Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: ClCCCCCCOC1CCCCO1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
6-Chlorohexanol (6.85 g, 10 mmol) and p-toluenesulphonic acid (500 mg), were dissolved in dry ether (75 ml) and cooled to 0-5° C. in an ice bath. Dihydropyran (4.3 g, 10 mmol) in dry ether (25 ml) was added dropwise with constant stirring over a 30 minute period. After complete addition, the cooling bath was removed and stirring continued for 16 hours. The solution was extracted with water (50 ml×2), dried (MgSO4), filtered and the solvent evaporated under reduced pressure to leave a pale yellow oil. This oil was shown by 13C NMR spectroscopy to be sufficiently pure to be used without purification in the subsequent reactions. Yield 10.1 g (91%).
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH:5]1[CH2:7][CH2:6]1)[CH2:3][OH:4].C(=O)([O-])O.[Na+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([F:15])=[C:8]([C:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])([CH:5]2[CH2:7][CH2:6]2)[CH2:3][OH:4])[CH:13]=1
Reactant: NC(CO)(c1cc(Br)ccc1F)C1CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)NC(CO)(c1cc(Br)ccc1F)C1CC1
Temperature: 25 °C

Procedure:
(RS)-2-Amino-2-(5-bromo-2-fluoro-phenyl)-2-cyclopropyl-ethanol (2.27 g, 8 mmol) was dissolved in a mixture of dichloromethane (85 ml) and a saturated aqueous solution of sodium hydrogen-carbonate (85 ml). The biphasic mixture was then treated with a solution of chloroacetylchloride (0.69 ml, 8.7 mmol) in dichloromethane. The reaction mixture was stirred at room temperature and the progress of the transformation checked by chromatography. After completion, the reaction mixture was diluted with dichloromethane, the organic layer separated and washed with water, then dried over sodium sulfate and evaporated. The (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-1-cyclopropyl-2-hydroxy-ethyl]-2-chloro-acetamide was obtained as a yellow oil (2.73 g, 94.0% of theory). Mass (calculated) C13H14BrClFNO2 [350.614]; (found) [M+H]+=350, [M+2-H]+=352, [M+4-H]+=354.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:33][S-:34].[Na+]>CN(C=O)C>[F:27][C:26]([F:29])([F:28])[C@:25]([C:23]1[N:22]=[N:21][N:20]([CH2:19][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[CH:11][C:2]([S:34][CH3:33])=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=1)([OH:32])[CH2:30][CH3:31]
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(SC)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (85 mg, 0.18 mmol) and sodium thiomethoxide (51 mg, 0.72 mmol) in DMF (3 mL) was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with ethyl acetate/hexanes, 1:9) gave the title compound. MS (+ESI): 477 (M+H)+.
Reaction SMILES: C([O:7][C:8]1[C:9]([CH3:28])=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27])(=O)C(C)(C)C.[OH-].[Na+].Cl>C(O)C>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:11]1[C:10]2=[C:9]([CH3:28])[C:8]([OH:7])=[CH:16][N:15]2[N:14]=[CH:13][N:12]=1
Reactant: Cc1c(OC(=O)C(C)(C)C)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
To a heterogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]-triazin-6-yl pivalate (1.45 g, 3.74 mmol) in absolute ethanol (19 mL), at room temperature under a nitrogen atmosphere, was added 1 N aqueous sodium hydroxide. The reaction mixture was stirred at ambient temperature for 1.5 h before being neutralized to pH 7 with 1 N aqueous hydrochloride. The reaction mixture was concentrated to remove ethanol, before being partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed twice with water, once with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by silica gel (Merck KGaA, 230-400 mesh particle size) flash chromatography, eluting with 2:1 hexane/ethyl acetate, afforded the title compound (602 mg, 53% for Steps A-B) as a yellow solid. 1H NMR (CDCl3) δ 8.20-8.12 (m, 2H), 7.84 (s, 1H), 7.58-7.53 (m, 1H), 7.53 (s, 1H), 4.76 (s, 1H), 2.48 (s, 3H); MS(ESI+) m/z 305.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:6][N:7](CC1C=CC(OC)=CC=1)CC1C=CC(OC)=CC=1)[CH3:2]>[Pd].C(O)(C)(C)C>[CH2:1]([O:3][CH2:4][CH:5]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:6][NH2:7])[CH3:2]
Reactant: CCOCC(CN(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1)Oc1ccccn1
Agent: [Pd]
Solvent: CC(C)(C)O
Product: CCOCC(CN)Oc1ccccn1
Temperature: 50 °C
Reaction time: 96 h
Yield: 88.8 %

