difluoro-cyclohexanecarboxylic acid and 1.3 ml diisopropylethlyamine in 10 ml anhydrous DMF at 0° C. The reaction was stirred at 0° C. for 0.5 hours when 0.891 g O,N-Dimethyl-hydroxylamine hydrochloride were added. The reaction was allowed to warm to rt overnight. The solution was concentrated in vacuo by co-evaporation with toluene (3×) and filtered. The filtrate was concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→3:1 petroleum ether/EtOAc).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[Si:11]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.O>C1COCC1.[Ti](Cl)(Cl)(Cl)Cl>[Si:11]([O:28][CH2:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5])([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](OCc1cccc(C=O)c1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(=Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 73.7 %

Procedure:
To a solution of titanium (IV) chloride (9.88 g) in THF (80 mL) were added dropwise a solution of meldrum's acid (3.75 g) and 3-(((tert-butyldiphenylsilyl)oxy)methyl)benzaldehyde (6.50 g) in THF (50 mL) at 0° C., and pyridine (11.0 g) was further added dropwise at 0° C. over 30 min. The reaction mixture was stirred at 0° C. for 50 min, and water (100 mL) was added dropwise at 0° C. over 5 min. Water was further added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.40 g) as a white amorphous solid.
Reaction SMILES: C([Li])CCC.C(OCC)C.Br[C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN[C:24](=[O:30])[CH:25](OC)[CH2:26][CH3:27]>C1COCC1>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:24](=[O:30])[CH2:25][CH2:26][CH3:27])[CH:13]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: CCC(OC)C(=O)NC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2ccccc2c1
Temperature: 0 °C
Yield: 58.1 %

Procedure:
In a dry 3-necked flask under argon at -50° C., n-butyl lithium (0.0025 M, 0.021 ml) was added to 150 ml diethylether. Then 4.16 grams 3-bromoquinoline in 2 ml THF was added dropwise while stirring and maintaining the temperature at -60° C. to -55° C. The solution was stirred for 30 minutes, and 2.3 grams N-methyl-methoxybutyramide were then added dropwise at -50° C. and the solution was stirred an additional 30 minutes. The solution was then allowed to warm to 0° C. and stirred for one hour. The reaction was quenched with a saturated solution of ammonium chloride and the THF layer separated, washed with brine, separated, and dried over magnesium sulfate. Filtration through diatomaceous earth, followed by concentration and subsequent thin layer chromatography (35% ethylacetate/65% CH2Cl2) gave a total yield of 2.03 g (51%) of the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[CH2:11]2)=[N:7][CH:6]=1)[NH2:4].[C:26](OCC)(=O)[CH2:27][OH:28].[O-]CC.[Na+]>C(O)C.O>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C@H:12]1[CH2:13][CH2:14][N:10]([C:8]2[S:9][C:5]([C:3]3[N:4]=[C:26]([CH2:27][OH:28])[O:1][N:2]=3)=[CH:6][N:7]=2)[CH2:11]1
Reactant: CCOC(=O)CO
Reactant: NC(=NO)c1cnc(N2CC[C@H](Oc3ccccc3C(F)(F)F)C2)s1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1nc(-c2cnc(N3CC[C@H](Oc4ccccc4C(F)(F)F)C3)s2)no1
Temperature: 25 °C

Procedure:
A mixture of N′-hydroxy-2-{(3S)-3-[2-(trifluoromethyl)phenoxy]-pyrrolidin-1-yl}-1,3-thiazole-5-carboximidamide (373 mg, 1 mmol), ethyl glycolate (380 μL, 4 mmol) and sodium ethoxide, (21 wt. % solution in ethyl alcohol, 1.6 mL, 4.2 mmol) in ethanol (10 mL) was refluxed for 30 min. After cooling to rt, the mixture was diluted with water and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. The residue was triturated with Et2O to give the title compound as a pale yellow powder. 1H NMR (500 MHz, acetone-d6): δ 7.83 (s, 1 H), 7.69-7.65 (m, 2 H), 7.41 (d, 1 H), 7.16 (t, 1 H), 5.52 (m, 1 H), 5.05 (s, 1 H), 4.87 (s, 2 H), 3.98 (m, 1 H), 3.85-3.69 (m, 3 H), 2.60-2.44 (m, 2 H).
Reaction SMILES: CS([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=O)=O.[CH:16]1([CH2:21][CH2:22][CH2:23][OH:24])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:21][CH2:22][CH2:23][O:24][C:5]2[N:15]=[C:8]3[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]3[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCCCC1CCCC1
Reactant: Cc1cc(C)n2nc(S(C)(=O)=O)nc2n1
Product: Cc1cc(C)n2nc(OCCCC3CCCC3)nc2n1
Yield: 52 %

