Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][OH:24])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N-]>C(Cl)Cl>[CH2:1]([N:8]([CH3:29])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:25])([CH2:23][O:24][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:16]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:17])=[CH:11][C:10]=1[N+:26]([O-:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CN(Cc1ccccc1)c1ccc(C(C)(CO)C(=O)N2CCCC2)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)COCC(C)(C(=O)N1CCCC1)c1ccc(N(C)Cc2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A solution of 8.0 g (20 mmol) of 2-[4-(N-benzyl-methylamino)-3-nitro-phenyl]-2-methyl-3-hydroxy-1-pyrrolidino-propan-1-one and 5 ml (48 mmol) of ethyl diazoacetate in 50 ml of methylene chloride is mixed with 2.0 ml of boron trifluoride-diethylether complex (16 mmol) at room temperature and refluxed for 14 hours. After cooling, the reaction solution is stirred into ice water and the organic phase is separated off. The aqueous phase is extracted three times with methylene chloride, the combined organic phases are washed with saline solution, dried over sodium sulphate and concentrated by evaporation. The residue is dissolved in ethyl acetate and purified on silica gel, extracting initially with petroleum ether, then with petroleum ether/ethyl acetate (1:1). The uniform fractions are combined and concentrated by evaporation.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[S:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]=[N:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:32]([C:30]4[N:29]=[N:28][S:27][CH:31]=4)=[O:33])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(O)c1csnn1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5csnn5)c4)CC3)cccc2n1
Yield: 75 %

Procedure:
The title compound was prepared in 75% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 1,2,3-thiadiazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].Cl[C:16]1[N:17]([CH2:24][C@:25]2([CH3:28])[CH2:27][O:26]2)[CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[N:20]=1>CN(C=O)C>[CH3:27][C@@:25]1([CH2:28][O:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=2)[O:26][C:16]2=[N:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][N:17]2[CH2:24]1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(COc2ccc(OC(F)(F)F)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
4-Trifluoromethoxyphenol (1.1 g, 6.17 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (260 mg, 6.45 mmol) was added at room temperature, and the solution was stirred for 15 minutes at 80° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (1.22 g, 5.61 mmol) was added with cooling on ice-bath, and the solution was stirred for further 2 hours at 80° C. The reaction mixture was poured into ice-water, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and and then crystallized from methylene chloride-diisopropyl ether to afford (R)-2-methyl-6-nitro-2-(4-trifluoromethoxyphenoxymethyl)-2,3-dihydroimidazo[2,1-b]oxazole (1.03 g, yield 51%) as a white powder.
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1)C)C.C([Li])CCC.CN(C)[CH:22]=[O:23]>CCOCC>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:22]=[O:23]
Reactant: CCOC(C)Oc1cccc(OC)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(O)c1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 3-(1-ethoxyethoxy)anisole was dissolved in ether (750 ml) and n-butyllithium (1.6M solution in hexanes; 500 ml) was added dropwise at ambient temperature under nitrogen. The mixture was stirred at ambient temperature for 2 hours, then it was cooled to 10° C. and a solution of dimethylformamide (94 g) in ether (150 ml) was added dropwise. The mixture was stirred at ambient temperature for 2 hours, then poured onto crushed ice. The product was extracted into ether, the combined extracts dried over magnesium sulphate, and the solvents removed in vacuo. The residual oil was dissolved in methanol (500 ml) and the stirred solution was cooled in ice and made strongly acidic by the addition of hydrochloric acid (2M). The resulting solid was collected by filtration, washed with water, dried in vacuo over phosphorus pentoxide and crystallised from petroleum ether (b.p. 60°-80° C.) to give 2-hydroxy-6-methoxybenzaldehyde as pale yellow needles (16 g), m.p. 69°-71° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:19]([NH2:22])(=[O:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[N:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:19](=[O:21])[CH3:20])[CH:7]=1
Reactant: CC(N)=O
Reactant: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2cnc([N+](=O)[O-])cc2C)ccn1
Temperature: 90 °C
Yield: 63.8 %

