Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](=[O:15])[NH:9][C:10](SC)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:18][C:19]1[C:20]([CH2:25][S:26][CH2:27][CH2:28][NH2:29])=[N:21][CH:22]=[CH:23][CH:24]=1.Cl>>[ClH:1].[Br:18][C:19]1[C:20]([CH2:25][S:26][CH2:27][CH2:28][NH:29][C:10]2[NH:9][C:8](=[O:15])[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][CH:16]=3)=[CH:12][N:11]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCCSCc1ncccc1Br
Reactant: CSc1ncc(Cc2ccc(Cl)cc2)c(=O)[nH]1
Agent: Cl
Product: O=c1[nH]c(NCCSCc2ncccc2Br)ncc1Cc1ccc(Cl)cc1

Procedure:
5-(4-Chlorobenzyl)-2-methylthio-4-pyrimidone (1.2 g) was reacted with 2-(3-bromo-2-pyridylmethylthio)ethylamine (1.1 g) according to the procedure of Example 2. The reaction mixture was acidified with dilute ethanolic hydrogen chloride, evaporated to dryness and the residue recrystallised from ethanol/water to give 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(4-chlorobenzyl)-4-pyrimidone monohydrochloride, m.p. 215°-218° (decomposes).
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[C@H:5]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[C@@H:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[H][H]>CCO.[Pd]>[C:31]([O:30][C:28]([C@H:4]1[CH2:3][C:2]([F:1])([F:35])[CH2:7][NH:6][C@@H:5]1[C:18]([OH:20])=[O:19])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN[C@@H]1C(=O)O

Procedure:
A solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5,5-difluoropiperidine-1,2,3-tricarboxylate (0.370 g, 0.000756 mol) in EtOH (7.0 mL) was hydrogenated in the presence of 10% Pd/C, under a ballon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was evaporated to dry. The residue was used directly in next step (190 mg, 94.77%). LC MS (M-Bu+1) 210.0.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](Cl)=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[F:18][C:19]([F:26])([F:25])[C@H:20]([NH2:24])[CH:21]([CH3:23])[CH3:22]>O1CCOCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]([NH:24][C@@H:20]([C:19]([F:26])([F:25])[F:18])[CH:21]([CH3:23])[CH3:22])=[N:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Clc1nc2ccnc(Cl)c2c2cc(Br)ccc12
Reactant: CC(C)[C@@H](N)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)[C@@H](Nc1nc2ccnc(Cl)c2c2cc(Br)ccc12)C(F)(F)F
Temperature: 150 °C

Procedure:
To a solution of dried 9-bromo-1,6-dichlorobenzo[c]-1,6-naphthyridine (0.80 g, 2.46 mmol) in dioxane (16 mL) was added (2R)-1,1,1-trifluoro-3-methylbutan-2-amine (2.4 g, 17.2 mmol) and heated to 150° C. for 24-48 hrs. The reaction was concentrated to dryness to give 9-bromo-1-chloro-N-[(1R)-2-methyl-1-(trifluoromethyl)propyl]benzo[c]-1,6-naphthyridin-6-amine. LRMS (ESI) calc'd for (C17H15BrClF3N3) [M+H]+, 432.0; found 432.0.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:33][CH3:34])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][C:31](=[O:46])[C@H:32]([CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[N:33]([C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:34])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1
Product: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(F)cc1

Procedure:
Using Procedure D, Boc-homophenylalanine (143 mg) and Nδ-Boc-Nα-methylornithine 2-(4-fluorophenyl)ethylamide (B) (crude product) gave desired compound (195 mg) as a glassy solid which was purified by flash chromatography: 1H NMR (400 MHz, CDCl3) δ1.52 (2 s, 18H).1.71 (m, 2H), 1.82 (m, 4H), 2.62-2.80 (m, 7H), 3.12 (m, 2H), 3.45 (m, 2H), 4.61 (m, 1H), 4.92 (m, 1H), 6.89 (m, 2H), 7.13 (m, 2H), 7.20 (m, 3H), and 7.32 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12](N2CCCCC2)[CH:11]([CH3:19])[N:10]=[N:9]1.FC1C=CC(N2C(N3CCCCC3)C(C)N=N2)=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[C:11]([CH3:19])[N:10]=[N:9]1
Reactant: CC1N=NN(c2ccccc2F)C1N1CCCCC1
Agent: CC1N=NN(c2ccc(F)cc2)C1N1CCCCC1
Product: Cc1cn(-c2ccccc2F)nn1
Yield: 65.4 %

