Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24].[CH3:27][S:28]([O-:30])=[O:29].[Na+].IC>[Cu]I.O>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:11][CH:10]=2
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc12
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (50 g, 118 mmol) was combined with copper(I) iodide (44.9 g, 236 mmol) and sodium methylsulfinate (24.07 g, 236 mmol) in a 2 L round bottom flask and the vessel was purged with N2 (3×). The solids were suspended in dimethyl sulfoxide (400 mL), the atmosphere was exchanged for nitrogen (3×Vac/N2 purges), and the reaction was heated to 120° C. overnight. The reaction was cooled to 50° C., and iodomethane (50.2 g, 354 mmol) was added. The reaction was stirred for 2 hours at 50° C. and cooled to RT. The crude reaction mixture was added slowly 1 L of water with stirring over 30 minutes. The resulting yellow slurry was filtered through a buchner funnel. The filter cake was washed with 3×500 mL water and dried overnight. The solids were suspended in 625 mL CH2Cl2, and the suspension was stirred for ca. 30 min. The solids were purified by flash chromatography eluting with 100% CH2Cl2→40% EtOAc/CH2Cl2. Fractions containing the product were further purified by trituration with MeOH. Mixed fractions were repurified using the same conditions and combined with the previously isolated solid to provide 31.9 g (64%) of the product as a white solid. MS (m/z) 423.7 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:3]=[C:2]([CH3:1])[CH:7]=1)[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(F)c1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCO)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4,6-dimethyl-2-fluoronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH2:1]([C:10]([OH:12])=O)[CH:2]([C:7]([OH:9])=O)[CH2:3][C:4]([OH:6])=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[NH2:20]>C1(C)C(C)=CC=CC=1>[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[NH:20][C:4]([CH2:3][CH:2]([C:7]([NH:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[CH3:13])=[O:9])[CH2:1][C:10]([NH:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[CH3:13])=[O:12])=[O:6]
Reactant: CC1CCCCC1N
Reactant: O=C(O)CC(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Product: CC1CCCCC1NC(=O)CC(CC(=O)NC1CCCCC1C)C(=O)NC1CCCCC1C

Procedure:
Next, 3.52 g (20 mmol) of 1,2,3-propanetricarboxylic acid (made by Nacalai Tesque) and 13.6 g (120 mmol) of 2-methylcyclohexylamine were added to the xylene solution of a tricresol boric acid ester obtained above, and the contents were refluxed under heating and reacted for 3 hours. This gave a crude 1,2,3-propanetricarboxylic acid tris(2-methylcyclohexylamide) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[Br:8])=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CN(C=O)C>[Br:8][C:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:3](=[O:4])[C:2]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CN1C(=O)C(Br)=C(Br)C1=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(Br)=C(N2CCOCC2)C1=O
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a room temperature, stirred solution of 2,3-dibromo-N-methylmaleimide (1 g, 0.004 mol) in DMF (10 mL) was added Cs2CO3 (1.34 g, 0.004 mol) followed by morpholine (360 mg, 0.004 mol) under N2 atmosphere. The reaction mixture was then stirred for 30 minutes, quenched with ice water, and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 3-bromo-1-methyl-4-morpholino-1H-pyrrole-2,5-dione (0.87 g, 85%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:31])=[O:30]
Reactant: COC(=O)c1ccccc1CSc1ccccc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccccc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 74.1 %

Procedure:
Following General Procedure B, the title compound (803 mg, 74%) was prepared from methyl 2-(((2-aminophenyl)thio)methyl)benzoate (652 mg, 2.39 mmol) and benzofuran-2-sulfonyl chloride (816 mg, 3.78 mmol) in pyridine (10 ml).
Reaction SMILES: [CH2:1]1[C@@H:11]2[C@H:5]([CH:6]=[CH:7][C:8]3[C:9]4[N:10]2[C:12]2[CH:21]=[CH:20][N:19]=[CH:18][C:13]=2[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH2:4][CH2:3][CH2:2]1.[I-].[K+].C(N(CC)CC)C.Cl[CH2:32][CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>CN(C=O)C>[CH2:1]1[CH:11]2[CH:5]([CH:6]=[CH:7][C:8]3[C:9]4[N:10]2[C:12]2[CH:21]=[CH:20][N:19]=[CH:18][C:13]=2[C:14]=4[CH2:15][CH2:16][CH:17]=3)[CH2:4][CH:3]([CH2:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])[CH2:2]1
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Reactant: O=C(CCCl)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCC1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1)c1ccccc1
Temperature: 60 °C
Yield: 82.4 %

