Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48].O>C1(C)C=CC=CC=1>[Br:48][CH2:26][C:11]1[CH:12]=[C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CO)c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(CBr)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
To a solution of (2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-yl)methanol (472 mg) and triphenylphosphine (675 mg) in toluene (10 mL) was added carbon tetrabromide (635 mg), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (434 mg) as a colorless oil.
Reaction SMILES: [ClH:1].[C:2]([CH2:4][CH:5]([CH2:11][S:12]C(=O)C)[CH2:6][S:7][C:8](=[O:10])[CH3:9])#[N:3].CO>O1CCCC1>[C:8]([S:7][CH2:6][CH:5]1[CH2:11][S:12][C:2](=[NH:3])[CH2:4]1)(=[O:10])[CH3:9].[ClH:1]
Reactant: CC(=O)SCC(CC#N)CSC(C)=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)SCC1CSC(=N)C1

Procedure:
Gaseous HCl is passed during 0.5 hour through a solution of 3 g of 2-cyanomethyl-1,3-bis(acetylthio)propane, obtained according to Example XIX e), and 1.8 g of methanol in 30 ml tetrahydrofurane; temperature 40°-55° C. The solution is evaporated; diethylether is added to the residue. The precipitate formed is aspirated off, washed with diethylether and dried. The second title compound, viz. 4-acetylthiomethyl-2-iminothiolane is obtained as its HCl sale in a yield of 600 rag; m.p. 186°-188° C. (decomp.). Identification by 1H NMR and 13C NMR. The compound can equally be converted to the free base.
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:9][C:10]([O:12]CC)=[O:11].Cl.[CH3:16][S:17]([C:20]1[CH:35]=[CH:34][C:23]([CH2:24][N:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)N)=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[F:33][C:30]1[CH:29]=[C:28]2[C:27](=[CH:32][CH:31]=1)[N:25]([CH2:24][C:23]1[CH:34]=[CH:35][C:20]([S:17]([CH3:16])(=[O:19])=[O:18])=[CH:21][CH:22]=1)[C:2]1[CH:3]([CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]2=1
Reactant: CS(=O)(=O)c1ccc(CN(N)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CC1CCCCCC1=O
Agent: Cl
Product: CS(=O)(=O)c1ccc(Cn2c3c(c4cc(F)ccc42)CCCCC3CC(=O)O)cc1

Procedure:
Following the procedure of Example 1, but using ethyl 2-oxo-cycloheptaneacetate and 1-(p-methylsulfonylbenzyl)-1-(p-fluorophenyl)hydrazine hydrochloride as starting materials, the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:13][NH:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C:25](=[NH:28])OC)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][N:12]([C:25](=[NH:28])[NH:24][C:22]([O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:23])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CNC1
Reactant: COC(=N)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CN(C(=N)NC(=O)OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
0.9 g (4.8 mmol) of 3-(N-tert-butyloxycarbonylaminomethyl) azetidine and 1.3 g (6.3 mmol) of N-benzyloxycarbonyl-O-methylisourea was mixed in 6.5 mL toluene and heated to 70° C. for 72 h and then left at roomtemperature for another 72 h. Evaporation followed by flash chromatography using EtOAc followed by MeOH (saturated with NH3 (g))/CH2Cl2, 1/9, as eluent gave 0.67 g (38%) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Ni]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cnccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cnccc1OCc1ccccc1

Procedure:
4-(benzyloxy)-3-nitropyridine (15 g, 65 mmol, 1 eq) was dissolved in THF, then Raney Nickel (2.25 g, 10% w/w) (washed with THF) was added under nitrogen atmosphere and the reaction was stirred at room temperature with 2 kg hydrogen pressure for 6 h. The reaction solution was filtered through celite and the filtrate was concentrated under vacuum to get brown oil. The product was taken to the next step without purification. Yield: 12.3 g (94%). 1HNMR (400 MHz, DMSO-d6): δ 4.86 (s, 2H), 5.18 (s, 2H), 6.88 (d, 1H, J=5.32 Hz), 7.31 (t, 1H, J=3.90 Hz), 7.4 (t, 2H, J=5.08 Hz), 7.5 (t, 2H, J=8.08 Hz), 7.71 (d, J=2.05 Hz, 1H), 7.89 (s, 1H).
Reaction SMILES: [Na].Cl[C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4]=1[C:5]([CH3:18])=[CH:6][CH:7]=[N:8]2.N1C=CC=CC=1.[CH3:25][OH:26]>>[CH3:25][O:26][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4]=1[C:5]([CH3:18])=[CH:6][CH:7]=[N:8]2
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Cl
Reactant: CO
Agent: [Na]
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC

