Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13])[N:6]([CH3:17])[C:5]=1[CH2:18][OH:19].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[CH2:20]([O:3][C:4]1[C:9](=[O:10])[CH:8]=[C:7]([CH:11]([OH:16])[C:12]([F:15])([F:13])[F:14])[N:6]([CH3:17])[C:5]=1[CH2:18][OH:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cn1c(C(O)C(F)(F)F)cc(=O)c(O)c1CO
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(O)C(F)(F)F)cc(=O)c(OCc2ccccc2)c1CO
Temperature: 25 °C
Yield: 76 %

Procedure:
A 6.00 N sodium hydroxide solution (785 μL, 4.71 mmol) was added to a suspension of 3-hydroxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.08 g, 4.26 mmol) in methanol (5 mL). Benzyl bromide (650 μL, 5.46 mmol) was added to the clear solution, and the resulting solution was heated to reflux for 45 min Some solid had separated out in the solution. Analysis of the reaction mixture using HPLC Method 1 (Example 24) indicated that the starting material was consumed. The reaction mixture was allowed to cool down to room temperature, and the first crop of solid product was collected by suction filtration, and washed with acetonitrile. The title compound was thus obtained as a solid product (1.11 g, 76% yield, HPLC Method 1 (Example 24), RT=12.6 min, HPLC purity (peak percent area): 99% at λ=280 nm). 1H NMR (DMSO-d6+D2O) δ ppm: 7.36 (m, 5H), 6.59 (s, 1H), 5.53 (q, J=6.5 Hz, 1H), 5.01 (s, 2H), 4.58 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([C:15]1[N:19]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1)[CH3:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([C:15]1[N:19]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:24][CH2:25]2)[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[N:16]=1)[CH3:14]
Reactant: CCc1nc2ccccc2n1C1CCNCC1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1C1CCN(CCCSc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 75.2 %

Procedure:
To a stirred solution of 1-(3-bromopropylsulfanyl)-4-fluorobenzene (0.5 g) and 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.5 g) in DMF (5 ml) was added K2CO3 (1.0 g) and KI (0.05 g). The mixture was heated at 100° C. for 1 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (9:1 DCM:MeOH) to yield 0.6 g of the title compound as colourless crystals. Mp. 182-184° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=2)=[CH:38][C:37]=1[CH3:49]>>[CH3:49][C:37]1[CH:38]=[C:39]([C:43]2[CH:44]=[N:45][N:46]([CH3:48])[CH:47]=2)[CH:40]=[C:41]([CH3:42])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cnn(C)c2)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cnn(C)c6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 4-(4-bromo-3,5-dimethylphenyl)-1-methyl-1H-pyrazole following a procedure analogous to that described in Step 2 of Intermediate 17. Mass spectrum (ESI+): m/z=527 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:3]1.Cl.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH2:25])[CH3:24])=[CH:19][C:18]=1[O:26][CH3:27]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C@H:23]([NH:25][C@H:2]2[CH2:6][CH2:5][C@@H:4]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=3)[CH2:3]2)[CH3:24])=[CH:19][C:18]=1[O:26][CH3:27]
Reactant: COc1cc([C@@H](C)N)ccc1F
Reactant: N#Cc1ccc([C@@H]2CCC(=O)C2)cc1
Agent: Cl
Product: COc1cc([C@@H](C)N[C@H]2CC[C@@H](c3ccc(C#N)cc3)C2)ccc1F

