Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][NH:27][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(C=O)COCc1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CNCc1ccc(F)cc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of tert-butyl 2-(benzyloxy)-1-formylethylcarbamate (3.29 g, 11.8 mmol) in anhydrous THF (12 mL) was added 4-fluorobenzylamine (2.03 mL, 17.7 mmol). After 10 min, sodium triacetoxyborohydride (3.99 g, 18.8 mmol) was added, and the reaction was stirred at ambient temperature under inert atmosphere for 30 min. Saturated aqueous NaHCO3 solution was added and the mixture stirred until gas evolution ceased. The aqueous layer was extracted with EtOAc, saturated with NaCl and again extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting cloudy yellow oil was purified by silica gel chromatography (EtOAc to 10% MeOH/EtOAc) to afford the title compound as a pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.23 (m, 7H), 7.03-6.96 (m, 2H), 5.04 (br s, 1H), 4.49 (dd, J=11.5, 18.0 Hz, 2H), 3.86 (br s, 1H), 3.76-3.70 (m, 2H), 3.60 (dd, J=3.0, 9.0 Hz, 1H), 3.53 (d, J=4.5 Hz, 1H), 2.83-2.80 (m, 1H), 2.76-2.72 (m, 1H), 1.44 (s, 9H). ES MS (M+1)=389.5.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:37])[CH3:36])[CH:30]=1.C(OC(=O)C)(=O)C>>[CH3:36][N:35]([CH3:37])[C:31]1[CH:30]=[C:29]([N:28]([CH3:38])[CH3:27])[CH:34]=[CH:33][C:32]=1[C:16]1([C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:18]2[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20](=[O:22])[O:21]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c2ccccc2c2cc(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)ccc21

Procedure:
A mixture of 3.43 g (0.01 mole) of 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid, 1.80 g (0.011 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 4.0 ml of acetic anhydride was interacted in a manner similar to that described in Example 1, part C above to yield 3-[2,4-bis(dimethylamino)phenyl]-3-(9-ethyl-3-carbazolyl)phthalide (Formula V: R0 =R1 =R2 =R3 =H; R=CH3 ; R4 =N(CH3)2 ; R8 =CH2CH3) which melted over the range 134°-142° C. A significant infrared absorption maximum appeared at 1753 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed a bordeaux-colored image.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:10]([CH2:18][CH3:19])=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=1.[Li+].[OH-].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:10]([CH2:18][CH3:19])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1CC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C(=O)O)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Part A: Ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylate was obtained according to WO03040107. To a magnetically stirred solution of ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylate (5.80 g, 0.0149 mol) in tetrahydrofuran (40 ml) was added a solution of LiOH (0.715 g) in water (40 ml). The resulting mixture was heated at 70° C. for 16 hours. The resulting mixture was allowed to attain room temperature and subsequently treated with concentrated hydrochloric acid (3.5 ml). The tetrahydrofuran was evaporated in vacuo and the resulting mixture was stirred overnight. The formed precipitate was collected by filtration and washed with petroleum ether (40-60) to give 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid (4.52 g, 84% yield). 1H-NMR (400 MHz, CDCl3): δ 1.09 (t, J=7, 3H), 2.90 (q, J=7, 2H), 3.70 (br s, 1H), 7.12 (dtm J=8 and 2, 2H), 7.22-7.28 (m, 1H), 7.29-7.38 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl.ClCCl>[CH3:1][C:2]1[N+:7]([O-:17])=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(n1)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c([n+]1[O-])COC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (150 mg, 1.0 mmol) in chloroform (5 mL) and dichloromethane (1 mL) is treated with m-chloroperoxybenzoic acid (258 mg, 1.5 mmol). The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is purified by chromatography (silica gel). The product containing fractions are concentrated to give the title compound as a solid (122 mg, 73%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.O=[C:24]1[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1.C(O)(=O)C.ClCCCl>ClCCCl.CC(O)C.CC(O)C>[NH2:22][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[CH:21][N:13]2[C@H:5]1[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]2[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:25]2)[O:4]1
Reactant: O=C1CC(CCC(=O)OCc2ccccc2)C1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClCCCl
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of the 9-[(3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-amine (1.45 g, 4.736 mmol), benzyl 3-(3-oxocyclobutyl)propanoate (1.21 g, 5.209 mmol) and acetic acid (246.45 μl, 4.31 mmol) in DCE:iPrOH (4:1, 50 ml) was stirred at RT for 1 h. A further aliquot of DCE (40 ml) and iPrOH (5 ml) was added to the reaction mixture and continued for 1 hour. STAB (1.28 g, 6.03 mmol) was then added and the reaction mixture was stirred for 18 hours. The reaction mixture was quenched with 1N Na2CO3 (10 ml), and the product was extracted with DCM (2×30 ml). This was dried over Na2SO4, filtered and evaporated to dryness. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-3:97) gave the desired product as a colourless oil, 1.51 g (58%); MS (ESI+) for C27H34N6O5 m/z 523.65 [M+H]+; HPLC purity 97% (ret. time, 1.43 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.35 (d, J=5.3 Hz, 1H), 7.87 (d, J=33.8 Hz, 1H), 7.40-7.29 (m, 5H), 6.08-5.94 (m, 1H), 5.59-5.42 (m, 3H), 5.10 (d, J=4.0 Hz, 2H), 5.03-4.96 (m, 1H), 4.33 (dq, J=7.3, 3.9 Hz, 1H), 3.12 (ddd, J=23.0, 14.6, 7.5 Hz, 1H), 2.85-2.77 (m, 1H), 2.74 (dd, J=12.5, 6.6 Hz, 1H), 2.39-2.07 (m, 4H), 1.90-1.64 (m, 5H), 1.61 (s, 4H), 1.38 (s, 3H), 1.28-1.06 (m, 1H).