Procedure:
To a solution of sodium metal (4.8 g, 0.2 g. atom) in methanol (300 ml) were added 50.6 g (0.2 mole) of 5-chloro-6-methoxy-4-methyl-8-nitroquinoline and 70 ml of pyridine. The mixture was stirred under reflux for 48 hr, treated with carbon and filtered hot. The residue was washed with hot methanol and the filtrate and washings were combined (total, 600 ml). On standing, 15 g of 5,6-dimethoxy-4-methyl-8-nitroquinoline, separated, mp 120°-124°. The filtrate was concentrated to 200 ml and cooled overnight to give an additional 15 g of 5,6-dimethoxy-4-methyl-8-nitroquinoline. Dilution of this filtrate with 6 liters of water provided 7 g of product for a total crude yield of 37 g. Crystallization from methanol (carbon) gave 34 g (68%) of 5,6-dimethoxy-4-methyl-8-nitroquinoline, mp 123°-125°. The same compound (m.p. and mixed m.p. 123°-125°) resulted when a Skraup reaction was performed on 4-amino-5-nitroveratrole and methyl vinyl ketone.
Reaction SMILES: C([N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]1[CH2:10][C:9]([CH:11]=O)=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])(=O)C.N1C=CC=CC=1.Cl.[CH3:35][O:36][NH2:37]>CO>[C:24]([O:23][C:21]([NH:4][N:5]1[CH2:10][C:9](/[CH:11]=[N:37]/[O:36][CH3:35])=[N:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6]1=[O:20])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CON
Reactant: CC(=O)N(C(=O)OC(C)(C)C)N1CC(C=O)=NN(C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CO/N=C/C1=NN(C(=O)OC(C)(C)C)C(=O)N(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl 4-[acetyl(tert-butoxycarbonyl)amino]-6-formyl-3-oxo-5H-1,2,4-triazine-2-carboxylate (1.15 g, 3.00 mmol) in MeOH (1.8 mL) at room temperature was added pyridine (0.88 mL, 10.9 mmol) followed by O-methylhydroxylamine HCl salt (376 mg, 4.50 mmol). The obtained mixture was stirred for 20 h at room temperature and then concentrated under reduced pressure. The residual was redissolved in EtOAc, washed with water and dried (Na2SO4). After evaporation of the solvent, the crude product was obtained as a viscous oil which was used in the subsequent step without further purification. LCMS (Method I) RT 1.77 min. [M+H]+ 372.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:16]([C:18]1([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20][CH2:19]1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].ClCCCl>CCOCC>[CH3:24][C:21]1([CH3:25])[O:20][CH2:19][C:18]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH2:16][NH:13][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:23][O:22]1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCCl
Product: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Yield: 71.3 %