Procedure:
A solution of 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (0.52 g, 1.957 mmol) in dioxane (15 mL) was sparged with Ar, treated with acetamide (0.347 g, 5.87 mmol), Cs2CO3 (0.638 g, 1.957 mmol), X-Phos (0.093 g, 0.196 mmol) and Pd2(dba)3 (0.179 g, 0.196 mmol) and heated at 90° C. overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth, washed with EtOAc and the filtrate was washed with water, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford N-(4-((4-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (360 mg, 64%). 1H NMR (400 MHz, DMSO-d6): δ 10.66 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 8.24 (d, J=5.7 Hz, 1H), 7.72 (d, J=2.4 Hz, 1H), 6.74 (dd, J=5.7, 2.4 Hz, 1H), 2.33 (s, 3H), 2.05 (s, 3H); MS (ESI) m/z: 289.1 (M+H+).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:23]([F:26])([F:25])[F:24])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([C:18]1[CH:22]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=1[C:23]([F:26])([F:24])[F:25])=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)csc1C
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-fluoro-2-(trifluoromethyl)benzoyl chloride (36.2 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3 H) 1.29-1.38 (m, 2H) 1.56-1.69 (m, 2 H) 2.28-2.32 (m, 3 H) 3.91-4.00 (m, 2 H) 6.00-6.05 (m, 1 H) 6.58-6.62 (m, 1 H) 7.37-7.45 (m, 2 H) 7.77-7.86 (m, 1 H); MS (ESI) positive ion 360 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[C:13]([CH2:17][CH2:18][C:19](OCCCC)=[O:20])[C:12](=[O:26])[NH:11]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[OH:20][CH2:19][CH2:18][CH2:17][C:13]1[C:12](=[O:26])[NH:11][N:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:15](=[O:16])[CH:14]=1
Reactant: CCCCOC(=O)CCc1cc(=O)n(Cc2ccc(OC)cc2)[nH]c1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2[nH]c(=O)c(CCCO)cc2=O)cc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
Butyl 3-(1-{[4-(methyloxy)phenyl]methyl}-3,6-dioxo-1,2,3,6-tetrahydro-4-pyridazinyl)propanoate (0.43 g, 1.19 mmol) was dissolved in dry THF (20 ml). The solution under argon was cooled to −30° C., treated dropwise with a 1M solution of lithium aluminium hydride in THF (1.4 ml, 1.4 mmol), allowed to warm gradually to 0° C. and stirred in an ice bath for 30 minutes. 2M Hydrochloric acid was added until the pH was 3 and the mixture was partitioned between water and ethyl acetate. The aqueous was re-extracted with ethyl acetate and the combined organic solution dried and evaporated. The resulting solid was triturated under ethyl acetate, filtered off, washed with ethyl acetate and dried under vacuum to give the product (241 mg, 70%).
Reaction SMILES: [CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26]O)=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2].S(Cl)([Cl:31])=O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:3]([C:12]1[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][C:23]([CH2:26][Cl:31])=[CH:24][N:25]=1)=[CH:17]2)[S:4]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(c1ccc(C)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(c1ccc(C)c2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 1 h
Yield: 93 %

Procedure:
N-Ethyl-N-{2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}thiophene-2-sulfonamide (0.27 g) was dissolved in absolute tetrahydrofuran (10 ml). This solution was ice-cooled, thionyl chloride (0.080 ml) and N,N-dimethylformamide (one drop) were added, and the mixture was stirred for 1 hr under ice-cooling, and then at room temperature for 2 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oil was crystallized from ethyl acetate-hexane to give the title compound (0.26 g, yield 93%) as pale-yellow prism crystals. melting point 177-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]1)=[O:7].CN(C)CCCN>>[CH3:14][N:11]([CH3:10])[CH2:12][CH2:13][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Agent: CN(C)CCCN
Product: COc1cc(C(=O)NCCCN(C)C)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 188, on a 9.28 mmol scale utilising N,N-dimethylpropane-1,3-diamine (Aldrich; 948 mg, 9.28 mmol), as a brown solid (2.33 g, 90%)
Reaction SMILES: C(=O)([O:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:11]=[C:10]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=[O:32])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[CH:9]=1)OC(C)(C)C.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[CH:31]([C:27]1[CH:26]=[C:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:10]3[CH:9]=[C:8]([OH:7])[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[N:11]=3)[CH:20]=2)[CH:30]=[CH:29][CH:28]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2cccc(-c3cccc(C=O)c3)c2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: O=Cc1cccc(-c2cccc(-c3cc(O)n(-c4ccccn4)n3)c2)c1

