Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:6][S:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.4 %

Procedure:
To a solution of L-isoleucine methyl ester hydrochloride (1.82 g, 10 mmol) and 4-chlorobenzenesulfonyl chloride (2.11 g, 10 mmol) in CH2Cl2 was added triethylamine (4.18 mL, 30 mmol). The mixture was stirred at 25° C. for 16 hours, then filtered and concentrated. The crude product was purified by flash chromatography over silica gel using 10% ethyl acetate in hexane to give N-4-chlorobenzenesulfonyl L-isoleucine methyl ester 3.53 g.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: Nc1cccc(O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of the (4-adamantan-1-yl-phenoxy)-acetic acid (85.9 mg, 0.3 mmol) and 3-amino-phenol (65.5 mg, 0.6 mmol) in DMF (5.0 mL) were added benzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (312.2 mg, 0.6 mmol), and N,N-diisopropylethylamine (DIPEA) (0.11 ml, 0.6 mmol). The reaction mixture was stirred at room temperature overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. Purification by silica gel column chromatography (n-Hexane:EtOAc:MeOH=15:3:1) gave 2-(4-Adamantan-1-yl-phenoxy)-N-(3-hydroxyl-phenyl)acetamide as a white solid (67.6 mg, 59.7% yield).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][C:8](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:14]/[C@@H:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]2)=[N:9][C:10]=1[O:11][CH3:12].O>CN(C)C=O>[C:38]([C:35]1[CH:36]=[CH:37][C:32](/[C:13](/[C:8]2[CH:7]=[CH:6][C:5]([S:2][CH3:1])=[C:10]([O:11][CH3:12])[N:9]=2)=[CH:14]\[C@@H:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[O:29][CH3:30])[C:18](=[O:31])[CH2:17][CH2:16]2)=[CH:33][CH:34]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: C[S-]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(SC)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34 %

Procedure:
Sodium thiomethoxide (44 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (150 mg) in N,N-dimethylformamide (1.5 mL), and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→0:10) to give (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[6-methoxy-5-(methylsulfanyl)pyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (53 mg, 34%).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:37]=[CH:36][C:9]2[C:10](=[O:35])[CH2:11][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])([CH3:14])[O:13][C:8]=2[C:7]=1[CH2:38][CH2:39][CH3:40].[OH-].[Na+].O.Cl>CO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]2([CH3:14])[CH2:11][C:10](=[O:35])[C:9]3[CH:36]=[CH:37][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:7]([CH2:38][CH2:39][CH3:40])[C:8]=3[O:13]2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCCCCCCC2(C)CC(=O)c3ccc(OCC(=O)OC)c(CCC)c3O2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCCCCC2(C)CC(=O)c3ccc(OCC(=O)O)c(CCC)c3O2)ccc(C(C)=O)c1O
Yield: 96.9 %

Procedure:
A solution of 1.1 g of the ester product from Example 5 and 0.966 g of sodium hydroxide, in 36 ml of methanol and 9 ml of water was stirred at room temperature for 5.5 hours then poured into 60 ml of cold 1N hydrochloric acid and 150 ml of water. The mixture was extracted 3 times with ether. The combined ether extracts were washed with 3 portions of saturated aqueous sodium bicarbonate. Each bicarbonate wash was back-extracted with ether. The bicarbonate washes were combined and acidified to pH 1 with 3N hydrochloric acid. The acidic mixture was extracted 3 times with ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo to yield 1.04 g of a yellow solid. This material was recrystallized from acetonitrile giving 0.82 g (76.6%) of rac.-[[2-[6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexyl]-3,4-dihydro-2-methyl-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid as a colorless solid, m.p. 120.5°-125.0° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:22])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>CO>[CH3:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:20])[F:21])=[C:8]([CH3:22])[NH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]c(C)c(-c2ccccc2C(F)(F)F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)O)c(C)c1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a solution of 3,5-dimethyl-4-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (0.96 g) in methanol was added 4 N NaOH (6 mL). The reaction mixture was then heated to reflux with stirring overnight. After cooling, solvent was removed and the crude material was diluted with water. Solids were removed by filtration and washed with water. The aqueous filtrate was acidified with formic acid to precipitate the product. The precipitates were collected by filtration and washed with water, and then dried under high vacuum to afford 3,5-dimethyl-4-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acid (0.30 g). MS (ES): 284 (MH+). In a manner similar to that described in Example 16D, the title compound was prepared from 3,5-dimethyl-4-(2-trifluoromethyl-phenyl)-1H-pyrrole-2-carboxylic acid. 1H-NMR (CDCl3): δ 9.68 (1H, s), 7.89 (2H, m), 7.79 (3H, m), 7.73 (1H, s), 7.59 (1H, m), 7.50 (1H, M), 7.24 (1H, d), 3.05 (3H, s), 3.05 (3H, s), 2.19 (3H, s), 2.06 (3H, s); MS (ES): 437 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=C(C)C=C(C)[C:3]=1N1CCCC2=C(N)N(C)N=C12.[CH3:21][N:22]1[C:30]([NH2:31])=[C:29]2[C:24]([N:25]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=3[CH3:40])[CH2:26][CH2:27][CH2:28]2)=[N:23]1>>[CH2:3]([NH:31][C:30]1[N:22]([CH3:21])[N:23]=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][N:25]2[C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[CH3:40])[CH2:2][CH3:7]
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(C)c1
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Product: CCCNc1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2