Procedure:
The title compound was prepared according to the experimentals described for Example 11 above from 2-methanesulfonyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 3-cyclopentyl-1-propanol in 52% yield. EM (calc.): 274.2; MS (ESI) m/e: 275.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2](C)/[CH:3]=[CH:4]/[C:5](=[O:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8].C(N)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:1]([NH:2]/[CH:3]=[CH:4]/[C:5](=[O:11])[CH:6]([O:9][CH3:10])[O:7][CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: COC(OC)C(=O)/C=C/N(C)C
Solvent: Cc1ccccc1
Product: COC(OC)C(=O)/C=C/NCc1ccccc1
Yield: 42.8 %

Procedure:
A mixture of (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (11 g, 63.5 mmol) and benzylamine (6.94 ml, 63.5 mmol) in toluene (130 ml) was stirred under reflux for 4 hours. Evaporated to dryness under vacuum, the residue was applied on a column, eluted with petroleum ether-ethyl acetate mixture 3:1, fractions collected to give (E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (6.4 g, 27.2 mmol, 42.8% yield) as dark yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[N:29]=[N:30][N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:32]=2)=[CH:18][CH:17]=1)[CH3:2].CO.[ClH:60]>ClCCl>[ClH:60].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:7](=[O:52])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(CC)nc(CC)cc2n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1=O
Reaction time: 0.33 h

Procedure:
Ethyl 5,7-diethyl-2-oxo-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6-naphthyridin-3-carboxylate (A) (0.42 g) was added to a mixture of methanol (5 ml), dichloromethane (1 ml) and concentrated hydrochloric acid (0.15 ml) and the mixture was stirred for 20 minutes. Volatile material was removed by evaporation and the residue was triturated with ether to give a white solid. The solid was purified by dissolution in hot ethanol and precipitation by adding ether to give ethyl 5,7-diethyl-2-oxo-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,2-dihydro-1,6naphthyridin-3-carboxylate hydrochloride (0.186 g); NMR (d6 -DMSO): 1.25(t, 3H), 1.32(t, 3H), 1.34(t, 3H), 2.95(q, 2H), 3.35(q, 2H), 4.34(q, 2H), 5.55(s, 2H), 7.07(d, 2H), 7.21(d, 2H), 7.4-7.8(complex m, 6H), 8.7(s, 1H), mass spectrum (+ve FAB, DMSO/NBA): 509 (M+H)+ ; microanalysis, found: C, 62.5; H, 5.6; N, 14.8%; C29H28N6O3.HCl.0.14 (CH3CO2C2H5).0.5 H2O requires: C, 62.6; H, 5.5; N, 14.8%.
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>ClCCl>[CH2:11]([CH:5]([CH2:6][S:7]([N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a 1 L round bottom flask was added the resultant compound from Example 1E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixture was cooled to 0° C. in an ice water bath and a solution of N-methyl piperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) was added dropwise with vigorous stirring over 90 min. After the addition was completed, the ice-water bath was removed and the mixture was stirred an additional 4 h while warming to ambient temperature. The solution was then poured into a separatory funnel containing 1 L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 200 g of silica gel using 4:1 hexane/ethyl acetate as an eluant. Concentration gave 84.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 cm-1 ; 1H NMR (CDCl3) δ 2.30 (s, 3H), 2.42 (t, 4H, J=4.8), 2.88 (dd, 1H, J=7.7, 14.0), 2.93 (dd, 1H, J=3.7, 14.0), 3.06 (dd, 1H, J=7.0, 13.6), 3.18-3.27 (m, 5H), 3.43 (dd, 1H, J=8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24-7.34 (m, 3H); 13C NMR (75 MHz, CDCl3 ) δ 37.91, 42.22, 45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129.06, 136.79, 173.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11](Cl)(=[O:13])[CH3:12].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cccc(OC)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(C)=O)c(OC)c1

