Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[CH3:2].Br[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:9][C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH2:1][CH3:2])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CCc1cnccc1C
Reactant: Clc1ccc(CCCBr)cc1Cl
Product: CCc1cnccc1CCCCc1ccc(Cl)c(Cl)c1
Yield: 46.8 %

Procedure:
1.83 g (15.1 mmol) of 3-ethyl-4-methypyridine and 4.05 g (15.1 mmol) of 1-bromo-3-(3,4-dichlorophenyl)-propane were reacted in the same manner as in Example 26. The reaction product was purified to obtain 2.18 g of the desired compound (yield: 46.9%). The resulting compound was identified as 1-(3,4-dichlorophenyl)-4-(3-ethyl-4-pyridyl)-butane (hereinafter referred to as compound 51) by the following analytical results.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.F[C:16]1[C:17]([CH3:36])=[N:18][C:19]2[C:24]([N:25]=1)=[C:23]([C:26]1[NH:34][C:33]3[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=3[CH:27]=1)[CH:22]=[CH:21][CH:20]=2>CS(C)=O>[CH3:36][C:17]1[C:16]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)=[N:25][C:24]2[C:19]([N:18]=1)=[CH:20][CH:21]=[CH:22][C:23]=2[C:26]1[NH:34][C:33]2[CH2:32][CH2:31][NH:30][C:29](=[O:35])[C:28]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 4.3 %

Procedure:
Prepared according to Example 131, (S)-3-amino-1-Boc-piperidine (180 μL, 0.759 mmol, CNH Technologies, Inc., Woburn, Mass.), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 75 mg, 0.253 mmol), and DMSO (2.5 mL) stirring at 100° C. for 2. Purification by sequential column chromatography (silica gel: 0.5 to 10% MeOH/DCM) and reverse phase chromatography (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 95%) provided tert-butyl (3S)-3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-2-quinoxalinyl)amino)-1-piperidinecarboxylate (5.2 mg, 4.3%) as the free base after washing with saturated aq. NaHCO3, extracting with 10% MeOH/DCM, drying over Na2SO4, and concentrating under reduced pressure. 1H NMR (CDCl3) δ: 7.92-7.97 (m, 1H), 7.65-7.71 (m, 1H), 7.37-7.45 (m, 1H), 7.13 (s, 2H), 5.42 (br. s., 1H), 4.12 (s, 1H), 3.62-3.70 (m, 3H), 2.91-2.99 (m, 2H), 2.57 (s, 3H), 1.94-2.07 (m, 1H), 1.89-1.90 (m, 1H), 1.80-1.91 (m, 1H), 1.68 (s, 9H), 1.33-1.55 (m, 5H). m/z (ESI, +ve) 477.2 (M+H)+.
Reaction SMILES: [CH2:1]([Cl:3])Cl.C(Cl)(=O)C(Cl)=O.[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15]([C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([CH:40]([OH:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=C2>CS(C)=O>[Cl:3][C:1]1[C:18]2[C:17](=[CH:13][CH:12]=[C:11]([F:10])[CH:19]=2)[N:16]([CH3:20])[C:15]=1[C:21]([NH:23][C@H:24]([C:28]([NH:30][CH:31]([C:40](=[O:43])[CH2:41][F:42])[CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22]
Reactant: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Product: CC(C)[C@H](NC(=O)c1c(Cl)c2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
DMSO (0.60 mL, 8.5 mmol) was added to a methylene chloride solution of oxalyl chloride (2.1 mL, 2.0 M, 4.2 mmol, in 15 mL of methylene chloride), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at −78° C. A methylene chloride solution of N-[(5-fluoro-1-methylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (820 mg, 1.7 mmol, in 8 mL of dry methylene chloride), and DMSO (0.4 mL) were added dropwise to the reaction mixture and stirred for 15 minutes at −78° C. TEA (1.4 mL, 10.2 mmol) was added to the mixture dropwise and the mixture was stirred for 10 minutes at −78° C., then was allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous layer was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution and brine, dried over sodium sulfate, and concentrated to give the title product as a slightly yellow solid. Trituration with ether afforded the title product as a white powder (705 mg, 85%). TLC: (methanol/methylene chloride, 1:9): Rf=0.63. MS for C24H30ClF2N3O5: MH+=514/516; (M−H)−=512/514.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][N:5]([CH3:28])[C:6]1[N:11]=[CH:10][C:9]2[O:12][C:13]3[C:18]([C:19](=[O:20])[C:8]=2[CH:7]=1)=[CH:17][C:16]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:15][CH:14]=3>C1COCC1>[CH3:4][N:5]([CH3:28])[C:6]1[N:11]=[CH:10][C:9]2[O:12][C:13]3[C:18]([C:19]([CH3:1])([OH:20])[C:8]=2[CH:7]=1)=[CH:17][C:16]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:15][CH:14]=3