Reaction SMILES: [NH2:1][C:2](C(Cl)(Cl)Cl)=[C:3]([C:10]#[N:11])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=O.CC([O-])=O.[K+].[OH2:21].[NH2:22][NH2:23].C(Cl)Cl>CN(C=O)C.C(#N)C>[NH2:1][C:2]1[C:3]([C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:21])=[C:10]([NH2:11])[NH:23][N:22]=1
Reactant: C=CCOC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Reactant: O
Reactant: NN
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(N)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
To a suspension of allyl 3-amino-4,4,4-trichloro-2-cyano-but-2-enoate 2 (619 g, 2.297 mol) and KOAc (676.3 g, 6.891 mol) in DMF (2.476 L) at 0° C. was slowly added hydrazine hydrate (172.5 g, 167.6 mL, 3.446 mol) over 15 min. The reaction mixture was then stirred at ambient temperature for 2 h, at which stage 1H NMR shows complete consumption of the starting material. Reaction mixture was then heated overnight at 110° C. before being allowed to cool to ambient and stirred for another 48 h. The mixture was filtered through a sintered glass funnel to remove the precipitated solid and the filtrate was evaporated under reduced pressure to give a thick liquid. DCM (approx 2 L) was added, and the mixture filtered again to remove additional solids that have precipitated. The filtrate was purified through a 1 kg silica gel plug (gradient of DCM/MeOH as an eluent), and the solvent was removed to afford an orange solid which was suspended in acetonitrile and heated at about 70° C. until all the solid went into solution, at which point the solution was allowed to cool to ambient temperature, then to 2° C. The precipitate that formed was isolated by filtration under vacuum, washed with chilled MeCN (˜50 mL) and dried to constant mass in a vacuum oven to furnish the title compound as an off-white powder (171.2 g, 41%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@:3]2([C:21]3[C:12](=[CH:13][C:14]4OC[CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C@@]2(C3C(=CC4OCCOC=4C=3)[O:33][CH2:32]2)C1=O.Cl.Cl[CH2:47][C:48]1[C:53]([C:54]([F:57])([F:56])[F:55])=[CH:52][CH:51]=[CH:50][N:49]=1.BrCCCCC>>[F:55][C:54]([F:57])([F:56])[C:53]1[C:48]([CH2:47][N:1]2[C:9]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C@:3]3([C:21]4[C:12](=[CH:13][C:14]5[CH2:32][O:33][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:49][CH:50]=[CH:51][CH:52]=1
Reactant: FC(F)(F)c1cccnc1CCl
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)OCCO3
Agent: Cl
Solvent: CCCCCBr
Product: O=C1N(Cc2ncccc2C(F)(F)F)c2ccccc2[C@@]12COc1cc3c(cc12)OCOC3

Procedure:
Following the procedure as described in EXAMPLE 7.3 and making non-critical variations using (R)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride to replace 1-bromopentane, (8R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,3]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (72%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=4.5 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.34-6.96 (m, 4H), 6.62 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 5.26 (ABq, 2H), 4.85 (2H), 4.21-4.08 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 178.1, 155.1, 152.3, 144.5, 142.3, 138.2, 134.3, 134.2, 134.1, 134.0, 132.7, 128.5, 125.6, 124.9, 124.5, 124.1, 123.8, 123.2, 122.1, 122.0, 121.6, 112.4, 108.5, 99.1, 80.0, 64.5, 63.9, 58.2, 42.2, 42.2; MS (ES+) m/z 454.8 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: CCCCCC(=O)Nc1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: CCCCCC(=O)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]hexanamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 87 mg of the title compound (86%) as a yellow powder in 98.5% purity by HPLC (Rt: 4.71, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][C:34]([CH2:39]O)([CH2:37][OH:38])[CH2:35][OH:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][CH2:39][C:34]([NH2:33])([CH2:37][OH:38])[CH2:35][OH:36])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: NC(CO)(CO)CO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)OCC(N)(CO)CO)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 7 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (5:1) and treated with 2-amino-2-[hydroxymethyl]-1,3-propandiol as for example 34. After stirring at RT for 60 h, a precipitate had formed. The solid was isolated by filtration and further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 2-amino-3-hydroxy-2-(hydroxymethyl)propyl 4-(2-fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (7%) as a white solid; m.p. (EtOAc/Hexane) 117-122° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2CO] δ 9.44 (br s, 1H), 8.61 (s, 1H), 7.67 (dd, J=9.9, 1.8 Hz, 1H), 7.66-7.62 (m, 1H), 7.35 (dt, J=8.4, 2.4 Hz, 1H), 5.62 (dd, J=6.3, 1.2 Hz, 1H), 4.26 (s, 2H), 3.56 (d, J=1.8 Hz, 4H), 3.49 (s, 3H). HRMS (FAB+) calcd for C17H20FIN3O5 492.0432 (M+), found 492.0450. HPLC 88.9% (254 nm).