Procedure:
General procedure B was followed using 4-[(1R)-3-oxocyclopentyl]benzonitrile as the ketone and (1R)-1-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride as the amine. 1H NMR (300 MHz, DMSO) δ 7.76-7.69 (m, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.15 (dd, J=8.6, 1.9 Hz, 1H), 7.09 (dd, J=11.5, 8.3 Hz, 1H), 6.88 (ddd, J=8.2, 4.5, 1.9 Hz, 1H), 3.82 (s, 3H), 3.75 (d, J=6.2 Hz, 1H), 3.07-2.85 (m, 2H), 2.23-2.03 (m, 2H), 2.00-1.54 (m, 3H), 1.40-1.19 (m, 1H), 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]1([CH2:11][C:12]([NH:14][CH:15]2[C:47](=[O:48])[N:17]3[C:18]([C:31]([O:33][CH:34]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])=[C:19]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:20][S:21](=O)[C@H:16]23)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CN(C)C=O>[C:5]1([CH2:11][C:12]([NH:14][CH:15]2[C:47](=[O:48])[N:17]3[C:18]([C:31]([O:33][CH:34]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[C:19]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:20][S:21][C@H:16]23)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS(=O)[C@H]12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
Phosphorus trichloride (15.2 g) was added to the solution of benzhydryl 7-phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate-1-oxide (trans isomer) (22.2 g) in dimethylformamide (220 ml) at -30° C. and the solution was stirred at -30° to -25° C. for 10 minutes. The reaction mixture was poured into cold water (1 l) and resulting precipitates were collected by filtration. The filtrate was dissolved in ethyl acetate (300 ml) and the ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (15.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[CH:27]=[CH:26][C:9]2[N:10](C(OC(C)(C)C)=O)[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1.ClC1C=CC=CC=1CSC1C=CC2N=C(C3C=CC=CN=3)N(C(OC(C)(C)C)=O)C=2C=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][S:5][C:6]1[CH:27]=[CH:26][C:9]2[NH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2cc(SCc3ccccc3Cl)ccc21
Agent: CC(C)(C)OC(=O)n1c(-c2ccccn2)nc2ccc(SCc3ccccc3Cl)cc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Clc1ccccc1CSc1ccc2[nH]c(-c3ccccn3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To stirred solution of tert-butyl 5-(2-chlorobenzylthio)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (or the isomer, tert-butyl 6-(2-chlorobenzylthio)-2-(pyridin-2-yl)-1H-benzo[d]imidazole-1-carboxylate) (18 mg, 0.04 mmol) in methanol (2 mL) was added 4M HCl in dioxane (1 mL, 4 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue was purified by reverse phase preparative HPLC to give 5-(2-chlorobenzylthio)-2-(pyridin-2-yl)-1H-benzo[d]imidazole (2TFA) (8.8 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C@@H:7]([CH3:19])[CH2:6]1.N1C=CC=CC=1.Cl[C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44].[OH-].[K+]>ClCCl.C1(C)C=CC=CC=1.O>[CH:46]([O:45][C:43]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C@H:5]([N:4]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:3]([O:2][CH3:1])=[O:35])[CH2:6][C@@H:7]1[CH3:19])=[O:44])([CH3:48])[CH3:47]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)Nc2ccc(C(F)(F)F)cc21
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of cis-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (Example 70) (95 mg, 0.185 mmol) and anhydrous pyridine (0.5 mL) in anhydrous dichloromethane (2 mL) was added isopropyl chloroformate (1.9 mL of a 1M solution in toluene, 1.85 mmol). After stirring at room temperature overnight, water (5 mL) and an aqueous 10% KOH solution (5 mL) were added, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic phases were then washed with 1N HCl (3×10 mL), then a saturated sodium bicarbonate solution, and then brine (10 mL of each). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 117 mg crude product. Purification by silica gel chromatography using 0-10% ethyl acetate/hexanes as eluent afforded 90 mg of the title compound (81%): MS m/z 602 (M+ +2), 619 (M+ +19); 1H NMR (CDCl3) δ 1.20 (Me, d, 3H, J=6.1 Hz), 1.28 (d, 3H), 1.31 (d, 3H), 3.83 (OMe, s, 3H), 5.04 (septet, 1H), 7.12 (C5, s, 1H).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([C:15]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[NH:20][C:19]2=[C:21]([NH2:25])[CH:22]=[CH:23][CH:24]=[C:18]2[O:17][CH2:16]1)[CH3:14]>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:13]([C:15]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[N:20]2[C:2](=[O:4])[NH:25][C:21]3=[CH:22][CH:23]=[CH:24][C:18](=[C:19]23)[O:17][CH2:16]1)[CH3:14]
Reactant: CCC1(c2ccccn2)COc2cccc(N)c2N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 1 h
Yield: 213.3 %

Procedure:
Triphosgene (40 mg, 0.1 mmol) was added to a solution of 3-ethyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (80 mg, 0.3 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (0.1 mL). The reaction was stirred at room temperature for 1 h and was then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.060 g. 60%). LCMS calculated for C16H16N3O2 (M+H)+: m/z=282.1. found: 282.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([OH:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:35][CH2:36][C:37]([NH:39][CH2:40][C:41](O)=[O:42])=[O:38])(=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[CH2:7][CH:8]([O:24][C:41](=[O:42])[CH2:40][NH:39][C:37](=[O:38])[CH2:36][NH:35][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCC(=O)NCC(=O)NCC(=O)O
Reactant: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(CC(=O)OC(C)(C)C)OC(=O)CNC(=O)CNC(=O)CCCCCCC
Yield: 29.6 %