Procedure:
As described for example 31c, 1-(1-(2-fluorophenyl)-4-methyl-4,5-dihydro-1H-1,2,3-triazol-5-yl)piperidine (1.32 g, 5.32 mmol), instead of 1-[3-(4-fluoro-phenyl)-5-methyl-4,5-dihydro-3H-[1,2,3]triazol-4-yl]-piperidine, was converted to the title compound (616 mg, 65%) which was obtained as a colorless liquid. MS: m/e=178.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[O:19][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10].[OH-].[Na+].Cl>CO>[Cl:27][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C:9]([C:11]1[C:16]2[CH:17]=[C:18]([C:20]([OH:22])=[O:21])[O:19][C:15]=2[C:14]([O:25][CH3:26])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)c1cc2c(C(=O)Cc3c(Cl)cncc3Cl)ccc(OC)c2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2cc(C(=O)O)oc12
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Ethyl 4-[2-(3,5-dichloro-4-pyridyl)-1-oxoethyl]-7-methoxybenzofuran-2-carboxylate (6.0 g) was dissolved in methanol (60 ml), 5 N aqueous NaOH (15 ml) was added thereto under cooling on ice, and the mixture was returned to room temperature and stirred for 1 hour. Under cooling on ice, the reaction mixture was acidified by dropwise adding 1 N aqueous HCl, and the precipitated crystals were collected by filtration and washed with water to give the desired compound (5.4 g, 96%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([CH:7]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][N+:9]([O-])=O)=[CH:5][CH:6]=1.O.[OH-].[Na+]>C(O)(=O)C.Cl.[Zn]>[Br:1][C:2]1[O:3][C:4]([CH:7]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][NH2:9])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])CC(Sc1ccccc1)c1ccc(Br)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NCC(Sc1ccccc1)c1ccc(Br)o1
Temperature: 80 °C

Procedure:
Zinc powder (0.80 g, 0.01224 mol) was added to 2-bromo-5-(2-nitro-1-phenylsulfanylethyl)furan (0.60 g, 0.001828 mol) dissolved in the mixture of glacial acetic acid (24 ml) and concentrated hydrochloric acid (2.4 ml) at 80° C. in nitrogen atmosphere. The mixture was heated at 80° C. for 2.5 h. Then, 0.40 g (0.00612 mol) of zinc powder was added and the mixture was heated for 1 h. The reaction mixture was cooled and 36 ml of water was added. pH was adjusted to 9 by 2.5 M NaOH. The product was extracted into ethyl acetate. The organic phase was washed with water, dried and evaporated. 1H NMR (400 MHz, DMSO-d6): 2.87 (1H, distorted dd), 2.97 (1H, distorted dd), 4.41 (1H, t), 6.21 (1H, d), 6.45 (1H, d), 7.31 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][C@H:19]2[CH2:39][CH2:38][C:21]3([O:25][C@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:22]3)[CH2:20]2)[C:13]([O:15]CC)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].O1CCCC1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:18][C@H:19]2[CH2:39][CH2:38][C:21]3([O:22][C@H:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C@@H:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:25]3)[CH2:20]2)[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CCOC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of ethyl 2-[3-chloro-4-(methylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propanoate in a mixed solvent of tetrahydrofuran (200 mL) and methanol (100 mL) was added 2M aqueous sodium hydroxide solution (50 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio) to give the title compound (17.6 g, yield 97%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH:8]([OH:14])[C:9]([CH3:13])([CH3:12])[CH2:10][Cl:11])=[CH:4][CH:3]=1.[Cl:22][CH:23]([Cl:27])[C:24](Cl)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[CH:8]([O:14][C:24](=[O:25])[CH:23]([Cl:27])[Cl:22])[C:9]([CH3:12])([CH3:13])[CH2:10][Cl:11])=[CH:20][CH:21]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)(CCl)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Product: CC(C)(CCl)C(OC(=O)C(Cl)Cl)C(Oc1ccc(Cl)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
19.8 g (0.06 mol) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-3,3-dimethyl-4-chlorobutan-2-ol were added to 200 ml of dichloroacetyl chloride at 0° C. The mixture was stirred at room temperature for 24 hours and excess dichloroacetyl chloride was distilled off in vacuo. The oil which remained was taken up in 400 ml of methylene chloride, the methylene chloride mixture was neutralized with 500 ml of aqueous sodium bicarbonate solution, the organic phase was separated off, washed with 200 ml of water and dried over sodium sulphate. The solvent was distilled off and the residue was taken up in 200 ml of diisopropyl ether. After leaving the mixture to stand for several hours, colorless crystals precipitated. 7.5 g (29% of theory) of 1-(4-chlorophenoxy)-1-(imidazol-1-yl)-2-dichloroacetoxy-3,3-dimethyl-4-chloro-butane of melting point 108°-110° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])=[CH:4][CH:3]=1.[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9](=[O:14])[CH2:10][CH2:11][C:12]#[CH:13])[C:16](=[O:15])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C#CCCC(=O)Nc1ccc(Cl)cc1
Product: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Yield: 93 %