Procedure:
Combine 3-ethoxy-N,N-bis[(4-methoxyphenyl)methyl]-2-(2-pyridyloxy)propan-1-amine (1.05 g, 2.41 mmol), palladium/carbon (5%, 0.11 g, 0.05 mmol), and tert-butyl alcohol (15 mL). Purge with hydrogen gas 3 times and then stir the mixture at 50° C. under an atmosphere of hydrogen gas for 4 days. Filter the reaction through a Celite® plug and rinse the plug with EtOAc (2×30 mL). Collect the filtrate and concentrate under reduced pressure to afford the title compound (0.42 g, 89.0%) as a yellow oil. MS (m/z): 197 (M+1).
Reaction SMILES: C([NH:4][C:5]1[C:6]([Br:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8]2)(=O)C.C[O-].[Na+].[CH:21]([C:23]([CH2:25][CH3:26])=[O:24])=[CH2:22]>CO>[NH2:4][C:5]1[C:6]([Br:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[C:9]([CH2:15][CH3:16])([CH2:22][CH2:21][C:23](=[O:24])[CH2:25][CH3:26])[CH2:8]2
Reactant: CCC1Cc2c(ccc(NC(C)=O)c2Br)C1=O
Reactant: C=CC(=O)CC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)CCC1(CC)Cc2c(ccc(N)c2Br)C1=O
Temperature: 60 °C
Yield: 102 %

Procedure:
A solution of 5-(acetylamino)-4-bromo-2-ethyl-1-indanone (1.0 g, 3.39 mmol) in MeOH (5.1 mL) was treated with 0.5M NaOMe in MeOH (3.4 mL, 1.7 mmol) and ethyl vinyl ketone (0.506 mL, 5.08 mmol). The mixture was stirred and heated at 60° C. for 4.5 hours, then evaporated under vacuum. The residue was partitioned between EtOAc (75 mL), brine (50 mL), and water (10 mL). The organic portion was dried over MgSO4, filtered, and evaporated under vacuum. The residue was added to a short column of silica gel (30 mL) which was washed with CH2Cl2 (150 mL) and eluted with EtOAc (150 mL). The EtOAc eluant was evaporated under vacuum to provide crude 5-amino-4-bromo-2-ethyl-2-(3-oxopentyl)-1-indanone (1.17 g) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=4)[NH:8][N:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O1CCOCC1>C1COCC1>[OH:3][CH2:4][C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:30])([F:32])[F:31])=[CH:18][CH:17]=4)[NH:8][N:7]=1
Reactant: CCOC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: OCCCNc1nc2cc(C(F)(F)F)ccc2n2c(-c3cc(CO)n[nH]3)cnc12
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of 5-[4-(3-Hydroxy-propylamino)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-1-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (0.08 mmol; 36 mg), in THF (0.2 mL) under argon cooled to 0° C., was added LAH (0.24 mmol; 10 mg). The reaction was slowly warmed up to room temperature over 4 hr, then to 45° C. overnight. After addition of dioxane (1 mL), the mixture was heated to 75° C. for 24 hr. After quenching with Rochelle's salt, the mixture was extracted with ethyle acetate. The organic phase was dried, concentrated. The residue was purified by preparative TLC (dichloromethane/methanol) to yield the title compound as a white solid (7 mg; 0.02 mmol; 21%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:30])([CH:27]([F:29])[F:28])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:26]([CH2:25][C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:30])([F:15])[CH:27]([F:29])[F:28])=[CH:20][CH:21]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1ccc(OCC(F)(F)C(F)F)nc1
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)(F)C(F)F)nc1
Yield: 60 %