Procedure:
5.5 grams of (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine, 3.6 grams of potassium iodide, 6.5 ml of triethylamine and 4.2 grams of β-chloropropiophenone were suspended in 100 ml DMF and heated to 60° C for 2 hours. The mixture was permitted to cool to room temperature, poured into 200 ml. of water and extracted with benzene. The benzene layer was washed with water, dried over potassium carbonate, filtered and evaporated to dryness in vacuo. The resulting oil was taken up in ether and converted to the hydrochloride salt as in Example 7, thus yielding 6.7 grams of the title compound, hydrochloride salt, m.p. 279° C (dec).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[CH3:30][CH:31]([CH3:33])[CH:32]=[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: C=C(C)CBr
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C=C(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to −78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and cooling to −78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at −78° C. for 1 h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)−.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:11][CH:10]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
Analogously to Method D, 1.09 g of tert-butyl 4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.720 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as slightly yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[P:20]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:21]Cl>O1CCCC1>[C:8]([CH:1]([P:20](=[O:21])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)#[N:9]
Reactant: CCOP(OCl)OCC
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C#N)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred solution of benzyl cyanide (2.5 g) in dry tetrahydrofuran (25 mL), slowly added lithium hexamethyl disilazane (26 mL, 1.0M in THF) under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for 1 hour and chloro diethyl phosphite (5 g) was added slowly under nitrogen atmosphere at −78° C. The reaction mixture was stirred at −78° C. for about 2 hours and quenched with saturated ammonium chloride solution (25 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvent under reduced pressure gave crude diethyl cyano(phenyl)methylphosphonate (3 g) as yellow liquid, which was used without any purification. 1H NMR (CDCl3): δ 1.24-1.28 (t, 3H), 1.30-1.33 (t, 3H), 4.14-3.90 (m, 4H), 4.20 (d, 1H), δ 7.45-7.20 (m, 5H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.[S:22]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[S:22]1[CH:26]=[CH:25][C:24]([CH2:27][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[CH:23]1
Reactant: OCc1ccsc1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccsc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 40.4 %

Procedure:
To a tetrahydrofuran (250 mL) solution of diethylazodicarboxylate (16.1 mL, 40.9 mmol) were added 4-hydroxybenzaldehyde (5 g, 40.9 mmol), 3-thiophene methanol (3.86 mL, 40.9 mmol) and PS-triphenylphosphine (29 g, 1.41 mmol/g, 40.9 mmol). This mixture was stirred for 7 hours at room temperature. This mixture was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (3.61 g, 40%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: COc1nc2c(N)nc(OC3CCCC3)nc2n1CCCCCl
Product: Nc1nc(OC2CCCC2)nc2c1[nH]c(=O)n2CCCCN1CCCCC1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-2-(cyclopentyloxy)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6][O:7][N:8]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14](I)[CH:15]=2)[CH:10]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[C:9]1=[O:32])[CH3:2].[CH:35]#[C:36][CH2:37][OH:38]>>[CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][CH2:6][O:7][N:8]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([C:35]#[C:36][CH2:37][OH:38])[CH:15]=2)[CH:10]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[C:9]1=[O:32])[CH3:2]
Reactant: C#CCO
Reactant: CCN(CC)CCCON1C(=O)C(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
Product: CCN(CC)CCCON1C(=O)C(c2ccc3ccccc3c2)c2c1cc(C#CCO)cc2C(F)(F)F
Yield: 34 %

Procedure:
The title compound (3.7 mg, 34%) was prepared from 3-diethylaminopropyloxy-4-trifluoromethyl-6-iodo-3-(2-naphthyl)oxindole (12.4 mg, 0.0213 mmol) and 1-propyn-3-ol by the procedure similar to that described in Reference Example 21.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[NH:40][CH:39]=[CH:38][C:35]3=[N:36][CH:37]=2)O1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:34]6[NH:40][CH:39]=[CH:38][C:35]6=[N:36][CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc3cc[nH]c3c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5cc[nH]c5c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[3,2-b]pyridine (PepTech, Burlington, USA) to give the title compound as a white solid. (HPLC: tR 2.03 min (Method A); M+H=410 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.52 (s, 1H), 8.96 (s, 1H), 8.43-8.41 (m, 1H), 8.18-8.16 (m, 1H), 8.13-8.10 (m, 1H), 8.00-7.95 (m, 1H), 7.83-7.81 (m, 1H), 7.72-7.69 (m, 1H), 7.60-7.58 (m, 1H), 6.60-6.58 (m, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[CH3:11].[ClH:12].C[OH:14]>CCOCC>[ClH:12].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7](=[NH:8])[OH:14])=[CH:5][C:4]=1[CH3:11]
Reactant: CO
Reactant: COc1ccc(C#N)cc1C
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C(=N)O)cc1C
Reaction time: 3 h
Yield: 82 %