Procedure:
The title compound was prepared in accordance with the general method of Example 34(B), from N-(4-chlorophenyl)pent-4-ynamide (820 mg, 3.95 mmol) and (BOC)2O (1.03 g, 4.74 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column, DCM 100% as eluent) to afford 1.13 g of tert-butyl 4-chlorophenyl(pent-4-ynoyl)carbamate as a colorless oil (Yield: 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[NH2:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[NH:16][CH3:17])[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:21]
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N

Procedure:
Prepared analogously to example 91a from N-(4-bromo-phenyl)-4-methylamino-3-nitro-benzamide and iron powder in acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:16]3[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCNC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (16.2 g, 92 mmol) (Crescent) and 4-chlorobenzaldehyde (12.9 g, 92 mmol) (Aldrich) in methanol (100 mL) was added pyrrolidine (6.55 g, 92 mol) (Aldrich) dropwisely. The mixture was then heated at 70° C. for 3 h. After cooling to 4° C., the resulting precipitate was collected and dried to give 21 g of E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid. MS: 291 (M+H)+.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:29][OH:30]>>[CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:12][CH:11]=2)=[N:29][OH:30])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1
Reactant: NO
Agent: Cl
Product: ON=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCCC1

Procedure:
In analogy to the procedure of Example IV, the title compound is prepared from 12.9 g (35.9 mmol) of the compound from Example XIII and 3.75 g (53.9 mmol) of hydroxylamine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[CH:29]=O>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2[C:29]1[NH:17][C:5]2[CH:6]=[C:7]([N:8]3[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]3)[C:2]([F:1])=[CH:3][C:4]=2[N:18]=1
Reactant: CC(C)N1CCN(c2cc(N)c(N)cc2F)CC1
Reactant: O=Cc1n[nH]c2ccc(F)cc12
Product: CC(C)N1CCN(c2cc3[nH]c(-c4n[nH]c5ccc(F)cc45)nc3cc2F)CC1

Procedure:
The title compound was synthesized as described in Example 4 from 4-fluoro-5-(4-isopropyl-piperazin-1-yl)-benzene-1,2-diamine and 5-fluoro-1H-indazole-3-carbaldehyde. LC/MS (m/z) 397.5 (MH+), Rt 2.78 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(F)cc4)c3C2=O)C(=O)N1
Yield: 75.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-fluorobenzoyl chloride (0.95 mL, 8.0 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2×10 mL) then methanol (5 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoro-benzamide as a yellow solid (1.2 g, 77% yield): mp, 283-285° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.48-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.4, 12.6 Hz, 1H, NCH), 7.42-7.49 (m, 2H, Ar), 7.69 (d, J=7.2, Hz, 1H, Ar), 7.91 (t, J=8.2 Hz, 1H, Ar), 8.03-8.08 (m, 2H, Ar), 8.54 (d, J=8.3 Hz, 1H, Ar), 10.41 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.10, 30.98, 49.29, 115.96 (d, JC-F=22 Hz); 118.03, 118.67, 128.09 (d, JC-F=235 Hz), 130.12, 131.49, 136.18, 136.75, 162.70, 164.08, 166.56, 168.22, 169.29, 172.27; Anal Calcd for C20H14N3O5F+0.2H2O: C, 60.21; H, 3.64; N, 10.53; F, 4.76; H2O, 0.90. Found: C, 60.17; H, 3.55; N, 10.47; F, 4.90; H2O, 0.95.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: OC1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCCC(O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 3-Hydroxypiperidine (Fluka)(67.0 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is crystallized in MeOH, affording Compound (26) as a brown solid (103 mg; 42%). M− (ESI): 365.20; M+ (ESI): 367.16. HPLC (method A), Rt: 2.35 min (purity: 99.4%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](O)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CC(C)=O>[C:13]([O:1][CH2:2][C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@@H:9]([OH:10])[CH:11]=[O:12])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O
Yield: 100.2 %