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 37 of Example C-11 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][C:6]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO>[C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(C(C)(C)C)c(OCCOC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCCOc1cc(OCC(=O)O)ccc1C(C)(C)C
Temperature: 90 °C
Yield: 101.2 %

Procedure:
To a methanol (3 mL) solution of ethyl [4-tert-butyl-3-(2-methoxyethoxy)phenoxy]acetate (260 mg, 0.84 mmol) was added 2M potassium hydroxide solution (1 ml) at ambient temerature. The stirred mixture was refluxed at 90° C. for 30 minutes. The reaction mixture was then quenched with saturated aqueous solution of ammonium chloride and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to recrystallization from hexane to furnish 0.24 g (100% yield) of the title compound as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:24]#[C:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[N:28]4)=[N:19][CH:20]=3)[C:15]2=[O:32])=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[O:32]=[C:15]1[C:16]2[C:21](=[CH:20][N:19]=[C:18]([C:24]#[C:25][CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[CH:17]=2)[CH:22]=[CH:23][N:14]1[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:33])=[O:5])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2ccc3cnc(C#CCn4ccnn4)cc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Cn2ccc3cnc(C#CCn4ccnn4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 4-[1-oxo-7-(3-[1,2,3]triazol-1-ylprop-1-ynyl)-1H-6-azaisoquinolin-2-ylmethyl]benzoic acid tert-butyl ester (0.29 g, 0.66 mmol, Example 14A) is treated with trifluoroacetic acid (10 mL) and stirred at room temperature for 40 minutes. The reaction mixture is evaporated to dryness, triturated with ethyl acetate, the solid collect by filtration, washed with water, washed with ethyl acetate, and dried under house vacuum. This will afford the desired product.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=3)[NH:9][C:8]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:25]([O:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:30])[CH3:26]>>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N:16]4[CH:20]=[CH:19][CH:18]=[CH:17]4)[CH:14]=3)[NH:9][C:8]=2[C:21]([NH:30][C@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1[nH]c2ccc(-n3cccc3)cc2c1-c1ccccc1