Reactant: CN(C)c1cc2c(=O)c3cc(-c4cccnc4F)ccc3oc2cn1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CN(C)c1cc2c(cn1)Oc1ccc(-c3cccnc3F)cc1C2(C)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methylmagnesium chloride, 22 wt % in THF (1.6 mL, 4.76 mmol), was added via syringe to a suspension of 3-(dimethylamino)-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one (0.53 g, 1.57 mmol) in THF (16 mL) at 0° C. The resulting solution was stirred at 0° C. for 1 h. The reaction was quenched with saturated aqueous ammonium chloride at 0° C. and diluted with water and extracted with DCM. The combined organic extracts were washed with a 9:1 mixture of aqueous saturated ammonium chloride/ammonium hydroxide, water, saturated aqueous sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:2 EtOAc in hexane, to provide 3-(dimethylamino)-7-(2-fluoropyridin-3-yl)-5-methyl-5H-chromeno[2,3-c]pyridin-5-ol as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16](=O)[NH2:17])=[CH:11][C:10]=1[CH2:19][CH3:20])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]#[N:17])=[CH:11][C:10]=1[CH2:19][CH3:20])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1cc(C(N)=O)cc(C)c1CCC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C#N)cc(C)c1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-(4-carbamoyl-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (30.0 g, 103 mmol) and NEt3 (31.3 g, 309 mmol) in DCM (300 mL), trifluoroacetic anhydride (23.8 g, 113 mmol) is added slowly. The exothermic reaction is kept below 5° C. with cooling. After complete addition, the mixture is stirred at rt for 1 h. The mixture is washed twice with water (2×300 mL) and the org. extract is evaporated to dryness to give 3-(4-cyano-2-ethyl-6-methyl-phenyl)-propionic acid tert-butyl ester (28.4 g) as a pale yellow oil; 1H NMR δ 1.25 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 2.32-2.37 (m, 2H), 2.38 (s, 3H), 2.70 (q, J=7.5 Hz, 2H), 2.95-3.02 (m, 2H), 7.30 (s, 1H), 7.34 (s, 1H).
Reaction SMILES: CS[C:3]([S:14][CH3:15])=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13].[CH2:16]([SH:18])[CH3:17].[CH3:19][O-].[Na+]>CO>[CH2:16]([S:18][C:3]([S:14][CH2:15][CH3:19])=[C:4]1[C:9](=[O:10])[O:8][C:7]([CH3:12])([CH3:11])[O:6][C:5]1=[O:13])[CH3:17]
Reactant: CSC(SC)=C1C(=O)OC(C)(C)OC1=O
Reactant: C[O-]
Reactant: CCS
Agent: [Na+]
Solvent: CO
Product: CCSC(SCC)=C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Yield: 23.2 %

Procedure:
A solution of 5-[bis(methylthio)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (2.3 g, 9.2 mmole, described in example 3), ethanethiol (8.4 g, 10 mL, 135 mmole) and sodium methoxide (480 mg, 20.7 mmole) in dry methanol (12 mL) was stirred at 20°-22° C. for 30 min. The solution was poured into ice water. The resultant mixture was extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and concentrated to dryness under reduced pressure. The residue was purified by HPLC (20% ethyl acetate in hexane, v/v). The purest fractions were combined. The solvent was removed under reduced pressure to give 0.59 g of the title compound as an oil; NMR (CDCl3) δ 1.36 (t, J=7 Hz, 6H), 1.72 (s, 6H), 3.11 (3t, J=7 Hz, 4H); IR (CHCl3) 1715 cm-1 ; UVλmax (MeOH) 345 nm (ε 13,040), 215 (8160).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[CH2:15](N(CC)CC)C.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.[C:22]1([C:28]#[C:29][C:2]2[CH:3]=[C:4]3[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=2)[NH:8][CH2:7][CH2:6][CH2:5]3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)CC
Reactant: C#Cc1ccccc1
Reactant: O=C(O)c1cc(I)cc2c1NCCC2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#Cc2ccccc2)cc2c1NCCC2
Product: COC(=O)c1cc(I)cc2c1NCCC2
Temperature: 80 °C
Reaction time: 10 h

Procedure:
Methyl 6-iodo-1,2,3,4-tetrahydroquinoline-8-carboxylate was prepared (quant.) in a similar manner to Example 32 (a) from 6-iodo-1,2,3,4-tetrahydroquinoline-8-carboxylic acid. To a mixture of this ester (2 g), bis-triphenylphosphine palladium dichloride (440 mg) and cuprous iodide (120 mg) in DMF (80 ml) was added triethylamine (7 ml) and phenylacetylene (780 mg). The reaction mixture was stirred at 80° C. for 10 hours and then evaporated. The resulting residue was purified by silica gel column chromatography eluting with ethyl acetate-n-hexane (1:7) to give methyl 6-(2-phenylethynyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:12][CH2:13][CH2:14][OH:15])[C:8]1=[O:24].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:12][CH2:13][CH2:14][O:15][S:33]([CH3:32])(=[O:35])=[O:34])[C:8]1=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CN2CCC(CCCO)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-hydroxypropyl)-2-oxopyrrolidine (2.6 mmol), and dichloromethane (15 mL). Cool to −5° C. using a salt-ice bath. Add dropwise, methanesulfonyl chloride (0.19 g, 1.62 mmol) at such a rate as to maintain the reaction temperature below 0° C. After 1 hour, the reaction mixture is extracted with 1 M hydrochloric acid solution and then a 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound: Rf=0.71 (silica gel, ethyl acetate).
