Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cnn(CCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In flask were introduced 4-iodopyrazole (10 g, 51.6 mmol), cesium carbonate (20.16 g, 61.9 mmol) and anhydrous DMF (98 mL). The suspension was stirred at rt for 5 min, before adding 2-(2-bromoethoxy)tetrahydro-2H-pyran (9.74 mL, 61.9 mmol) and heating at 70° C. for 17 h. Then the RM was quenched with 100 mL water and extracted with 3×120 mL EtOAc. The combined organic layers were washed with 3×100 mL water and 1×100 mL brine, before being dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography (6×25 cm, Hexane/EtOAc 0%-30%) to afford the title compound as a colorless oil (tR 3.12 min (conditions 8), MH+=323).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:38][CH2:39][CH2:40][CH2:41]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH2:41][CH2:40][CH2:39][F:38])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: FCCCBr
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(N(CCCF)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The compound was prepared by analogy to the methods described for Preparation Example 2 and Example 1 from 4-{5-[(3-difluoromethoxybenzenesulfonyl)-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was reacted with sodium hydride and 3-fluoro-1-bromopropane to yield 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-(3-fluoropropyl)amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was deprotected to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13].[Cl:15]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CO.O>[O:1]=[C:2]1[C:7]([Cl:15])=[C:6]([CH2:8][OH:9])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: O=C(O)COc1c[nH]c(CO)cc1=O
Solvent: O
Solvent: CO
Product: O=C(O)COc1c[nH]c(CO)c(Cl)c1=O
Yield: 121.2 %

Procedure:
2-(4-Oxo-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy)acetic acid (5.97 g) was dissolved in a mixture of methanol (300 ml) and water (420 ml) at 65° to 70° C. and the solution was stirred at the same temperature. Trichloroisocyanuric acid (2.79 g) was added thereto, and the resultant mixture was stirred at the same temperature for 1.5 hours and then allowed to stand at room temperature over-night. The reaction mixture was cooled and the resulting crystals were collected by filtration, washed with water and dried. Thus obtained crystals (4.1 g) were recrystallized from water (100 ml) to give crystals (3.4 g) of 2-(4-oxo-5-chloro-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy) acetic acid, mp 240° to 245° C.(dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([O:24][CH3:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Product: COc1cc(N2CCN(C(C)=O)C2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 58.5 %