Procedure:
Under a nitrogen atmosphere was prepared a slurry of 21 (25.6 g, 0.174 mol) in a mixture of MeOH (10 ml) and Et2O (12 ml). With cooling, a stream of hydrogen chloride was passed through, giving a solution momentarily followed by a precipitate. The total uptake of HC1 was 15 grams. The reaction mixture was refrigerated for 3 hours, and the solid collected and washed with Et2O to yield 31 grams (82%) of 4-methoxy-3-methylbenzimidate hydrochloride; m.p. 137-140°.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH2:37][O:38][CH3:39])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH2:37][O:38][CH3:39])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COCC1(CBr)COC1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC)c2OCC2CC2)COC1
Temperature: 70 °C
Yield: 27.7 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (15 mL), was added potassium carbonate (101 mg, 0.736 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (95 mg, 0.490 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 28%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[CH:3][C:2]=1[O:1][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc([N+](=O)[O-])cn1

Procedure:
In the same method as in Example C1(v), the title compound (8.35 g, 98%) was obtained as an orange oil using N-(3-hydroxy-4-methylphenyl)-3-(trifluoromethyl)benzamide (6.00 g, 20.3 mmol), 2-chloro-5-nitropyridine (3.22 g, 20.3 mmol), potassium carbonate (8.43 g, 60.9 mmol) and N,N-dimethylformamide (150 mL) as starting materials. The title compound was used for the next reaction without further purification operation.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (250 mg) was dissolved in tetrahydrofuran (7 ml) under a nitrogen atmosphere, and then morpholine (0.187 ml) was added thereto. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was further added morpholine (0.187 ml), followed by stirring for 2 hrs and 15 min. The reaction mixture was warmed up to 50° C., followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (152 mg, 61.9%) as a brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30]CC)=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([OH:30])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(C)=C/c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C/C(=C\c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
A mixture of methyl ester 4.1 (50 mg, 0.112 mmol) and 1N LiOH (2 ml) in 3 ml of MeOH/THF (1:2) was stirred at rt for 18 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, and dried (Na2SO4) before being concentrated to afford 47 mg (100%) of 4.2. HRMS (ESI) calc'd for C26H29N2O3 417.2178, found 417.2174 (MH+); 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=1.1, 1H), 7.49–7.36 (m, 5H), 7.30 (d, J=8.7, 2H), 7.07 (d, J=8.7, 2H), 6.45 (s, 1H), 5.14 (s, 2H), 4.14–4.07 (m, 1H), 2.26 (d, J=1.5, 3H), 2.07–2.00 (m, 2H), 1.95–1.84 (m, 4H), 1.36–1.22 (m, 4H).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][N:16]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=1)(C)(C)C>Cl.O1CCOCC1>[Cl:30][C:26]1[CH:25]=[C:24]([CH2:23][CH2:22][CH2:21][N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH2:14][C:10]2[CH:9]=[C:8]([CH2:7][C:6]([OH:31])=[O:5])[CH:13]=[CH:12][CH:11]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Cc1cccc(CCN(CCCc2cccc(Cl)c2)S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCCc1cccc(Cl)c1)CCc1cccc(CC(=O)O)c1
Yield: 13.6 %

Procedure:
A solution of [3-(2-{[3-(3-chloro-phenyl)-propyl]-methanesulfonyl-amino}-ethyl)-phenyl]-acetic Acid tert-butyl ester (170 mg, 0.36 mmol) in HCl/dioxane (5 mL) was stirred for 48 h at room temperature. The reaction was concentrated and the residue was taken up in dilute aqueous NaOH (10 mL, pH=9.3). The aqueous solution was washed with EtOAc (10 mL) and the layers were separated. The aqueous layer after extraction with EtOAc (10 mL) was acidified with dilute aqueous HCl to a pH of 2.5. After extraction of the acidic aqueous layer with EtOAc (10 mL) the organic solution was dried over MgSO4, filtered, and concentrated to afford the title compound as an oil (20 mg). 1H NMR (400 MHz, CDCl3) δ 6.90-7.50 (m, 8H), 3.00-3.30 (m, 4H), 2.95 (s, 3H), 2.45-2.85 (m, 4H), 1.80 (m, 2H); MS 408 (M−1).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:21])[C:19]=1[OH:20])[CH:15]=O>>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:15][C:14]2[CH:17]=[C:18]([CH3:21])[C:19]([OH:20])=[C:12]([CH3:11])[CH:13]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=CC(=O)c2ccc(Cl)cc2)cc(C)c1O

Procedure:
This compound was synthesized from 4-chloroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described hereinabove.