Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43](O)=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41].Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:44])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccc(Cl)c(Cl)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3,4-dichlorophenylacetic acid (0.49 g, 2.4 mmol) were added. The mixture was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo. The resulting oil solidified on standing and the mixture was stirred in acetone (10 mL) then in MeOH (10 mL). The resulting solid was filtered and dried in vacuum oven to afford 2-(3,4-dichloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide as an off-white solid (0.69 g, 67%): mp, 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.5 min. (98%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.58 (s, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.26-7.82 (m, 6H), 8.69 (t, J=6 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.92, 40.80, 48.83, 121.95, 127.16, 129.13, 129.58, 130.29, 130.65, 131.15, 131.52, 133.31, 134.68, 137.19, 138.92, 166.88, 167.39, 169.77, 172.72. Anal Calcd for C22H17Cl2N3O5+0.2H2O: C, 55.29; H, 3.67; N, 8.79; Cl, 14.84. Found: C, 55.19; H, 3.33; N, 8.83; Cl, 14.71.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[Cl:20]Cl>C(O)(=O)C.Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:18][CH3:19])[Cl:20]
Reactant: ClCl
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Yield: 98 %

Procedure:
To a suspension of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (6.06 g., 0.02 mole) in glacial acetic acid (100 ml.) and concentrated hydrochloric acid (2 drops) is added, with stirring, a solution of glacial acetic acid (50 ml.) and chlorine (1.56 g., 0.22 mole) over a period of 10 minutes. During the addition the reaction vessel is heated on a steam bath. After the addition is complete, the mixture is stirred without heating for 30 minutes and then poured into ice water (600 ml.). The white solid that separates is collected by filtration, washed with water and dried to afford 6.6 g. (98% yield) of (1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)acetic acid, m.p. 185°-187° C. After recrystallization from acetic acid (25 ml.) the yield of (1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)acetic acid is 5.7 g., m.p. 186°-188° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[N+:2]=[N-:3].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[C:25]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([C:24]1[C:25]([C:30]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:13])([F:12])[F:14])[CH:6]=3)[C:31]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23]
Reactant: O=C(c1ccccc1Cl)c1cccnc1C#Cc1ccncc1
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cccc(C(F)(F)F)c2)c1-c1ccncc1
Temperature: 150 °C
Yield: 20.2 %

Procedure:
Add 1-azidomethyl-3-trifluoromethyl-benzene (152 mg, 0.75 mmol), (2-chloro-phenyl)-(2-pyridin-4-ylethynyl-pyridin-3-yl)-methanone (200 mg, 0.63 mmol), and toluene (2 mL) to a sealed tube. Flush with nitrogen, seal, and heat at 150° C. overnight. Concentrate to dryness and triturate with diethyl ether to afford the title compound (66 mg, 20%) as a pink solid: MS(IS) 520(M+1); TLC (5% MeOH/dichloromethane) Rf=0.48.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Br)c(Nc2ccccc2)n1

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (6.84 g, 30.0 mmol), aniline (2.79 g, 30.0 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in n-butanol (75 ml) was heated under reflux for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in DCM (100 ml). The solution was washed with water (3×100 ml) and saturated brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 15% ethyl acetate/isohexane, to give the product as an oil which solidified on standing (5.12 g, 60%). NMR: 7.1 (t, 1H), 7.4 (t, 2H),7.55 (d,2H), 8.4 (s,1H), 9.2 (br s, 1H); MS (MH+): 284, 286, 288.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:16]=1[C:17]([O:19]C)=[O:18])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:15]2[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:19][C:17](=[O:18])[C:16]=2[CH:21]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)c(=O)oc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
Methyl 2-(2-benzyloxyphenyl)-5-nitrobenzoate (Reference Compound No. 1-1-(1), 21.0 g, 57.8 mmol) was dissolved in a mixture of methanol (135 mL) and tetrahydrofuran (90 mL), then 5% palladium on charcoal (2.19 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere at room temperature overnight. After the unsoluble materials were filtered, the filtrate was removed under reduced pressure. A mixture of ethyl acetate and hexane was added to the obtained residue, and then the mixture was filtered to give the titled reference compound (8.92 g) as a pale yellow solid. (Yield 73%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:14][O:15][CH:16]3[CH:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=5[O:40][CH3:41])=[CH:24][CH:23]=4)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:17]3)[C:11]=2[Br:13])[C:6]([CH3:52])=[CH:5]1.N1C=CC=CC=1.[CH:59]1([C:62](Cl)=[O:63])[CH2:61][CH2:60]1>ClCCl>[Br:13][C:11]1[C:10]([CH2:14][O:15][CH:16]2[CH:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[O:40][CH3:41])=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])[CH2:17]2)=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][CH2:2][NH:1][C:62]([CH:59]1[CH2:61][CH2:60]1)=[O:63])[CH:5]=[C:6]2[CH3:52]
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCN)c3c2Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)cn(CCNC(=O)C4CC4)c3c2Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The solution of 0.400 g of benzyl 3-[1-(2-aminoethyl)-7-bromo-3-methyl-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 76b) in 2.5 ml of dichloromethane is admixed successively with 0.74 ml of pyridine and 0.43 ml of cyclopropanecarbonyl chloride, and stirred at room temperature over 30 minutes. The reaction mixture is poured onto water (50 ml) and extracted with dichloromethane (2×40 ml). The organic phases are washed successively with 1M sodium hydrogencarbonate solution (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a white foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].[OH-].[Na+].Cl>CO>[O:14]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C=CC(=O)c2ccccc2)cc1
Reaction time: 16 h
Yield: 86 %