Procedure:
2 ml of acetone were added to the reactor which contained 100 mg of Novozim 435, 60 mg of glucose and 200 mg of lauric acid. The reaction was carried out under mild continual agitation at 40° C. and water was continually removed from the reaction medium. 121 mg of glucose 6-monolaurate were obtained after 3 days of reaction corresponding to a yield of 99%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN
Reactant: ClCCCCOc1cccnc1
Solvent: CO
Product: CNCCCCOc1cccnc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
The 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.47 g (75.5%) of an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH:20]=[C:21]1[CH2:24][O:23][CH2:22]1)([O-:19])=[O:18].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:20]([N+:17]([O-:19])=[O:18])[C:21]2([CH2:24][O:23][CH2:22]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C=C1COC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC12COC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a solution of benzyl-methoxymethyl-trimethylsilanylmethyl-amine (3.0 g, 12.6 mmol) and 3-nitromethylene-oxetane (1.38 g, 12.0 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (0.93 mL, 12.6 mmol) dropwise. The mixture was stirred at room temperature for 2 hours, quenched with sodium carbonate, extracted with dichloromethane. The organic layer was dried over sodium sulfate, concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 2 g of product as colorless oil. It was used for next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH2:20]1[O:29][C:28]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:29]1[C:28]2[CH:27]=[CH:26][C:24]([NH:25][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:23][C:22]=2[O:21][CH2:20]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)OCO4)c2cc1OCC
Temperature: 100 °C
Yield: 96.4 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 258 mg (1.88 mM) of 3,4-(methylenedioxy) aniline in 10 ml of ethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 526 mg of 4-(Benzo[1,3]dioxol-5-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 378.0, mp=200-203° C.
Reaction SMILES: C(N(CC)CC)C.[S:8](/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[C:9]#[N:10].CS(Cl)(=O)=O.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C1C=CC=CN=1)C.[K+].[Br-]>C1(C)C=CC=CC=1.C(Cl)Cl.O>[S:8](/[CH:11]=[CH:12]\[C:13]([O:15][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:14])[C:9]#[N:10]
Reactant: N#CS/C=C\C(=O)O
Reactant: Oc1ccccc1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: N#CS/C=C\C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (2.3 g., 0.031 mole) in 5 ml of dry toluene was added dropwise to a stirred suspension of compound 2 (4.0 g., 0.031 mole) in 30 ml of dry toluene at 0° C. To the resulting solution, methanesulfonyl chloride (3.55 g., 0.031 mole) in 15 ml of dry toluene was added dropwise at 0° C. and stirred for 30 minutes. A solution of phenol (2.9 g., 0.031 mole) and dimethylaminopyridine (DMAP) (3.5 g., 0.028 mole) in 40 ml of dry toluene was added dropwise with stirring at 0° C. The mixture was allowed to warm to room temperature and stirred for an additional 3 hours. The mixture, consisting of yellowish gum in a two-phase mixture with toluene, was diluted with methylene chloride, poured into water and the organic phase was separated. The aqueous phase was extracted with methylene chloride. The combined organic phase was washed with sodium bicarbonate solution, water, dried (MgSO4) and concentrated. The residue was column-chromatographed on silica gel using hexane/ether (4:1) as eluant to give product as white crystals, 2.9 g: mp 79°-83° C.; IR (KBr) 1700, 2175 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:18][OH:19].[OH-].[K+]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](=[N:18][OH:19])[NH2:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1

Procedure:
A mixture of 97 g (0.45 mole) of 5-(p-nitrophenyl)-2-furonitrile, 34 g (0.49 mole) of hydroxylamine hydrochloride, 27 g (0.49 mole) of KOH and 1450 ml of absolute ethanol was refluxed for one hour, cooled and filtered. The solid was stirred in dilute HCl/H2O, and was filtered and air dried to yield 86 g (67%). An analytical sample was prepared by drying a sample in the vacuum pistol at room temperature, m.p. 230°.