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=O)[CH3:14]>>[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[N:11][OH:12])[CH3:14]
Reactant: CCC1Cc2ccccc2C1=O
Reactant: O/N=C1\CCOc2ccccc21
Product: CCC1Cc2ccccc2C1=NO

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting (+/−)-2-ethyl-2,3-dihydro-1H-inden-1-one and making non-critical variations provided the title compound as a colorless syrup. MS-(ESI+) for m/z 176.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[N+:19]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[N+:19]([C:22]1[CH:23]=[C:24]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cccc([N+](=O)[O-])c1
Yield: 87.6 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and 3-nitrophenyl isothiocyanate (0.183 g, 1.0 mmol). Trituration in hexanes/ethyl acetate (4:1) gave the product (0.370 g); m.p. 188-189° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[OH-].[NH4+:17]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH2:17])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 18 h
Yield: 87.6 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 3.8 g (4 ml) (0.06 mole) of 57% ammonium hydroxide. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.3 g. Recrystallization from ethanol-water yielded 4.75 g (87.6%) of fine white crystals, m.p. 193°-194° C.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1N)=[O:12])[CH3:9].[ClH:23]>C(#N)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[Cl:23])=[O:12])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1N
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CCOC(=O)c1cnn(C(C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a mixture of t-butyl nitrite (7.2 mL, 60.5 mmol), cuprous chloride (4.8 g, 48.5 mmol), and anhydrous acetonitrile (120 mL) was added 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylic acid ethyl ester (8.4 g, 39.8 mmol) in portions over 30 minutes at 0° C. The reaction mixture was stirred at room temperature for 1 h, then at 65° C. for 1 h. The mixture was then poured into 6N HCl (120 mL) and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane. After the combined organic phases were concentrated in vacuo, the crude residue was purified by flash chromatography eluting with a gradient of 0-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid ethyl ester (5.5 g, 39%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[CH:12]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1>C(Cl)Cl>[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17](=[O:19])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=3)[CH:14]=[C:13]([O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:11]=2[CH:12]=1
Reactant: Cc1cc2c(OCC(C)C)cc(C(=O)O)cc2o1
Reactant: COC(=O)c1ccc(N)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)c3cc(C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
Oxalyl chloride (410 mg, 282 μl, 3.225 mmol, 5 eq) was added to a solution of 2-methyl-4-isobutoxy-6-carboxybenzofuran (Method 2; 0.160 mg, 0.645 mmol) in DCM (5 ml) and the reaction mixture stirred for 4 hrs at ambient temperature. Further reagent was added, the reaction mixture stirred for 16 hrs, and then warmed to 40° C. As starting acid still remained, the solvent was removed in vacuo and the residue treated with neat oxalyl chloride. The reaction mixture was then concentrated in vacuo and dissolved in pyridine (5 ml); to the resulting solution was added methyl 2-aminopyridine-5-carboxylate (98 mg, 0.645 mmol). After stirring for 16 hrs the reddish solution was concentrated in vacuo and the resulting gum dissolved in DCM and chromatographed (20 g Bondelut, eluting with hexane containing ethyl acetate, 0-100%) to give the title compound (122 mg, 49.5% yield) as a colourless gum which slowly set solid; LC-MS 383 (M+H)+, 94.4% strength.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:25]=[CH:24][C:16]4[C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[O:19][C:15]=4[CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:37]=[CH:38][CH:39]=[N:40]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CC1>CN(C=O)C.O>[CH:39]1([NH:40][C:21]([C:17]2[C:16]3[CH:24]=[CH:25][C:13]([O:12][C:6]4[C:5]5[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=5)[N:9]=[CH:8][CH:7]=4)=[CH:14][C:15]=3[O:19][C:18]=2[CH3:20])=[O:23])[CH2:37][CH2:38]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1oc2cc(Oc3ccnc4cc(O)ccc34)ccc2c1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc2cc(Oc3ccnc4cc(O)ccc34)ccc2c1C(=O)NC1CC1