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: COc1ccc2c(c1)CCC(I)C(=O)N2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCC(N=[N+]=[N-])C(=O)N2
Reaction time: 2 h
Yield: 85.1 %

Procedure:
3-Iodo-7-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (4.074 g, 12.85 mmol) and sodium azide (4.178 g, 64.3 mmol, 5 eq.) were dissolved in 50 mL of dimethylformamide and heated with stirring at 60° for 2 hours. The solvent was evaporated under vacuum at room temperature and the residue redissolved in 150 mL of ethyl acetate and washed with water (3×50 mL) and brine (1×50 mL). The organic layer was separated, dried over MgSO4, filtered and evaporated to dryness under vacuum to yield 2.538 g (10.94 mmol, 85%) of product. 1H NMR (200 MHz, CDCl3): 2.2-2.7 (m,3H), 2.90 (m,1H), 3.75 (s,3H), 3.80 (m,1H), 6.75 (m,2H), 6.95 (d,8 Hz,2H), 8.22 (br s,1H). FAB-MS: calculated for C11H12N4O2 232; found 233 (M+H,30%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16]2)=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 1,4-dibromobenzene (3.89 g, 16.49 mmol) in tetrahydrofuran (80 mL) was added n-butyllithium (10.3 mL, 16.5 mmol, 1.6 M in hexane) dropwise. After 15 minutes, a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (3.05 g, 16.49 mmol) in tetrahydrofuran (10 mL) was added over 5 minutes. The reaction continued to stir at −78° C. for 15 minutes and was then quenched by the addition of saturated NH4Cl (150 mL) and diethyl ether (150 mL). After warming to room temperature, the layers were separated, and the aqueous was extracted with additional diethyl ether (2×100 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% ethyl acetate in hexane to 50% ethyl acetate in hexane) to give the title product. MS (ESI) m/z 342 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[NH:15][N:14]=2)=[N:4][C:5](Cl)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[CH:17]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[NH:15][N:14]=2)=[N:4][C:5]([NH:31][C@H:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH3:30])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)c([N+](=O)[O-])cc2Cl)n[nH]1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2Cl)n[nH]1
Temperature: 145 °C
Yield: 98.1 %

Procedure:
A mixture of 3,6-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridin-2-amine (Method 27, 0.25 g, 0.75 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.13 g, 0.90 mmol) and DIEA (0.16 ml, 0.94 mmol) in n-BuOH (3 ml) was heated in a sealed tube at 145° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.32 g, 98%). 1H NMR (400 MHz) δ 12.22 & 11.40 (s, 1H), 9.74 & 9.37 (s, 1H), 8.93 (d, J=7.6 Hz, 1H), 8.33 & 8.27 (s, 1H), 7.34 & 7.27 (m, 2H), 7.12 & 7.05 (m, 2H), 5.75 & 5.62 (s, 1H), 5.35 & 5.25 (m, 1H), 4.66 & 4.03 (m, 1H), 1.55 (d, J=6.4 Hz, 3H), 1.29 (d, J=6.0 Hz, 6H). MS: Calcd.: 434. Found: [M+H]+ 435.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].Cl.Cl.[NH2:15][C@@H:16]([CH3:29])[C:17]([NH:19][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:15][C@@H:16]([CH3:29])[C:17]([NH:19][C@@H:20]([CH3:28])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:18])=[O:12])=[N:5][CH:4]=1)=[O:2]
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reactant: O=Cc1cnc(NCC(=O)O)s1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)CNc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
Following the general procedure as described in Example 24, except using 2-(5-formylthiazol-2-ylamino)acetic acid, 1.00 HCl (582 mg, 2.62 mmol), (S)-tert-butyl 2-((S)-2-aminopropanamido)propanoate hydrochloride (661 mg, 2.62 mmol), 1-hydroxy-7-azabenzotriazole (175 mg, 1.29 mmol), CH2Cl2 (30 mL), EDC (588 mg, 3.07 mmol) and stirring at room temp for 18 h, 781.5 mg (78%) of the title compound is isolated by filtration as a light pink solid. LC/MS (Condition A): ret. T=2.64 min, (M+H)+ 385. 1H NMR (500 MHz, methanol-d4) δ ppm 9.66 (1 H, s), 7.97 (1 H, s), 4.37-4.53 (1 H, m), 4.21-4.32 (1 H, m), 4.16 (2 H, d, J=0.92 Hz), 1.47 (9 H, s), 1.38 (6 H, dd, J=15.72, 7.17 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]=[CH2:18])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:19])[NH:10]2)(=[O:3])[CH3:2].[H-].[Na+].[H][H].O.[CH3:25]N(C=O)C>>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]=[CH2:18])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:19])[N:10]2[CH3:25])(=[O:3])[CH3:2]
