Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]([CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])#[N:2].[N:32]([Sn](C)(C)C)=[N+:33]=[N-:34]>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([NH:9][C:10]([C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:17]([CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11])[CH2:3][C:1]1[NH:34][N:33]=[N:32][N:2]=1
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](CC#N)CC(C)C)ccc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@H](Cc3nnn[nH]3)CC(C)C)ccc21
Yield: 41.8 %

Procedure:
218 mg of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyanomethyl-3-methyl-butyl)-amide and 124 mg of azidotrimethyltin in 10 ml of dry toluene were heated under Argon for 48 h. The precipitated crude product was isolated by suction and then dissolved in 10% aqueous sodium bicarbonate solution and filtered with addition of charcoal. The pH of the filtrated was adjusted to 5, and the precipitated product was isolated by suction, washed with water and dried in vacuo to obtain 100 mg (42%) of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid [(S)-3-methyl-1-(1H-tetrazol-5-ylmethyl)-butyl]-amide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([N+:15]([O-])=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.[Ni]>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[CH:11][C:12]([F:18])=[C:13]([CH:14]=1)[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Cc1cc(F)c(N)cc1OCc1ccccc1
Yield: 100.1 %

Procedure:
5-Benzyloxy-2-fluoro-4-methyl-1-nitrobenzene (500 mg, 1.9 mmol) in methanol (110 ml) was added to a suspension of Raney nickel (75 mg) and hydrazine hydrate (0.47 ml, 9.5 mmol) in methanol (10 ml) and heated at reflux. The mixture was maintained under reflux for 15 minutes and then the insoluble materials removed by filtration through diatomaceous earth. The filter pad was washed with methanol and the solvent removed from the filtrate by evaporation to give 5-benzyloxy-2-fluoro-4-methylaniline (440 mg, 99%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C.O>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)[C:16]=1[C:17]#[N:18]
Reactant: Oc1ccc2ccccc2c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1Oc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 106.9 %

Procedure:
To a 20 mL vial containing a magnetic stir bar was added sodium hydride (103.7 mg, 4.32 mmol, 60% in mineral oil) followed by anhydrous DMF (2 mL) resulting in gas evolution. To this stirring reaction mixture was added 2-naphthol (623 mg, 4.32 mmol) as a solid in small portions over 5 min. The mixture was stirred at room temperature for 3 min and then 2,6-difluorobenzonitrile (601 mg, 4.32 mmol) in anhydrous DMF (4 mL) was added in one portion. The reaction mixture was heated in an oil bath at 100 ° C. for a total of 2 h and allowed to cool to room temperature. The reaction mixture was diluted with water (15 mL) and the resulting mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (3×20 mL), dried (Na2SO4), filtered and concentrated to give K-1 as brown solid (1.216 g) of sufficient purity (contained 2-naphthol) to be used in the subsequent step. 1H NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Br:31])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCCc1ccc(CCCCCCO)c(CCC(=O)OCC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)CCCCc1ccc(CCCCCCBr)c(CCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 75.9 %

Procedure:
A mixture of 0.673 g (1.65 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-(6-hydroxyhexyl)benzenepentanoic acid ethyl ester from the preceding example, 1.1 g (3.3 mmol) of carbon tetrabromide, and 0.9 g (3.3 mmol) of triphenylphosphine in 25 mL of ether was stirred at room temperature for 23 hr. The mixture was diluted with 250 mL of ether, and the solution worked-up in the usual manner. The crude product was purified by flash chromatography on 80 g of silica gel, eluting with hexane-ethyl acetate (10:1). There was obtained 0.588 g (75.7%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[S:34]([CH3:37])(=[O:36])=[O:35])=[O:17])[CH2:19][CH2:20]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Reactant: C[C@H]1CNS(=O)(=O)C1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)CS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 40.3 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (140 mg) described in Preparation Example 4 and (4-bromo-2-methanesulfonylphenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (330 mg) described in Preparation Example 126 and by the reaction and treatment in the same manner as in Example 4, the title compound (148 mg) was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:15]1([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 600 mg, 3.00 mmol) in dry DCM (10 ml) was added cyclobutanone (CAS number 1191-95-3; 248 μl, 3.30 mmol), acetic acid (257 μl, 4.49 mmol) and molecular sieves. The reaction was then stirred at room temperature for 1 hour. To this was then added sodium triacetoxyborohydride (952 mg, 4.49 mmol) and the reaction was allowed to stir at room temperature for 17 hours. The reaction was basified by the addition of 2M NaOH (aq) and the organics were extracted DCM, filtered through a hydrophobic frit and concentrated in vacuo.
Reaction SMILES: C[O-].[Na+].[C:4]([O:8][C:9]([N:11]([CH2:45][C@H:46]([OH:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH2:32][CH2:33][C:34]([O:36]C)=O)(=[O:31])=[O:30])=[O:27])=[C:22]([O:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:21]=2)=[CH:16][CH:15]=1)=[O:10])([CH3:7])([CH3:6])[CH3:5].C([NH2:56])=O>>[NH2:56][C:34](=[O:36])[CH2:33][CH2:32][S:29]([NH:28][C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][N:11]([CH2:45][C@H:46]([OH:53])[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:15][CH:16]=2)=[CH:21][C:22]=1[O:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:27])(=[O:30])=[O:31]
Reactant: COC(=O)CCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCC(N)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Sodium methoxide (38.1 mg) was added to a solution of methyl 3-[[[[4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]carbonyl]amino]sulfonyl]propanoate (125 mg) in formamide (2.0 ml) at room temperature. The mixture was stirred for 1.5 hours at 60° C. The product was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl [2-[4′-[[[(3-amino-3-oxopropyl)sulfonyl]amino]carbonyl]-3′-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (22.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15]OS(C)(=O)=O)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([O:23][CH3:24])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][CH2:15][N:36]3[CH2:35][CH2:34][N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])[CH2:38][CH2:37]3)=[C:9]([CH3:21])[C:8]=2[CH:22]=1)[CH3:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOc1cc2c(C)c(CCOS(C)(=O)=O)c(=O)oc2cc1OC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOc1cc2c(C)c(CCN3CCN(c4ccccc4OC)CC3)c(=O)oc2cc1OC
Yield: 54 %