Procedure:
Using a Perrier modification, Perrier, Chem. Ber., Vol. 33, pp. 819 et seq. (1900), and Perrier, Bull. Soc. Chim. France, pp. 859 et seq. (1904), 1,3-dimethoxybenzene (138.0 g) (which may be obtained from Aldrich Chemical Company, Inc., Milwaukee, Wis.) is reacted with acetyl chloride (72.0 g), methylene chloride (500 ml), and aluminum chloride (145 0 g) to provide 2',4'-dimethoxy-acetophenone, which may then be purified using standard vacuum fractional distillation.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][NH:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[C:12](#[N:15])[CH:13]=[CH2:14]>>[OH:9][CH:6]([CH2:7][OH:8])[CH2:5][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:14][CH2:13][CH2:12][NH2:15]
Reactant: OCC(O)CNCC(O)CO
Reactant: C=CC#N
Product: NCCCN(CC(O)CO)CC(O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bis-(2,3-dihydroxypropyl)amine (16.5 g., 0.1 mole) and acrylonitrile (6.4 g., 0.12 mole) is mixed in an ice bath and then warmed to room temperature. After standing for 2 hours, the mixture was then heated at 45° C.-55° C. for 3 hours. The excess acrylonitrile is removed by gentle warming under reduced pressure. The residue was taken up in ethyl alcohol, mixed with sponge nickel catalyst and hydrogenated under 200 psi hydrogen using good agitation. After filtration of catalyst the solvent and excess acrylonitrile is removed by stripping under reduced pressure to leave the product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:28]1([CH2:34][CH2:35][OH:36])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:31]5[CH2:32][CH2:33][N:28]([CH2:34][CH2:35][OH:36])[CH2:29][CH2:30]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: OCCN1CCNCC1
Product: O=C(c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1)N1CCN(CCO)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 2-(piperazin-1-yl)ethanol via General Procedure B. The product was purified via reverse phase HPLC to give 20.7 mg of 244. MS (Q1) 493.8 (M)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]([NH:17][C:18](=O)[CH3:19])=[C:5]([N+:21]([O-])=O)[CH:4]=1)#[N:2]>C(O)(=O)C.[Fe]>[CH3:19][C:18]1[NH:21][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:17]=1
Reactant: CC(=O)Nc1c(OCc2ccccc2)cc(C#N)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1nc2c(OCc3ccccc3)cc(C#N)cc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A mixture of N-{4-cyano-2-nitro-6-[(phenylmethyl)oxy]phenyl}acetamide (5.5 g, 17.7 mmol, STEP 2) and iron powder (2.96 g, 53.0 mmol) in acetic acid (90 mL) was refluxed with stirring for 2 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuum. The residue was poured into water, and the aqueous layer was extracted with ethyl acetate/methanol (20:1). The organic layers were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuum to afford the title compound as a brown solid (3.82 g, 82%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([N:26]=[N+:27]=[N-:28])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(N)C>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([S:23]([N:26]=[N+:27]=[N-:28])(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(S(=O)(=O)N=[N+]=[N-])cc2)cc1
Agent: CCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(Oc2ccc(CCN)cc2)cc1
Yield: 271.6 %

Procedure:
Dissolve the mixture of {2-[4-(4-azidosulfonylphenoxy)phenyl]ethyl}carbamic acid tert-butyl ester (0.291 g, 0.695 mmol) in dichloromethane (12 mL). Add TFA (12 mL) and stir at room temperature for 5 hours. Concentrate the reaction mixture. Load the product onto an SCX column with methanol. Wash the column with methanol then elute with 50% (2.0 M NH3 in methanol) in methanol to give a mixture of 2-4-(4-fluorobenzenesulfonyl)oxyphenyl)ethylamine and the title compound (0.601 g, 98.5%): MS ES+ 336.9 (M+H+18(NH4))+; TLC [silica gel 60 F254, 30% ethyl acetate, 5% (2.0 M NH3 in methanol and 65% hexanes] Rf=0.034.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[NH:7][C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2].CS(O[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][C:38]=1[CH:47]1[CH2:49][CH2:48]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][C:38]=2[CH:47]2[CH2:48][CH2:49]2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Reactant: CS(=O)(=O)OCc1c(C2CC2)cnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-acetyl-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (100 mg, 239 μmol) in DMF (597 μl) was added (3-cyclopropylquinolin-4-yl)methyl methanesulfonate (79.5 mg, 287 μmol), cesium carbonate (101 mg, 311 μmol), and sodium iodide (46.6 mg, 311 μmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-1-acetyl-5-((3-cyclopropylquinolin-4-yl)methyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (65 mg, 45%) as a white solid. MS m/z 600 (MH)+.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]3[CH2:29][C:28](=[O:30])[O:27][CH:26]3[O:31]CC3C=CC=CC=3)=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C1C=CC=CC=1>CN1CCCC1=O.CCN(C(C)C)C(C)C>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([CH:26]=[O:31])[CH2:29][C:28]([OH:30])=[O:27])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(NC(=O)C2CCCN3C(=O)CCC(NC(=O)c4ccccc4)C(=O)N23)C(OCc2ccccc2)O1
Solvent: O=C(Cl)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12
Yield: 30 %

Procedure:
Method 2. Synthesis of 213e. Following a similar procedure as method 1, resin 403 was acylated with 0.5M benzoyl chloride in N-methypyrrolidone (1 mL) and 1.6M DIEA in N-methypyrrolidone (0.35 mL) for 2 hr at rt. The acylation step was repeated. Cleavage of the aldehyde from the resin gave 214e (5.1 mg, 30%).