Procedure:
Ethyl N-{[3-phenyl-5-(1H-pyrrol-1-yl)-1H-indol-2-yl]carbonyl}-L-phenylalaninate was prepared from 3-phenyl-5-(1H-pyrrol-1-yl)-1H-indole-2-carboxylic acid and L-phenylalanine ethyl ester hydrochloride followed the procedure of Example 2 Step 4 as a pale yellowish solid: 1H NMR (DMSO-d6) δ 1.12 (t, J=7.0 Hz, 3 H), 2.93 (dd, J=13.5, 6.2 Hz, 1 H), 3.05 (dd, J=13.5, 8.0 Hz, 1H), 4.08 (q, J=7.0 Hz, 2 H), 4.70 (dd, J=8.0, 6.2 Hz, 1 H 6.21 (t, J=2.0 Hz, 1 H), 6.95-7.05 (m, 1 H), 7.20-7.60 (m, 16 H), 11.89 (s, 1 H); MS (ESI) m/z 478 (MH+); MS (ESI) m/z 476 ([M-H]−); HRMS calcd for C30H28N3O3: 478.2131; found (ESI+): 478.2113; Anal. calcd for C30H27N3O3: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.30; H, 5,79; N, 8.72.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)O
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(3R,4R)-1-Benzyl-4-methyl-3-pyrrolidine carboxylic acid (6.27 g) was suspended in dichloromethane (250 mL). To this suspension, cyclopropylamine (1.76 mL) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.2 g) were sequentially added and the mixture was stirred at room temperature for 4 hours. Subsequently, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=10:1) to give (3R,4R)-1-benzyl-N-cyclopropyl-4-methyl-3-pyrrolidine carboxamide (3.32 g) as white crystals.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12]/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].[CH3:18][C:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>C1COCC1>[OH:23]/[C:22](/[C:19]1([CH3:18])[CH2:21][CH2:20]1)=[CH:16]\[C:15](=[O:17])/[CH:14]=[CH:13]/[O:12][CH3:11]
Reactant: CO/C=C/C(C)=O
Reactant: CC1(C(=O)Cl)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CO/C=C/C(=O)/C=C(\O)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
LiHMDS (1M in THF, 845 mmol) was added dropwise to a solution of trans-4-methoxy-3-buten-2-one [51731-17-0] (845 mmol) in THF (2 L) at −78° C. After stirring for 15 min, a solution of 1-methyl-cyclopropanecarbonyl chloride [16480-05-0] (407 mmol) in THF (100 mL) was added. The resulting mixture was allowed to warm to rt over 2.5 h and then quenched by addition of a saturated solution of NH4Cl. The mixture was extracted with Et2O (2×). The combined organic phases were successively washed with a saturated solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as a yellow solid. ESI-MS: [M+H]+ 183; TLC: Rf=0.29 (9:1 Hex/EtOAc).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=1)[C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])=O)(C)(C)C.[ClH:30].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:30].[NH2:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=1)[C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C[C@H](N)C(=O)NCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl [(S)-2-tert-butoxycarbonylamino-3-(4-but-2-ynyloxy-phenyl)-propionylamino]-acetate (141 mg, 0.349 mmol) was dissolved in ethyl acetate (2.0 mL), and 4 M hydrogen chloride/ethyl acetate (0.2 mL) was added. The mixture was stirred at room temperature for 18 hours.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCOCC>CN(C=O)C>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Reactant: COc1ccc(N)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(NCCn2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (1.00 g, 2.7 mM, prepared in Example 4a. and p-anisidine (1.33 g, 10.8 mM) were stirred and heated to reflux in DMF (20 mL) for 1.5 hours to give a brown solution. The solution was cooled to room temperature and ether (80 mL) was added to give a dark suspension. The suspension was stirred for two hours and filtered. The collected solids were washed with ether (150 mL) to give the title compound as a tan powder (1.17 g, 60%), mp 239-241° C.; MS(CI):413.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=2)=[O:5])[CH3:2].[S-:19][C:20]#[N:21].[NH4+].BrBr>CO>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:19][C:20]#[N:21])=[C:10]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C)(C)C)cc2[nH]1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cc2cc(SC#N)c(C(C)(C)C)cc2[nH]1

Procedure:
The title compound was prepared according to General Method 13 using 6-tert-butyl-1H-indole-2-carboxylic acid ethyl ester (prepared in Example YY; 3.5 g, 14 mmol), ammonium thiocyanate (1.63 g, 21.4 mmol), bromine (3.42 g, 21.4 mmol), and MeOH (50 mL). The crude product was purified by flash silica gel chromatography (5%-50% EtOAc in hexanes as eluents). MS(APCI): 301 (M−H).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:16](Br)([F:18])[F:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O.[Zn]>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:16]([F:18])[F:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(Br)Br
Reactant: O=CCCCCOCc1ccccc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: FC(F)=CCCCCOCc1ccccc1

Procedure:
Another multi-step synthesis of ethers started with the reaction of a commercially available alkylene diol, e.g., 1,6-pentanediol, with an alkyl or aralkyl halide, e.g., phenylmethyl bromide, in the presence of potassium hydroxide in xylene solvent, yielding 7-phenyl-6-oxaheptan-1-ol (XVI). Oxidation of (XVI) with pyridinium chlorochromate produced the corresponding aldehyde, 7-phenyl-6-oxaheptanal (XVII). Reaction of (XVII) with dibromodifluoromethane, triphenylphosphine, and powdered zinc in dimethylacetamide provided 6,6-difluoro-5-hexenyl phenylmethyl ether (XVIII). This synthesis is detailed in Example 11.
Reaction SMILES: [C:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd].CO>[CH:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CCCCC2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2CCCCC2)C1
Reaction time: 12 h
Yield: 93.1 %

Procedure:
A mixture of tert-butyl 9-(cyclohexa-1-en-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (160 mg, 0.486 mmol) and 10% palladium on carbon (100 mg) in methanol (5 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated to give the desired product (150 mg, 93.2%) as an oil.