Procedure:
Using (4-bromo-2-methoxyphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.01 g) described in Preparation Example 252 and 1-acetylimidazolidin-2-one (0.38 g) and by the reaction and treatment in the same manner as in Example 1, the title compound (0.66 g) was obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[CH3:12]O>>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH3:12])=[O:7]
Reactant: CO
Reactant: O=C(O)c1cccc(F)c1
Agent: Cl
Product: COC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of anhydrous hydrochloric acid (10.5 g) in anhydrous methanol (100 ml) is added m-fluorobenzoic acid (13.3 g.; 0.095 mole). The reaction mixture is stirred at room temperature overnight. The solvent and anhydrous hydrochloric acid are then removed under vacuum and the residue slurried with hexane (100 ml). The hexane insoluble layer is decanted and the hexane solution water washed (2×100 ml) before drying with anhydrous magnesium sulfate. The hexane filtrate is then concentrated under vacuum to afford 11.0 g (75% yield) of methyl 3-fluorobenzoate as a yellow liquid. Elemental anal. calcd. for C8H7FO2 : C, 62.35; H, 4.57; F, 12.33. Found: C, 62.52; H, 4.70; F, 11.89.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH:34]([S:36][C:37]3[NH:41][N:40]=[N:39][N:38]=3)[CH3:35])[CH2:32][S:33][C@H:28]12)=[O:25])=O)(C)(C)C>CCOCC>[NH2:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH:34]([S:36][C:37]3[NH:38][N:39]=[N:40][N:41]=3)[CH3:35])[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=C(CNC(=O)OC(C)(C)C)CCCC3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=C(CN)CCCC3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of trifluoroacetic acid (2 ml.) and 5c (1.30 g., 2.4 mmoles) was stirred magnetically for 30 min. at room temperature. The mixture was diluted with ether (50 ml.) to precipitate the trifluoroacetate of 6c. The trifluoroacetate was suspended in a small amount of water (2 ml.) and the suspension was adjusted at pH 6 with ammonium hydroxide and diluted with acetonitrile (200 ml.) to give 6c which was washed with acetonitrile (50 ml.) and dried.
Reaction SMILES: [P:1]([O:50]CC[Si](C)(C)C)([O:43]CC[Si](C)(C)C)([O:3][C:4]([CH3:42])([CH2:6][CH2:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]=[C:22]([O:24][CH:25]4[CH2:30][CH2:29][N:28]([C:31]5[N:36]=[CH:35][C:34]([CH2:37][CH2:38][CH3:39])=[CH:33][N:32]=5)[CH2:27][CH2:26]4)[S:23][C:19]=3[CH:18]=2)=[CH:13][CH2:12]1)(=[O:10])=[O:9])[CH3:5])=[O:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[P:1]([OH:43])([OH:50])([O:3][C:4]([CH3:42])([CH2:6][CH2:7][S:8]([N:11]1[CH2:16][CH2:15][C:14]([C:17]2[CH:41]=[CH:40][C:20]3[N:21]=[C:22]([O:24][CH:25]4[CH2:30][CH2:29][N:28]([C:31]5[N:32]=[CH:33][C:34]([CH2:37][CH2:38][CH3:39])=[CH:35][N:36]=5)[CH2:27][CH2:26]4)[S:23][C:19]=3[CH:18]=2)=[CH:13][CH2:12]1)(=[O:9])=[O:10])[CH3:5])=[O:2]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)OP(=O)(OCC[Si](C)(C)C)OCC[Si](C)(C)C)CC5)cc4s3)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCC(C)(C)OP(=O)(O)O)CC5)cc4s3)CC2)nc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 2-methyl-4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butan-2-yl bis(2-(trimethylsilyl)ethyl) phosphate (85 mg, 0.098 mmol) in CH2Cl2 (511 μl) at 0° C. was added TFA (51.1 μl, 0.663 mmol). The mixture was stirred and gradually warmed to rt for 4 h. It was cooled to 0° C. and an aqueous solution of NaHCO3 (saturated, 0.5 mL) was added. The solvent was removed and the solid was collected via filtering. The solid was rinsed with cold H2O and ether. It was dried under vacuum to yield 2-methyl-4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butan-2-yl dihydrogen phosphate (53 mg, 0.079 mmol, 80% yield) as a white solid. 1H NMR (500 MHz, DMSO) δ 8.17 (s, 2H), 7.90 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 6.14 (s, 1H), 5.33 (s, 1H), 4.12 (d, J=13.6 Hz, 2H), 3.90 (s, 2H), 3.47 (dd, J=24.6, 14.8 Hz, 4H), 2.53 (s, 4H), 2.35-2.24 (m, 3H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.46 (dd, J=14.7, 7.4 Hz, 2H), 1.20 (s, 6H), 0.81 (t, J=7.3 Hz, 3H). LCMS (m/z)=665 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:41])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][CH:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33]C(=O)OC(C)(C)C)[CH:28]=3)[CH3:26])=[CH:15][CH:14]=2)[N:7]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][C:29]1[CH:28]=[C:27]([CH:25]([CH3:26])[CH2:24][O:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]([NH:12][C:11]([NH:10][C:8]3[N:7]([C:42]4[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=3)=[O:41])=[CH:14][CH:15]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCC(C)c3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCC(C)c3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
To a suspension of the tert-butyl carbamate (56) (0.57 g, 0.88 mmol) in DCM (10.0 mL) was added TFA (5.0 mL) and the resulting dark green solution stirred at RT for 1 hr. The mixture was evaporated in vacuo and the residue was dissolved in MeOH (10.0 mL) and subjected to SCX capture and release to afford the title compound (Intermediate K) as a red oil (488 mg, 98%): m/z 549 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]([Si](C)(C)C)([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:17]([F:19])([F:18])[F:16])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CCC1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Dry tetrahydrofuran (20 ml) was added to a stirred mixture of 1-benzyl-3-methylpiperidin-4-one (4 g, 19.7 mmole) and (Trifluoromethyl) trimethylsilane (3.35 g, 23.64 mmole) at 0° C. and stirred for 5 min. Tetrabutyl ammonium fluoride (0.05 g) was added to it at 0° C. and stirred for another 30 min at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 3 hr, acidified with 2N HCl to pH 2 and extracted with ether (3×50 ml). Ether extract was dried (Na2SO4) and concentrated in vacuum to give 1-benzyl-3-methyl-4-hydroxy-4-trifluoromethylpiperidine. Yield 5.1 g (95%), C14H18F3NO, m/z 274 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:26])[NH:14][C:15]([C:19](=[O:25])[C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>[Pd].C(OCC)(=O)C.CO.CN(C=O)C>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:26])[NH:14][C:15]([C:19](=[O:25])[C:20]([CH3:23])([CH3:24])[CH2:21][CH3:22])=[N:16]2)=[CH:11][CH:10]=1
Reactant: CCC(C)(C)C(=O)c1nc2cc(OCc3ccccc3)ccc2c(=O)[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCC(C)(C)C(=O)c1nc2cc(O)ccc2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 83.2 %