Reactant: C=CCOc1ccc(OC(C)=O)c2c1NC(=O)CC2
Reactant: CN(C)C=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCOc1ccc(OC(C)=O)c2c1N(C)C(=O)CC2

Procedure:
9 Grams of 5-acetoxy-8-allyloxy-3,4-dihydro-2(1H)-quinolinone was dissolved in 100 ml of DMF, 1.51 g of 60%-sodium hydride was added gradually in limited amounts to this solution, this reaction mixture was stirred at room temperature until generation of hydrogen gas ceased. Under stirring and ice-cooling conditions, 100 ml of water was added to this reaction mixture, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, the dried extract was concentrated under reduced pressure. The oily product thus obtained was purified by a silica gel column chromatography, there was obtained 7 g of 5-acetoxy-8-allyloxy-3,4-dihydro-1-methyl-2(1H)-quinolinone as pale yellow oily product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([CH3:12])[CH:11]=2)=[N:3]1.[I:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[I:13][C:5]1[C:4]([C:7]2[S:8][CH:9]=[C:10]([CH3:12])[CH:11]=2)=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1csc(-c2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1csc(-c2nn(C)cc2I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 1-methyl-3-(4-methyl-2-thienyl)-1H-pyrazole (4.7 mmol) in 14 mL dry 1V, N-dimethylformamide under argon atmosphere was added N-iodosuccinimide (5.0 mmol) in small portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h, then extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (cyclohexane:dichloromethane 100:0 to 0:100) to afford 1.26 g 4-iodo-1-methyl-3-(4-methyl-2-thienyl)-1H-pyrazole (84% yield).
Reaction SMILES: O[CH:2]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])[CH2:3][CH3:4].S(Cl)([Cl:22])=O>CCCCCC>[Cl:22][CH:2]([C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:6]=1[CH:17]([CH3:19])[CH3:18])[CH2:3][CH3:4]
Reactant: CCC(O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: CCC(Cl)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A 100 milliliter flask was equipped with a magnetic stirrer and a pressure equalized addition funnel/drying tube. The flask was filled with a solution containing 50 milliliters of hexane and 15 grams (0.057 mole) of 1-(1-hydroxypropyl)-2,4,6-triisopropylbenzene (1-ethyl-2',4',6'-triisopropylbenzyl alcohol). The addition funnel was filled with a solution containing 10 milliliters of hexane and 8.9 grams (0.075 mole) of thionyl chloride. The solution of the thionyl chloride was slowly added to the solution of the 1-ethyl-2',4',6'-triisopropylbenzyl alcohol over a 45 minute period while stirring the reaction mixture. During the addition there was vigorous gas evolution, and after the addition the reaction mixture was left standing over night and then was cooled in an ice bath. After the reaction mixture was cooled, about 20 milliliters of ice water was rapidly added with stirring. After warming the reaction mixture to room temperature, the organic phase and water phase were separated, and the organic phase was washed with 5 portions of 20 milliliters of water, and then with a 20 milliliter solution of saturated sodium chloride. Then the organic phase was dried over magnesium sulfate and filtered. The solvent was evaporated from the organic phase using a rotary evaporator, to give 14.0 grams (92 percent) of a pale yellow liquid of the composition 1-(1-chloropropyl)-2,4,6-triisopropylbenzene.