Procedure:
To a stirred suspension at room temperature of 4-formylbenzoic acid (2.58 g, 17 mmol) and acetophenone (2.0 ml, 17 mmol) or acetophenone derivatives (1.0–1.1 equiv.) in MeOH (100 ml) was added a solution of NaOH (34 ml, 1N in H2O). After 16 h, the reaction mixture was acidified with conc. HCl (pH=1–2), filtered off, rinsed with H2O and dried to afford the title compound XXIIIa (3.73 g, 14.6 mmol, 86% yield) as a yellow solid.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:17]4[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=4)=[N:14][O:15][CH:16]=3)=[N:6][CH:5]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 31 %

Procedure:
As described for example 324, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.61 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (70 mg, 31%) which was obtained as a white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][OH:39]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][OH:39])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: OCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccc(C)n3)ccnc2cc1OCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
6-Methoxy-4-(5,6,6′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 443) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (54 mg) and 2-bromoethanol (0.03 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (29 mg, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:21]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:22][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]=1.IC.[C:40]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]([CH3:40])[C:12]([C:14]2[N:19]=[C:18]3[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:21]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:22][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)Cn1c(N=CN(C)C)nc2ccc(-c3[nH]c(-c4c(Cl)cccc4Cl)nc3-c3ccccc3)nc21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Cn1c(N=CN(C)C)nc2ccc(-c3c(-c4ccccc4)nc(-c4c(Cl)cccc4Cl)n3C)nc21

Procedure:
Stir N′-{5-[2-(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl}-N,N-dimethylformamidine prepared essentially as described in EXAMPLE 63 (0.10 g, 0.188 mmol), iodomethane (0.040 g, 0.282 mmol), and Cs2CO3 (0.09 g, 0.28 mmol) in DMF (1.5 mL) at RT for about 24 h. Extract with EtOAc and wash with water (3×), saturated aqueous NaCl, then dry over Na2SO4. Filter and concentrate to give a mixture of methyl isomers. Purify (silica gel chromatography) eluting with 1:1:0.4 CH2Cl2:acetonitrile:hexanes to give the title compound (0.02 g).
Reaction SMILES: Br.Br[CH:3]([C:5]1[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]2[C:14]=1[O:13][C:12]([N:15]1[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]1)=[CH:11][C:10]2=[O:22])[CH3:4].[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>CC(N(C)C)=O>[F:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][CH:3]([C:5]2[CH:6]=[C:7]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:8]=[C:9]3[C:14]=2[O:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][C:10]3=[O:22])[CH3:4])=[CH:31][CH:30]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Reactant: Nc1ccc(F)cc1
Agent: Br
Solvent: CC(=O)N(C)C
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCO[C@H](C)C3)oc12
Yield: 58.8 %