Procedure:
5% Palladium-on-charcoal catalyst (0.7 g, 50% in water) was added to a solution of 7-benzyloxy-3-methylpivaloyl-3,4-dihydroquinazolin-4-one (6.85 g, 18.7 mmol) in ethyl acetate (300 ml), methanol (40 ml), DMF (40 ml), and acetic acid (0.7 ml). The mixture was vigorously stirred under hydrogen at atmospheric pressure for 4.5 hours. The catalyst was removed by filtration through diatomaceous earth, the filtrate concentrated by evaporation to about 60 ml, diluted with water (300 ml) and extracted with ether (3×300 ml). The combined extracts were washed with brine, dried (MgSO4), and the volatiles removed by evaporation. The resulting crude solid was dissolved in acetone (200 ml) and acetic acid (0.2 ml) and cooled to 0° C. Potassium permanganate (1.8 g) was added and the mixture stirred for 10 minutes. The reaction mixture was poured into water (250 ml) and ethyl acetate (250 ml) was added. The precipitate was removed ;by filtration, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (2×100 ml). The combined extracts were washed with water and brine, dried (MgSO4) and the volatiles removed by evaporation to give 7-hydroxy-3-methylpivaloyl-3,4-dihydroquinazolin-4-one (4.05 g, 78%) as a cream solid.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26][CH:27]=[CH2:28])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].I[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[C:34]([CH3:46])[CH:33]=1.C(N1CCOCC1)C>C(#N)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26]/[CH:27]=[CH:28]/[C:32]1[CH:33]=[C:34]([CH3:46])[C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=2)=[CH:36][CH:37]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: COc1cccc(-c2ccc(I)cc2C)c1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)C
Agent: CCN1CCOCC1
Solvent: CC#N
Product: COc1cccc(-c2ccc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc3ccccc3)C(C)(C)C)cc2C)c1
Yield: 79.8 %

Procedure:
By the method of Preparation 3 a), tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)hex-5-enoate (2.085 g, 5.0 mmol) was reacted with 4-iodo-1-(3-methoxyphenyl)-2-methylbenzene (Preparation 20) (889 mg, 2.13 mmol) under palladium catalysis, using N-ethylmorpholine as base at reflux in acetonitrile for 14.5 h. Work-up as before followed by purification by flash chromatography (hexane:ethyl acetate=10:1) gave mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)-6-(3′-methoxy-2-methylbiphen-4-yl)hex-5-enoate as a pale yellow gum (1.043 gm, 80%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see b, below).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=O.[NH2:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[CH2:32]([O:31][C:29](=[O:30])[C:28]([CH3:35])([CH3:34])[CH2:27][NH:26][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=[O:2])[CH3:33]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O

Procedure:
7-(3-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.07 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (41 mg, 0.28 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 26 mg. MS: (−) m/z 466.42 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[NH2:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17](Cl)[C:14]=1[C:15]#[N:16]>>[NH2:12][C:13]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ccc([N+](=O)[O-])c(N)c1C#N
Yield: 59 %

Procedure:
The title compound was prepared in 59% yield from 2-methoxy-phenylboronic acid and 2-amino-6-chloro-3-nitro-benzonitrile according to the procedure outlined for Example 5A. 1H NMR (400 MHz, CDCl3): δ 8.36 (d, 1H, J=8.8 Hz), 7.42-7.48 (m, 1H), 7.24-7.28 (m, 1H), 7.01-7.10 (m, 2H), 6.82 (br s, 2H), 6.78 (d, 1H, J=8.8 Hz), 3.86 (s, 3H). MS (ES) [m+H] calc'd for C14H11N3O3, 270; found 270.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][C:28]1[O:32][C:31](=[O:33])[O:30][C:29]=1[CH2:34]Br>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:34][C:29]3[O:30][C:31](=[O:33])[O:32][C:28]=3[CH3:27])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: Cc1oc(=O)oc1CBr
Agent: [Na+]
Product: Cc1oc(=O)oc1COC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.7 %