Procedure:
To a mixture of 4-n-octylaniline (0.21 g; 1 mmol), tert-butyl 5-formyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate (Ooii et al, J. Org. Chem., 2004, 69, 7765; 0.26 g; 1 mmol) and NaBH(OAc)3 (0.3 g; 1.4 mmol) in 1,2-dichloroethane (3.5 ml) AcOH (0.06 ml; 1 mmol) was added at room temperature with stirring under N2. After stirring for 2 h, the mixture was diluted to 20 ml with Et2O, washed with 1.M NaOH (2×5 ml), brine and dried over anhydrous MgSO4 and filtered. The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in hexane (5 ml) and kept in the freezer (−18° C.) overnight. The crystals formed were filtered off, washed with small volume of hexane and dried to give the title compound (0.32 g; 71%), as colourless crystals. 1H-NMR (CDCl3) 6.96 (d, 2H, J=8.4 Hz); 6.58 (d, 2H, J=8.4 Hz); 4.84 (broad s, 1H); 4.01 (d, 2H, J=11.9); 3.85 (broad s, 1H); 3.8 (d, 2H, J=11.9 Hz); 3.44 (s, 2H); 2.46 (t, 2H, J=7.9 Hz); 1.5 (m, 2H); 1.45 (s, 3H); 1.43 (s, 9H); 1.42 (s, 3H); 1.26 (m, 10H); 0.86 (t, 2H, J=6.95 Hz).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[NH:31][C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.Cl[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([Cl:41])=[C:23]([C:37]([Cl:40])=[CH:38][CH:39]=2)[CH2:24][O:25][C:26]2[C:34]3[N:33]=[C:32]([O:35][CH3:36])[N:31]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=4)[C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccn1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(C)=O)nc4)c3Cl)cccc2n1Cc1ccccn1
Reaction time: 28 h
Yield: 43.4 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole (100 mg) and 2-chloromethylpyridine hydrochloride (29 mg) in N,N-dimethylformamide (2 ml) was added potassium carbonate (93 mg) at ambient temperature, and the mixture was stirred for 28 hours at the same temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=12:1, V/V; chloroform:methanol=12:1, V/V) to give 4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-pyridylmethyl)-1H-benzimidazole (50 mg) as an amorphous powder.
Reaction SMILES: [Na].[H-].[Na+:3].Cl[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14]([O-:17])(=[O:16])=[O:15].[Na+].[CH3:19][CH2:20][O:21][CH2:22][CH2:23][OH:24]>>[CH2:20]([O:21][CH2:22][CH2:23][O:24][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14]([O-:17])(=[O:16])=[O:15])[CH3:19].[Na+:3]
Reactant: CCOCCO
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: CCOCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of sodium 2-ethoxyethylate prepared by adding 7.3 g of sodium hydride (14.6 g of 50% suspension in liquid paraffin) to 300 ml of ethyl Cellosolve was added 55 g of sodium 2-chloro-5-nitrobenzenesulfonate. The reaction mixture was heated at 80° to 85° C. with stirring for 30 minutes. After completion of the reaction, the insoluble materials were removed by filtration and from the filtrate 150 ml of ethyl Cellosolve was distilled off under reduced pressure. To the concentrated solution was added 300 ml of isopropyl alcohol and the mixture was cooled with ice. The crystals which thus precipitated were recovered by filtration, washed with 100 ml of isopropyl alcohol and air-dried. Yield: 33 g; Melting Point: 248° to 249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][C@@H:41]([CH2:45][OH:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:29])([F:31])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH:41]([CH2:45][OH:46])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C(CO)C1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 3-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C[O-].[Na+:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:38]
Reactant: O=C(NC(CO)Cc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NC(CO)Cc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To a solution of 6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.087 g, 0.168 mmol) in methanol (2 ml) was added 0.5M sodium methanolate in methanol (0.354 ml, 0.177 mmol), and the reaction was stirred for 2 hours. It was concentrated, taken up in dichloromethane and hexanes, and concentrated again to yield 87 mg of the title compound (95.9% yield). MS (apci) m/z=515.9 (M−Na+2H).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:5])([CH3:4])[CH3:3].[CH2:23]([C@H:25]1[O:27][CH2:26]1)[Cl:24]>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].O>[C:2]([O:6][C:7](=[O:22])[C@@H:8]([NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:26][C@H:25]([OH:27])[CH2:23][Cl:24])([CH3:5])([CH3:3])[CH3:4]
Reactant: ClC[C@@H]1CO1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC[C@H](O)CCl)C(=O)OC(C)(C)C
Yield: 39 %

Procedure:
A solution of 3 (4.83 g, 14.3 mmol) in chloroform (100 mL) was extracted with saturated NaHCO3 solution (2×100 mL) and water (100 mL). The organic layer was dried, concentrated, and further dried in vacuo. The resulting oil was dissolved in cyclohexane (26 mL), and (S)-(+)-epichlorohydrin (1.58 g, 17.1 mmol) was added under an Ar atmosphere. The precipitated product was filtered after 27 h, washed with cold cyclohexane, and dried in vacuo to give 12a (2.20 g, 39%) as a fine, white powder: mp 87-88° C.; 1H NMR δ 1.30-1.83 (m, 6H), 1.44 (s, 9H), 1.46 (s, 9H), 2.57-2.66 (m, 3H), 2.77 (dd, 1H, J=12.2, 3.9), 3.51 (dd, 1H, J=11.2, 5.7), 3.56 (dd, 1H, J=11.2, 5.2), 3.84-3.91 (m, 1H), 3.94 (dd, 1H, J=8.6, 5.3); 13C NMR 6 24.6, 28.3, 28.7, 30.0, 32.6, 48.2, 50.3, 53.5, 55.8, 71.1, 80.4, 82.5, 158.1, 173.8; HRMS m/z calcd for C18H36ClN2O5 395.2313, found 395.2303. Anal. calcd. for C18H35ClN2O5: C54.74, H 8.93, Cl 8.98, N 7.09. Found: C 54.80, H. 8.99, Cl 9.02, N 7.08 [α]22D−26.1° (c 1.00, CH3OH).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].O1CCCC1.[CH3:11][C:12](=O)[CH2:13][C:14](=[O:16])[CH3:15]>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:12]([CH3:11])=[CH:13][C:14](=[O:16])[CH3:15]
Reactant: COCCN
Reactant: CC(=O)CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COCCNC(C)=CC(C)=O
Reaction time: 8 h