Procedure:
1.96 g of 3-hydroxyoctadecanoic acid tert-butyl ester and 1.43 g of N-octanoylglycylglycine were mixed with 40 ml of methylenechloride. By following the same procedure as in Example 23-(i) after adding 60 mg of DMAP and 1.14 g of DCC, 970 mg of 3-(N-octanoylglycylglycyloxy)octadecanoic acid tert-butyl ester was obtained.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[N+:17]([O-])([O-:19])=[O:18].[K+]>>[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Temperature: 25 °C
Yield: 35.2 %

Procedure:
Conc. H2SO4 was added slowly to 2-chloroquinoline (1.0 g, 6.13 mmol), followed by portionwise addition of potassium nitrate (800 mg, 7.97 mmol) at 0° C. The mixture was allowed to warm to room temperature overnight. After completion of the reaction (monitored by TLC and HPLCMS), the solution was poured slowly over ice, and the precipitate was extracted with EtOAc. The organic phase was washed with brine and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAC (17:3) as the eluent to give the title compound (450 mg, 38%).
Reaction SMILES: [Br:1]Br.[OH-].[Na+].[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)([O-:7])=[O:6].S([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[NH:13][N:12]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Reaction time: 3.5 h
Yield: 26.3 %

Procedure:
A solution of bromine (0.75 ml, 14.6 mmol) in a 2N-aqueous sodium hydroxide solution (20 ml) was added dropwise to a mixed solution of 5-nitro-1H-indazole (3.26 g, 20.0 mmol), dioxane (60 ml) and a 2N-aqueous sodium hydroxide solution (30 ml) at 0° C. and stirred at 0° C. for 30 minutes and then at room temperature for 3.5 hours. An aqueous sodium hydrogensulfite solution was added thereto until a solid was precipitated, to terminate the reaction, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous sodium thiosulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was suspended in ethyl acetate and extracted with a 0.1N-aqueous sodium hydroxide solution. After 6 times of the extraction, the combined aqueous layer was acidified with hydrochloric acid and then re-extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 3-bromo-5-nitro-1H-indazole (0.93 g, 19%) was obtained.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.COC(=O)[CH2:28][C:29]([N:31]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[CH2:32][CH2:33][C:34]([O:36]C)=O)=[O:30].Cl>C1(C)C=CC=CC=1.O>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:31]2[CH2:32][CH2:33][C:34](=[O:36])[CH2:28][C:29]2=[O:30])=[CH:44][CH:43]=1
Reactant: COC(=O)CCN(Cc1ccc(OC)cc1)C(=O)CC(=O)OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CCC(=O)CC2=O)cc1
Reaction time: 0.67 h
Yield: 69 %