Procedure:
Compound 5-55 was prepared according to the procedure in Example 15, steps 1 and 2, except that in step 1, 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-45) was replaced with 2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-44).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:27]Br>C(Cl)(Cl)Cl.II>[Br:27][C:9]1[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([CH3:13])[C:8]=1[C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)cc(C(=O)c2ccc(Cl)cc2)n1C
Reactant: BrBr
Agent: II
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(Br)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A solution of 20 g. (0.053 mole) of ethyl 5-p-chlorobenzoyl-3-ethoxycarbonyl-1-methylpyrrole- 2-acetate in 200 ml of chloroform containing a few crystals of iodine as catalyst is heated to reflux and a solution of 3.0 ml (0.058 mole) of bromine in 20 ml of CH Cl3 is added over 45 min. The whole is heated under reflux for 11/2 hours, cooled, and washed successively with aqueous sodium bicarbonate solution, aqueous sodium bisulfite solution and brine. After the solution is dried over magnesium sulfate, the solvent is evaporated in vacuo and the resulting residue is recrystallized successively from methycyclohexane and 75% ethanol-water to give ethyl 4-bromo-5-(p-chlorobenzoyl)-3- ethoxycarbonyl-1-methylpyrrole-2-acetate as white crystals; m.p. 88°-90° C.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][CH2:26][NH:27][CH3:28]>C(O)CCC>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([N:24]([CH3:23])[CH2:25][CH2:26][NH:27][CH3:28])[N:12]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CNCCNC
Agent: Cl
Solvent: CCCCO
Product: CNCCN(C)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Yield: 79.8 %

Procedure:
A solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (120 mg, 0.36 mmol) and N,N′-dimethylethylenediamine (0.14 mL, 1.26 mmol) in 2 mL of 1-butanol was heated at 100° C. overnight with stirring. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (101 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 7.42 (d, 1H, J=8.4 Hz), 7.31 (t, 1H, J=6.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.86 (m, 3H), 6.64 (t, 1H, J=6.8 Hz), 3.90 (t, 2H, J=6.4 Hz), 3.82 (s, 3H), 3.50 (s, 3H), 3.30 (s, 3H), 2.92 (t, 2H, J=6.4 Hz), 2.50 (s, 3H); ESI-MS m/z 352 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[C:2]#[CH:3].C(NC(C)C)(C)C.I[C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[CH:26]\[CH2:27][O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=2)=[CH:21][CH:20]=1>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:10][CH:7]1[CH2:8][CH2:9][N:4]([CH2:1][C:2]#[C:3][C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:47]=3)=[CH:26]\[CH2:27][O:28][C:29]3[CH:40]=[CH:39][C:32]([O:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[C:31]([CH3:41])[CH:30]=3)=[CH:23][CH:24]=2)[CH2:5][CH2:6]1
Reactant: C#CCN1CCC(O)CC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCC(O)CC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Propargylpiperidin-4-ol (215 mg, 1.55 mmol) and diisopropylamine (0.51 mL, 3.64 mmol) were added to a solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethyl-phenyl)-allyloxy]-2-methylphenoxy]acetate (450 mg, 0.773 mmol; example 4) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (12 mg, 0.063 mmol) and bis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.039 mmol) were added. The reaction mixture was stirred at ambient temperature for 20 h and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 98:2-97:3-95:5) yielding methyl (E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]-phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][PH:11](=[O:15])[O:12][CH2:13][CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([P:11]([CH3:10])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCO[PH](C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc(C=O)cc1
Temperature: 110 °C
Reaction time: 10 h