Procedure:
Process A; starting materials: 6-ethoxy-3-[2-(methanesulphonyloxy)ethyl]-7-methoxy-4-methyl-2H-1-benzopyran-2-one (Example 29) and 1-(2-methoxyphenyl)piperazine; yield 54%; m.p. 143°-145° C. (from ethanol/chloroform).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH2:14][CH:10]([C:11]([OH:13])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:18]1([NH:17][C:11]([CH:10]2[CH2:14][CH2:15][CH2:16][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]2)=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of N-Boc-nipecotic acid 33 (102 mg, 0.445 mmol) and aniline (41 μL, 1.0 eq.) in 2 mL of dry CH2Cl2 was added DCC-resin (430 mg). The reaction mixture was shaken at room temperature overnight. Filtration and removal of the solvent gave oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford 1-Boc-piperidine-3-carboxylic acid phenyl amide 34 as a colorless oil (120 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2.[CH3:22][N:23]([CH:25](N(C)C)OC(C)(C)C)[CH3:24]>CN(C)C=O>[CH3:22][N:23]([CH:25]=[C:10]1[C:11]2[C:7](=[CH:6][C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:2]=3[F:1])=[C:13]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:8][CH2:9]1)[CH3:24]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: O=[N+]([O-])c1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Solvent: CN(C)C=O
Product: CN(C)C=C1CCc2cc(Oc3ccc(F)cc3F)c([N+](=O)[O-])cc21

Procedure:
4.58 g of 5-(2,4-difluorophenoxy)-6-nitroindan and 8.2 g of bis(dimethylamino)tert.-butoxymethane were stirred in 5 ml of dimethylformamide for 60 minutes at 140° C. Concentration under vacuum yielded crude 1-dimethylaminomethylene-5-(2,4-difluorophenoxy)-6-nitroindan.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCCC1>[O:20]1[CH2:21][CH2:22][N:17]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:18][CH2:19]1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCOCC1)c1ccccc1-2
Reaction time: 20 h
Yield: 42.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was suspended in 5 ml of dry tetrahydrofuran, while cooling in an ice bath. Morpholine(0.37 ml, 4.27 mmol) dissolved in 2 ml of dry tetrahydrofuran was added over 2 min. After 1 hour the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran, 10% acetic acid, water and dried to give 0.365 g of the crude product. Recrystallization from ethanol afforded 0.257 g (42%) of the title compound. M.p. 265°-267° C. 1H-NMR (DMSO-d6, δ): 2.47 (m, 2H), 2.61 (m, 2H), 3.56 (m, 4H), 4.54 (s, 1H), 7.13 (t, 1H), 7.3 (t, 1H), 7.47 (d, 1H), 7.53 (d, 1H), 11.8 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([OH:13])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[C:16]([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:8]1[CH:12]=[C:11]([O:13][CH3:16])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cnn(Cc2ccccc2)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 1-benzyl-1H-pyrazol-4-ol (compound 244.2, 1.40 g, 8.04 mmol) in N,N-dimethylformamide (20 mL). Iodomethane (703 μL, 11.3 mmol) and Cs2CO3 (3.68 g, 11.3 mmol,) were added and the resulting mixture was stirred for 3 h at room temperature. The mixture was concentrated under reduced pressure, then diluted with EtOAc (200 mL). The mixture was washed with brine (3×80 mL), and the organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as a yellow oil (1.30 g, 86%).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(#N)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:17])=[C:10]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl(2-bromo-4-chlorophenoxy)acetate (350 mg; 1.09 mmol) and phenylacetylene (Aldrich; 122 mg; 1.20 mmol) in degassed, anhydrous ACN (2.80 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (38 mg; 0.05 mmol), copper(I) iodide (10 mg; 0.05 mmol) and triethylamine (0.45 mL; 3.26 mmol). The reaction mixture was heated at 50° C. under stirring for 16 hours. The solvent was evaporated, the residue dissolved in DCM (4 mL) and TFA (1 mL) was added. After stirring for 45 minutes, the solvents were removed under vacuum and the crude product purified by preparative HPLC. The title compound was obtained as a brown solid.
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][C:4]1=[O:13])=[N-:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[C:15]#[CH:16]>C1(C)C(C)=CC=CC=1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][C:4](=[O:13])[N:1]3[N:2]=[C:15]([C:14]([O:18][CH2:19][CH3:20])=[O:17])[CH:16]=[C:3]3[C:11]=2[CH:10]=1
Reactant: C#CC(=O)OCC
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(Cl)cc21
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c3cc(Cl)ccc3[nH]c(=O)n2n1
Temperature: 25 °C
Yield: 88 %