Procedure:
A mixture of anhydrous K2CO3 (3.2 g, 23.2 mmol, 5 eq) and 18-crown-6 (azetroped several times with toluene) (122 mg, 0.464 mmol, 10 mol %) in dry toluene (4 ml), under nitrogen, was heated to reflux and then treated, dropwise, over 40 min, with a solution of N-(4-Methoxy-benzyl)-N-(2-methoxycarbonyl-ethyl)-malonamic acid methyl ester. After 7 h at reflux the reaction was diluted with water (4 ml) and toluene (4 ml), then cooled to 0° and carefully acudified to pH 1.7 with 0.1N HCl. The mixture was then extracted several times with CH2Cl2 (3×80 ml) and the combined organics dried and evaporated to a brown oil (1.33 g). The brown oil was treated with 10% aqueous oxalic acid and heated to reflux for 6.5 h. The mixture was then extracted repratedly with CH2Cl2 and the combined organics dried and evaporated to a dirty yellow oil (1.03 g). The crude material was purified on silica gel using (CH2Cl2:MeOH=30:1) as eluent to give 1-(4-Methoxy-benzyl)-piperidine-2,4-dione as a pale brown solid (750 mg, 69%); (300 MHz, CDCl3) 2.52 (t, J=5.7 HZ, 2H), 3.41 (s, 2H), 3.47 (t, J=5.7 Hz, 2H), 3.80 (s,3H), 4.62 (s, 2H), 6.16-6.88 (m, 2H), 7.20 (m, 2H).
Reaction SMILES: [N:1]1([C:7]([C:9]2[N:10]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=O)=[CH:13][CH:12]=3)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:38]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])[CH3:39]>O1CCCC1>[CH:38]([N:41]1[CH2:46][CH2:45][N:44]([C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([CH2:21][C:22]([F:23])([F:25])[F:24])[C:9]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])=[CH:17]3)=[O:20])[CH2:43][CH2:42]1)([CH3:40])[CH3:39]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)cc(C(=O)N1CCOCC1)n2CC(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCOCC2)n3CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 2-(morpholine-4-carbonyl)-1-(2,2,2-trifluoro-ethyl)-1H-indole-5-carboxylic acid (100 mg, 0.28 mmol) and 1,1′-carbonyl-diimidazole (59 mg, 0.37 mmol) in tetrahydrofuran was stirred at room temperature overnight. 1-Isopropylpiperazine (72 mg, 0.56 mmol) was then added and the mixture was stirred for an additional 40 min. The volatiles were removed in vacuo and the residue was purified by flash chromatography on silica gel with dichloromethane:methanol:ammonia (95:5:0.25 v/v) as eluant, to give 90 mg (68%) of the desired compound as an off-white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH2:14]([O:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=1[NH2:20])[CH:15]=[CH2:16].Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:14]([O:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=1[NH:20][C:1](=[O:3])[CH3:2])[CH:15]=[CH2:16]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOc1cc(OC)ccc1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCOc1cc(OC)ccc1NC(C)=O
Temperature: 25 °C

Procedure:
3 mg of 4-(dimethylamino)pyridine and 1 ml of acetic anhydride were successively added to 2 ml of pyridine containing 1.09 g of 2-allyloxy-4-methoxyaniline, and the reaction solution was then stirred at room temperature. After the disappearance of the raw material had been confirmed, 5 N HCl and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with a saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then solidified from t-butyl methyl ether-hexane, so as to obtain 1.04 g of the subject compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][N:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][C:31]([I:34])=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Fc1ccc(I)cn1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(I)cn5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-5-iodo-pyridine following a procedure analogous to that described for Intermediate 12. LC (method 6): tR=1.24 min; Mass spectrum (ESI+): m/z=562 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:13]=[N:12][CH:11]=1
Reactant: CN(C)CCO
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cncc(Br)c1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of N,N-dimethylethanolamine(0.5 mL) in DMF (10 mL) at room temperature was treated with sodium hydride (0.2 g, 8.4 mmol), stirred for 30 minutes, and treated with 3,5-dibromopyridine (1.0 g, 4.2 mmol). The mixture was stirred at 90° C. for 8 hours, and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel with 50% ethyl acetate/hexane provided the desired product (0.8 g, 78%). MS (DCI/NH3) m/e 246 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[CH3:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]=1[NH:28][C:29](=[O:44])[CH2:30][NH:31][CH2:32][C:33]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:18]>C(OCC)(=O)C>[CH3:18][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([CH3:26])[CH3:27])[C:20]=1[NH:28][C:29](=[O:44])[CH2:30][N:31]([C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[O:15])[CH2:32][C:33]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:16]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(CC1(c2ccccc2)CCCC1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C

Procedure:
2,6-Diisopropylphenylisocyanate (0.24 g) and the product of Example 6 (0.45 g) were mixed and then diluted with a few mL of ethyl acetate. The solution was heated on the steambath and then concentrated to an oil which was heated on the steambath. Upon cooling to room temperature the oil partially solidified. Addition of hexane/EtoAc, 1/1 caused crystallization of the product which was collected by filtration. 0.30 g (44%). NMR (CDCl3) δ 1.08 (12H ,d), δ 1.17 (12H, d), δ 1.60-2.13 (8H, m), δ 2.65 (2H, m), δ 3.04 (2H, m), δ 3.71 (2H, s), δ 4.04 (2H, bs), δ 5.24 (1H, bs), δ 7.04-7.48 (11H, m), δ 7.94 (1H, bs). IR (KBr) 3025, 2965, 2871, 1682, 1637, 1519, 1364, 1230, 958, 801, 700 cm-1.