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A solution of 90-E (1.6 g, 4.8 mmol), HATU (2.1 g, 5.7 mmol) and triethylamine (970 mg, 9.6 mmol) in DMF (10 ml) was stirred at room temperature for 20 minutes. To the solution was added cyclopropanamine 90-F (547 mg, 9.6 mmol). The reaction mixture was stirred for 30 minutes, poured into water and extracted with EtOAc. Silica gel column chromatography using 5% MeOH in CH2Cl2 yield N-cyclopropyl-6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxamide 90-G (1.4 g, 77% yield) as a solid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]1[CH:39]=[CH:38][C:34]2=[N:35][O:36][N:37]=[C:33]2[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[N:35]1[O:36][N:37]=[C:33]2[CH:32]=[C:31]([CH2:30][N:19]3[C:14]4[C:15](=[O:18])[N:16]([CH3:17])[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])=[C:12]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)[C:13]=4[CH:21]=[CH:20]3)[CH:39]=[CH:38][C:34]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc4nonc4c3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (10 mg, 0.026 mmol) and 5-(bromomethyl)benzo[c][1,2,5]oxadiazole (22.28 mg, 0.105 mmol) in Acetonitrile (1 mL) was treated with cesium carbonate (34.1 mg, 0.105 mmol) and the resultant was stirred at 70° C. for 2 hours. The mixture was cooled to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was used crude in the next step without further purification. LC/MS (m/z) ES+=515 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>N1C=CC=CC=1>[C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[O:7][CH:8]1[CH2:9][N:10]([C:19]([NH:18][CH2:16][CH3:17])=[O:20])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OC1CNC1
Reactant: CCN=C=O
Solvent: c1ccncc1
Product: CCNC(=O)N1CC(Oc2ccccc2C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
To a stirred solution of 3-(2-tert-Butylphenoxy)azetidine (0.21 g, 1.02 mmol) in pyridine (10 ml) was added ethyl isocyanate (0.078 g, 1.10 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with water and saturated sodium chloride, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was triturated with heptane/ethyl acetate to provide 3-(2-tert-Butylphenoxy)-N-ethylazetidine-1-carboxamide (0.15 g, 53%) as a white powder.
Reaction SMILES: C([Li])CCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:23]([CH3:25])C)[C:21]#[N:22])=[CH:16][CH:15]=1.BrCC[CH2:29][Cl:30]>O1CCCC1>[Cl:30][CH2:29][CH2:25][CH2:23][CH:20]([C:17]1[CH:16]=[CH:15][C:14]([F:13])=[CH:19][C:18]=1[CH:10]([CH3:11])[CH3:12])[C:21]#[N:22]
Reactant: ClCCCBr
Reactant: CC(C)C(C#N)c1ccc(F)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1cc(F)ccc1C(C#N)CCCCl
Temperature: -78 °C
Reaction time: 0.04 h

Procedure:
n-Butyllithium (1.5 M, 20.7 mL) was added to a chilled (0° C.) solution of diisopropylamine (4.34 mL, 31 mmol) in tetrahydrofuran (60 mL). After 2-3 minutes, the flask was cooled to −78° C., and a solution of the product from Example 2, Step (a) (5.0 g, 28.2 mmol) in tetrahydrofuran (6 mL) was added over a three minute period. After allowing the yellow anion to stir for 40 minutes, 1-bromo-3-chloro-propane (3.06 mL, 31 mmol) was added, the bath was removed, and the mixture was allowed to stir at ambient temperature for 1 hour. Solvent was removed by rotary evaporation. The crude product was diluted with ether (150 mL) and the ether layer was washed with water (20 mL). The ether layer was dried using MgSO4 and concentrated. The residue was diluted with dichloromethane and filtered through a silica plug, rinsing with additional dichloromethane. Concentration afforded the title compound as an oil product characterized by NMR as follows: NMR(CDCl3, 400 MHz, partial): 3.48(m, 2h), 1.21(d, 3H, J=6 Hz), 0.78(d, 3H, J=6 Hz); 13CNMR(CDCl3, 100 MHz, partial): 52.8, 44.5, 38.0, 35.2, 28.5, 18.8, 18.5.