Procedure:
Seven and one-half g (0.039 mole) of 3-diazo-5-chloro-oxindole and 8.4 g (0.086 mole) of ethyl propiolate are dissolved in 400 ml of xylene and heated to reflux (under nitrogen) for 1.5 hours, during which time a copious amount of solid forms. The reaction mixture is cooled to room temperature, filtered, washed with ether and dried to give 10 g (88% yield) of TLC pure material. This is crystallized from chloroform/methanol (4:1) and then from methanol to give 8.1 g of analytically pure compound.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=O)=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1>>[O:12]1[C:17]2[CH:18]=[CH:19][C:20]([CH2:22][NH:4][C:3]3[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=3[CH3:1])=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: Cc1c(NCc2ccc3c(c2)OCCO3)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitroaniline and 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH:28]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17]2)=[O:10].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][C:27]1[CH:26]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]=2[F:1])[CH:28]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17]2)=[O:10]
Reactant: CCOC(=O)c1cc2cccc(NC(=O)c3cc(OCc4ccccc4F)cc(OCc4ccccc4F)c3)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cccc2cc(C(=O)O)[nH]c12)c1cc(OCc2ccccc2F)cc(OCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a mixed solution of ethyl 7-({3,5-bis[(2-fluorobenzyl)oxy]benzoyl}amino)-1H-indole-2-carboxylate (170 mg) in tetrahydrofuran (8 mL)-methanol (8 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (150 mg), and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (147 mg, yield 91%) as colorless crystals. melting point 271-273° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([N:6]2[CH:7]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][C:3]4[N:4]=[CH:5][N:6]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[CH:7]=4)[CH2:22][CH2:21]3)[N:4]=[CH:5]2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-n2cnc(CCl)c2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-n2cnc(CN3CCN(Cc4cn(-c5cc(OC)c(OC)c(OC)c5)cn4)CC3)c2)cc(OC)c1OC

Procedure:
4-Chloromethyl-1-(3,4,5-trimethoxyphenyl)imidazole (87 mg) and piperazine (13 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: OCCCF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCF)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
5 g of 3-fluoro-propanol (64.03 mmol) and 18 ml of triethylamine (129.32 mmol) were dissolved in 50 ml of dichloromethane. At 0-5° C., 12.9 g toluene-4-sulfonylchloride (67.66 mmol) were added and the reaction mixture stirred at room temperature for 18 h. Standard work-up yielded 13.7 g of toluene-4-sulfonic acid 3-fluoro-propyl ester.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14]O)=[CH:5][CH:4]=1.O1CCCC1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1>[Cl:25][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=1
Reactant: OCc1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(-c2oncc2CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of 5-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (5.65 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (4.15 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated and recrystallized from ethyl acetate-hexane to give 4-chloromethyl-5-(4-trifluoromethylphenyl)isoxazole (4.70 g, yield 77%) as a colorless prism. melting point: 99–100° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46][C:47]1[N:52]=[C:51](O)[CH:50]=[CH:49][CH:48]=1>O.C1COCC1>[Cl:46][C:47]1[N:52]=[C:51]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:50]=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cccc(Cl)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
Diethyl azodicarboxylate (11 ml, 40% Tol solution) was dropwise added to a THF (30 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (4.6 g), triphenylphosphine (6.1 g) and 6-chloro-2-pyridinol (2.0 g) at 0° C., followed by stirring at room temperature for 24 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (3.8 g).