Procedure:
In the same manner as in Example 81, 156 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 122 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1N=CN(C2C=[C:20]3C(=CC=2)NC=[C:21]3[CH2:27][CH2:28][OH:29])C=1>CS(C)=O>[N:1]1([C:6]2[CH:12]=[C:11]3[C:9](=[CH:8][CH:7]=2)[NH:10][CH:20]=[C:21]3[CH2:27][CH2:28][OH:29])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: OCCc1c[nH]c2ccc(-n3cnnc3)cc12
Solvent: CS(C)=O
Product: OCCc1c[nH]c2ccc(-n3ccnc3)cc12

Procedure:
Prepared from 4-(imidazol-1-yl)aniline (EP497512) as described for Intermediate 3, δ (360 MHz, D6 -DMSO) 2.87 (2H, t, J=7.2 Hz, CH2), 3.64-3.70 (1H, m, CH2 --OH), 4.61 (1H, t, J=5.3 Hz, OH), 7.08 (1H, s, Ar--H), 7.25-7.27 (2H, m, Ar--H), 7.44 (1H, d, J=8.8 Hz, Ar--H), 7.64 (1H, d, J=2.5 Hz, Ar--H), 7.70 (1H, d, J=2.1 Hz, Ar--H), 8.11 (1H, s, Ar--H), 11.00 (1H, s, NH), m/e 228 (M+1)+.
Reaction SMILES: O[N:2]=[C:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCO.[Pd]>[NH2:2][CH:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)C1CN(c2ccccc2)C(=O)C1=NO
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CN(c2ccccc2)C(=O)C1N
Yield: 60.1 %

Procedure:
A solution of oxime of Example N (3.08 g, 10.6 mmol) in EtOH (B0 ml) was hydrogenated at 1000 psi at 70° C. on 10% palladium on carbon. Filtration and concentration of the filtrate gave an oil which was chromatographed on silica gel eluting with 2/97.75/0.25 EtOH/CH2Cl2 /NH4OH to afford the title compound (1.76 g, 60%) as a white solid. Anal calcd for C15H20N2O3 : C, 65.20; H, 7.30; N, 10.14. Found: C, 64.95; H, 7.39; N, 10.04. MS calcd for C15H20N2O3 276, found 276. DSC=105.0°-121.1° at 57.2 J/g.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:7](=[O:40])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([NH:27]C(=O)OCC5C=CC=CC=5)(=[O:26])=[O:25])=[CH:22][C:16]=4[S:15](=[O:39])(=[O:38])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1>[Pd].CO.C(OCC)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:44][CH2:45][CH3:46])([CH2:41][CH2:42][CH3:43])[C:7](=[O:40])[C:8]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([NH2:27])(=[O:25])=[O:26])=[CH:22][C:16]=4[S:15](=[O:39])(=[O:38])[N:14]=3)=[C:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2cc(F)ccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)=C(O)c2cc(F)ccc21
Yield: 57.7 %

Procedure:
A solution of the product of Example 17D (28 mg, 0.042 mmol) in 2:1 methanol-ethyl acetate (15 mL) was treated with 10% Pd/C (20 mg) and hydrogenated at one atmosphere for 18 h. The mixture was filtered through celite® and the filtrate concentrated in vacuo to afford the title compound (13 mg).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:32]=[CH:31][C:15]([CH2:16][NH:17][C:18]2[C:27]3[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:31][CH:32]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc2c(NCc3ccc(NS(=O)(=O)c4ccccc4)cc3)ncnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Benzenesulfonyl chloride (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at rt overnight. The title compound was obtained by pre-HPLC in 34% yield. Mass: M+H+: 434.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:4][CH:3]=1.[CH3:19][C:20](C)([O-:22])[CH3:21].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:20]2[CH2:21][O:22]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCCCc2ccccc2O)cc1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(CCCCc2ccccc2OCC2CO2)cc1
Yield: 73 %

Procedure:
Following a procedure similar to that described in Example 1(a), 0.70 g of 2-[4-(4-methylphenyl)butyl]phenol (prepared as described in Preparation 6), 0.33 g of potassium t-butoxide and 0.8 g of epibromohydrin were reacted in 40 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 0.63 g (yield 73%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([F:30])([F:29])[F:18])=[CH:10][CH:9]=2)=[O:4]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Product: COC(=O)c1c(O)c2cc(-c3ccccc3C(F)(F)F)ccc2sc1=O

Procedure:
4-Hydroxy-2-oxo-6-(2-trifluoromethyl-phenyl)-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 2-trifluoromethyl-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.572 (s, 1H), 7.838-7.676 (m, 4H), 7.487-7.354 (m, 2H), 4.028 (s, 3H).