Procedure:
8-(1-bromoethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.30 mmol) and 4-fluoroaniline (0.113 mL, 1.19 mmol) in DMA (1 mL) were stirred at RT for 4 hrs. The reaction mixture was filtered and purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. A further purification was done by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford a oil which was triturated with pentane to give 8-(1-(4-fluorophenylamino)ethyl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (80 mg, 59%) as a white solid. NMR Spectrum (DMSOd6): 1.16 (d, 3H), 1.50 (d, 3H), 2.66 (bs, 3H), 2.81 (ddd, 1H), 2.93 (bs, 3H), 3.14 (ddd, 1H), 3.57-3.70 (m, 2H), 3.87-4.03 (m, 3H), 4.93-5.01 (m, 1H), 5.62 (s, 1H), 6.24-6.29 (m, 1H), 6.43-6.50 (m, 2H), 6.85 (t, 2H), 7.55 (d, 0.5H), 7.56 (d, 0.5H), 7.77 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[C:4]([O:16][CH3:17])[CH:3]=1.Cl[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=[O:20].N1C=CC=CC=1>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[O:20])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(F)ccc1Oc1ccccc1N
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccc(F)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a slurry of title compound 91 (4 g, 17.15 mmol) and methyl 4-(chlorocarbonyl)benzoate (3.58 g, 18.01 mmol) in benzene (60 mL) at 0° C. was added pyridine (4.85 mL, 60.0 mmol) drop wise followed by a single crystal of DMAP. The temperature was raised to room temperature and the reaction mixture was left to stir for 1 h. The reaction mixture was filtered and the filtrate was diluted with 5% aq HCl and ethyl acetate. The organic layer was washed with 5% aq HCl, water and brine then left in the fridge over the weekend. The precipitated solid was filtered, washed with water and hexanes to afford title compound 92 (6.38 g, 94%) as an off-white solid. LRMS (ESI): (calc) 395.12 (found) 396.4 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:3]=1[C:4]([OH:6])=[O:5].CO.[N+](=[CH2:18])=[N-]>C1COCC1>[CH3:18][O:5][C:4](=[O:6])[C:3]1[C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c(F)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a stirred solution of 2-fluoro-6-nitro-benzoic acid (2.15 g, 0.0116 mol) in THF (25 mL)/methanol (10 mL) under nitrogen was added diazomethane (5.8 mL) dropwise. The reaction mixture was stirred at room temperature overnight. HPLC indicated complete conversion to product. The reaction solvent was removed in vacuo to give a tannish yellow solid 2-Fluoro-6-nitro-benzoic acid methyl ester (2.2 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, 1H, J=7.6 Hz), 7.88 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1.B.CNC.Cl>CO.O>[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH:13]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)[C:12](=[O:17])[CH2:11]2)[CH:7]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: B
Agent: CNC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared by treating a suspension of 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione (350 mg, 0.917 mmol) and 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxaldehyde (described in Step 3 of example B(75))(242 mg, 1.375 mmol, 1.5 equiv, from Step 3 of Example B(75)) in MeOH (10 mL) with dimethylamine borane (65 mg, 1.1 mmol, 1.2 equiv). The resulting mixture was stirred at room temperature for 18 h. A 1 M solution of HCl (3 mL) was added to the reaction mixture to acidify to a pH of 3. The mixture diluted with water and extracted with dichloromethane containing 10% methanol (3×10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to a white amorphous foam. The foam was chromatographed on silica gel, eluting with 2% methanol in dichloromethane affording a white solid. This solid was recrystallized from ethyl acetate/hexanes to give 100 mg (19%) of the product as a fine white powder. Isolated as a monohydrate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:13][CH2:14][O:18][C:16]1=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCOC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.7 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-homoserine (9.0 g), 1-hydroxybenzotriazole (HOBt) (5.4 g) and N,N-dimethylformamide (DMF) (50 ml) was provided and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (7.5 g) was added to the mixture under ice-cooling. The whole mixture was stirred at room temperature for 14 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 1% aqueous citric acid, water, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride in the order mentioned and dried over MgSO4 and the solvent was distilled off, whereby (S)-3-(N-benzyloxycarbonylamino)tetrahydrofuran-2-one (7.0 g, 84.3%) was obtained. This product was recrystallized from dichloromethane-isopropyl ether. Colorless needles, m.p. 129°-130° C. Optical rotation [α]D -0.5° (C=0.52, CHCl3).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:7]=1[C:15]#[N:16])=[O:5])C.[Li+].[OH-]>CO>[C:11]([C:8]1[C:7]([C:15]#[N:16])=[C:6]([C:4]([OH:5])=[O:3])[O:10][N:9]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1onc(C(C)(C)C)c1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1noc(C(=O)O)c1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-tert-Butyl-4-cyano-isoxazole-5-carboxylic acid ethyl ester (809 mg, 3.64 mmol, prepared as described in the previous step) was dissolved in MeOH (9 mL) and 1 M LiOH (4.73 mL, 4.73 mmol) was added. The resulting mixture was stirred at room temperature for 3 h and the solvent was removed under reduced pressure. The resulting residue was dissolved in H2O (10 mL) and extracted with DCM (3×10 mL). The aqueous layer was acidified to pH˜2 using 3 M HCl and extracted with EtOAc (3×20 mL). The combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 3-tert-butyl-4-cyano-isoxazole-5-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ: 9.90 (br. s., 1H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=1)(C)(C)[CH3:2].C(Cl)(=[O:27])C.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=1)(=[O:27])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(C)=O)n(CCc2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Bioorganic & Medicinal Chem. Lett., 14 (2004), 1295-1298, was used as a reference. A 1.00 g portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in 15 ml of toluene, 0.26 ml of acetyl chloride was added thereto, and 3.6 ml of tin(IV) chloride (a 1 M dichloromethane solution) was added dropwise thereto at 0° C., followed by stirring at room temperature for 6 hours. After adjusting to pH 12 by adding 25 ml of a 1 M sodium hydroxide aqueous solution at 0° C., extraction was carried out with ethyl acetate, followed by washing with saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:7-1:5) to obtain 668 mg of ethyl 5-acetyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a beige solid.