Procedure:
The title compound is prepared in 60% yield (132 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methanamine hydrochloride (156 mg, 0.57 mmol, Amine-14) in a similar manner to Intermediate-2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH:27]2[CH2:28][CH2:29][CH:23]1[CH2:24][CH:25]([NH2:30])[CH2:26]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:30][CH:25]2[CH2:26][CH:27]3[N:22]([CH3:21])[CH:23]([CH2:29][CH2:28]3)[CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1C2CCC1CC(N)C2
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1C2CCC1CC(NC(=O)c1cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s1)C2

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 8-methyl-8-azabicyclo[3.2.1]octan-3-amine (71.0 mg, 0.52 mmol). The title compound was obtained as a solid (40 mg, 20% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.97 (2H, m), 8.52 (1H, s), 8.44 (1H, s), 3.85 (1H, m), 3.79 (2H, m), 2.64 (3H, m), 2.25 (2H, m), 2.22 (4H, m), 2.16 (2H, m). MS m/z: 475.35, 477.33 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Cl:45])[CH:43]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=2[O:31][Si](C(C)(C)C)(C)C)[C:9]1=[O:46])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:45][C:42]1[CH:43]=[C:44]2[NH:8][C:9](=[O:46])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[OH:31])[C:39]2=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cc(I)ccc1O[Si](C)(C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Racemic (2′R,3R,4′S)-2′-[2-(tert-butyl-dimethylsilanyloxy)-5-iodo-phenyl]-6-chloro-4′-(3-chlorophenyl)-2,6′-dioxo-spiro[3H-indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (200 mg, 0.25 mmol) was dissolved in 30% TFA/CH2Cl2 (5 mL) and the solution was stirred at rt for 2 h. The solvent was removed and the residue was partioned between water and methylene chloride. The organic layer was separated and dried with sodium sulfate and concentrated. The residue was chromatographed to give a white solid which was directly used for next step. MS (H+), 579.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][C@H:11]1[C@H:16]([CH3:17])[CH2:15][CH2:14][CH2:13][N:12]1[C:18]([C:20]1[N:21]=[C:22]([CH3:32])[S:23][C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:19]>>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([NH:9][CH2:10][C@H:11]2[C@H:16]([CH3:17])[CH2:15][CH2:14][CH2:13][N:12]2[C:18]([C:20]2[N:21]=[C:22]([CH3:32])[S:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:19])=[N:7][CH:6]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@@H]2CNc2ncc(Cl)cn2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example 16 using 2,5-dichloropyrimidine and rac-trans-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. MS (ESI) 460.4 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[C:24]([CH3:40])=[CH:23][C:21]=1[NH2:22]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:22][C:21]3[CH:23]=[C:24]([CH3:40])[C:25]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[CH2:29][CH2:28]4)=[CH:26][C:20]=3[O:19][CH3:18])[N:7]=2)=[CH:9]1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1N
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 26).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.[CH2:26]([O:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37](O)=[C:36]([F:41])[CH:35]=1)[CH3:27].C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:43])[CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([O:15][CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[C:2]([CH3:1])[CH:7]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:36]([F:41])[CH:35]=1)[CH3:27]
Reactant: CCOC(=O)CCNC(=O)c1ccc(O)c(F)c1
Reactant: CCCCCCC(O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
Combine 1-(2-methyl-4′-trifluoromethyl-biphenyl-4-yl)-heptan-1-ol (0.090 g, 0.25 mmol) and 3-(3-fluoro-4-hydroxy-benzoylamino)-propionic acid ethyl ester (0.050 g, 0.20 mmol) in toluene (1.0 mL). Add 1,1′(diazocarbonyl)dipiperidine (0.076 g, 0.3 mmol) followed by tributyl-phosphane (0.074 mL, 0.3 mmol) under inert atmosphere. Stir at room temperature for 16 hours. Dilute reaction with ethyl acetate filter and remove solvent under reduced pressure. Purify on silica gel chromatography (0-50% Ethyl acetate/hexanes gradient) to provide 0.105 g of title compound (90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCCCBr
Product: CC(=O)c1cccc(OCCCCl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 1-(3-hydroxyphenyl)ethanone and 1-bromo-3-chloropropane.
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[C:17](O)(=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccccc1
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(-c3ccccc3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
1,3-dipropyl-5,6-diaminouracil (0.01 mol) was dissolved in 30 ml methanol, followed by 0.01 mol of benzoic acid and then 0.01 mol of DICD. The solution was stirred for 30 min at room temperature, filtered, and washed with a small amount of methanol. The solid was boiled for ten minutes in 2.5N KOH, filtered hot, and the liquid neutralized with concentrated HCl. The solid was collected by filtration, washed with water, redissolved in 100 ml with a minimum amount of KOH, precipitated by neutralization with HCL, filtered, washed with water, and dried. The product was identified by chemical ionization mass spectrometry and elemental analysis. Yield 77%.
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[O:9][C:8]1=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N=C=NCCCN(C)C)C.[CH:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31]>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH:30]([NH:32][CH2:33][C:34]([O:17][C@H:12]([CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:11][C@H:10]1[C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:18])[O:9]1)=[O:35])=[O:31]
Reactant: C=CCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: O=CNCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: C=CCC[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CNC=O
Yield: 53.9 %