Procedure:
7.50 g of 2-Methoxyethylamine (0.1 moles) were dissolved into 100 ml of tetrahydrofuran to which 10.0 g of 2,4-pentanedione (0.1 moles) were added dropwise over 5 minutes. The resulting mixture was then stirred overnight after which time the solvent and water of condensation formed during the reaction was removed by vacuum distillation. The final product was then vacuum distilled as a clear liquid. Yield of MeC(O)CH2C(NCH2CH2OMe)Me=11.8 g (75% of theoretical).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13](O)([CH3:16])([CH3:15])[CH3:14].S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: Brc1ccc(-c2nn[nH]n2)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(-c2ccc(Br)cc2)n1
Yield: 70.9 %

Procedure:
5-(4-Bromophenyl)-2H-tetrazole (19.0 g. 81.9 mmol), t-butanol (12.1 g. 164 mmol). trifluoroacetic acid (80 mL) and concentrated sulfuric acid (4.6 g, 41 mmol) were stirred at ambient temperature for 24 hours. The mixture was concentrated and dissolved in ethyl acetate (200 mL). After washing with water (3×25 mL), 1M NAOH (3×25 mL) and brine (25 mL) the organic layer was dried (Na2SO4), filtered and concentrated. The oil was purified by chromatography on a Waters Prep 500 liquid chromatograph fitted with two silica gel cartridges eluting with a mixture of hexanes and ethyl acetate (9:1) to provide 5-(4-bromophenyl)-2-(1,1-dimethylethyl)-2H-tetrazole (17.1 g. 58.1 mmol) as a yellow oil in 71% yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[N:5]2[CH:31]=1.[Cl:32][C:33]([Cl:38])([Cl:37])[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:21])([F:23])[F:22])(=[O:19])=[O:18])[N:5]2[C:31]=1[C:34](=[O:35])[C:33]([Cl:38])([Cl:37])[Cl:32]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cn2c(CN(CCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)cccc2n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccc(CN(CCCCNS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C)n2c1C(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Yield: 64.9 %

Procedure:
To a solution of 2.90 g (6.24 mmol) of 2-methyl-5-[N-tert-butoxycarbonyl-N-[4-(trifluoromethane-sulfonamido)butan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 2.29 g (18.73 mmol) of 4-dimethylaminopyridine in 25 ml of chloroform was added dropwise, for 3 minutes, 2.1 ml (18.73 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 20 hours under reflux. The reaction mixture was then poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution and dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.47 g of the desired compound (65.2%, pale yellow liquid).
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].O1CCN([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)CC1.O(C)[Na]>C1COCC1>[C:20]1([CH:21]=[CH:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:23]=[CH:24][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Reactant: O=C(CO)c1ccccc1
Agent: CO[Na]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Yield: 83.5 %

Procedure:
2.5 g (15.8 mmol) of 2-hydroxyacetophenone, 2.8 g of 4-morpholinobenzaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH3 were reacted in 50 ml of dry THF to give 2.52 g (56%) of chalcone after purification. 1H NMR (300 MHz, CDCl3): δ 12.99 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.93-7.84 (m, 3H), 7.52-7.48 (m, 2H), 7.03 (d, d, J=0.9, 8.4 Hz, 1H), 6.97-6.92 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 3.86-3.83 (m, 4H), 3.69-3.66 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:18]([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Yield: 82 %

Procedure:
(a)(b) To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (800 mg, 2.5 mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (1 mL, 6.25 mmol) in 30 mL of dry DCM was added TiCl4 (2.5 mL of 1.0 M DCM solution, 2.5 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, concentrated to give methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoat. Crude methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoate was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, concentrated in vacuo, and purified by HPLC to give 770 mg (82% yield, 2 steps) of acid 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoic acid. MS found: (M+H)+=375.