Procedure:
Prepared according to representative procedure described in Example 48 above (i.e., acylation) using hydroxy β-lactone 13j (15.0 mg, 0.059 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (14.8 mg, 0.077 mmol), 4-dimethylaminopyridine (8.71 mg, 0.071 mmol), 0.5 mL of xylene were azeotroped in vacuo for 1.0 h. After twelve hours the residue was then dissolved in CH2Cl2 (1.5 mL) and N-formyl glycine (9.12 mg, 0.089 mmol) was added. The resulting mixture was purified twice by chromatography (SiO2, gradient 10-40% EtOAc:hexanes) to afford β-lactone 17f (10.8 mg, 55%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N:12]1([CH2:18][CH2:19][CH2:20][NH:21][C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: NCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(NCCCN2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 3-(4-morpholinyl)-1-aminopropane (3.1 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature, poured into water (200 mL) and extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 90/10 EtOAc/MeOH) to yield the product as an orange solid (0.45 g, 23%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16]2>ClCCl>[CH3:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N+:19]([O-:9])=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[CH:16]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2ncc([N+](=O)[O-])cc2c1
Solvent: ClCCl
Product: Cc1ccc2c(c1)cc([N+](=O)[O-])c[n+]2[O-]
Reaction time: 70 h
Yield: 43.2 %

Procedure:
A solution of 46 g of m-chloroperbenzoic acid in 19 ml of dichloromethane is added dropwise to a solution of 17.6 g of 6-methyl-3-nitroquinoline (compound E2) in 400 ml of dichloromethane. The reaction mixture is stirred for 70 h, diluted with 20 ml of dichloromethane and extracted two times each with 800 ml of halfsaturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 98:2). 8.25 g of the title compound are obtained as yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C@H:4]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1.[H-].[Na+].CI.[C:36](OCC)(=O)C>C1COCC1>[CH3:36][N:23]([C@@H:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH:22]=1)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C)c2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of (S)-tert-butyl (4-methyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (200 mg, 0.470 mmol) (Preparation description in Example 2, Part D) in THF (4 mL) at 0° C. was added NaH (37.6 mg, 0.940 mmol). The reaction was stirred at 0° C. for 30 min then MeI (0.044 mL, 0.705 mmol) was added. The reaction mixture was then stirred at 0° C. for 16 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers and washed with brine (1×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using petroleum ether: ethyl acetate mobile phase to afford (S)-tert-butyl methyl(4-methyl-1-(6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yloxy)pentan-2-yl)carbamate (180 mg, 0.409 mmol, 87% yield) as a yellow solid. LC/MS (ESI) m/e 440.4, [(M+H)+, calcd for C25H34N3O4, 440.3]; LC/MS retention time (method I): tR=2.4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13](Cl)(=[O:15])=[O:14].[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[S:13]([NH:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([O:25][CH3:26])=[O:24])(=[O:15])=[O:14]
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 69.9 %

Procedure:
Synthesized as described for 3 using 2,6-dichloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride (2.5 g; 7.97 mmol), methyl 3-aminothiophene-2-carboxylate (1.14 g; 7.25 mmol), 4-dimethylaminopyridine (221.4 mg; 1.81 mmol), pyridine (11.81 mL; 145.0 mmol) and anhydrous dichloromethane (50 mL). Purification by automated silica gel chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) afforded the title compound as a white solid (2.20 g).