Procedure:
To a solution of 4-bromobenzaldehyde, 38-a, (500 mg, 2.7 mmol) and ethyl methylphosphinate, 38-b, (650 mg, 5.4 mmol) in toluene (10 mL) was added triethylamine (1.1 g, 11 mmol). After being allowed to stir for 10 h at 110° C. under nitrogen atmosphere, the mixture was cooled to ambient temperature, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried over Na2SO4, filtrated and concentrated to give a residue, which was purified by chromatography on silica gel (dichloromethane/methanol=70:1) to afford compound 38-c as a colorless oil. (530 mg, 93%). 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.93-8.05 (m, 4H), 3.90-3.98 (m, 2H), 1.68-1.73 (d, J=14.4 Hz, 3H), 1.16-1.24 (m, 3H). LC-MS 213 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:19][CH2:20][CH3:21]>>[F:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: Fc1cc(N2CCNCC2)cc(C(F)(F)F)c1
Reactant: CCCBr
Product: CCCN1CCN(c2cc(F)cc(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(3-fluoro-5-trifluoromethyl-phenyl)-piperazine and 1-bromopropane, the title compound was recovered by the procedure described in Example 2. m.p. 242° C. (HCl); MS m/z (rel. intensity, 70 eV) 290 (M+, 34), 261 (bp), 218 (22), 190 (20), 70 (37).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][N:10]([CH3:11])[C:6]=2[N:5]=[C:4]2[NH:12][C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1>C1COCC1>[Cl:1][C:2]1[CH:7]2[N:8]=[CH:9][N:10]([CH3:11])[CH:6]2[N:5]=[C:4]2[N:12]([S:37]([CH:34]3[CH2:36][CH2:35]3)(=[O:39])=[O:38])[C:13](=[O:23])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[F:22])[C:3]=12
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cn1cnc2c(Cl)c3c(nc21)[nH]c(=O)n3-c1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C=NC2C(Cl)=c3c(n(S(=O)(=O)C4CC4)c(=O)n3-c3ccc(I)cc3F)=NC21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-chloro-1-(2-fluoro-4-iodophenyl)-5-methyl-3,5-dihydrodiimidazo[4,5-b:4′,5′-e]pyridin-2(1H)-one (200 mg, 0.36 mmol) in THF (6 ml) at −78° C. is added LiHMDS (0.54 ml, 1 M in THF, 0.54 mmol). The reaction mixture is stirred at −78° C. for 10 min and cyclopropylsulfonyl chloride (100 mg, 0.72 mmol) is added to the mixture. The reaction is slowly warmed to room temperature and stirred at the temperature for 3 h. The reaction is quenched with saturated aqueous NH4Cl solution (10 ml) and extracted with EtOAc (2×10 ml). The combined organic solution is washed with brine (10 ml), dried over MgSO4 and concentrated. Silica gel chromatography yields the title compound.
Reaction SMILES: O[C@@:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([C:31]([NH:33][CH3:34])=[O:32])[CH:25]=[CH:24]2)([C:6]1[N:7]=[CH:8][N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1)[CH2:3][CH2:4]O.C(N(C(C)C)C(C)C)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH2:55]>C1COCC1>[OH:55][C:10]1[N:9]=[CH:8][N:7]2[CH2:4][CH2:3][C@@H:2]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[C:26]([C:31]([NH:33][CH3:34])=[O:32])[CH:25]=[CH:24]4)[C:6]=12
Reactant: O
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(S(=O)(=O)c4ccc(C)cc4)cn3)ccc2c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc([C@@H]3CCn4cnc(O)c43)ccc2c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To THF (4.8 mL) was added 6-[(1S)-1,3-dihydroxy-1-(1-tosyl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (479.6 mg, 1.0 mmol). The reaction mixture was cooled to 10° C., and ethyldiisopropylamine (505.9 mg, 4.0 mmol) and methanesulfonyl chloride (458.8 mg, 4.0 mmol) were successively added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added a solution of sodium carbonate (530.0 mg, 5.0 mmol) in water (2 mL), and the mixture was warmed to 57° C., and stirred for 5 hr. The separated organic layer was concentrated under reduced pressure. Methanol (4 mL) and activated carbon (40 mg) were added thereto. The reaction mixture was stirred at the same temperature for 20 min, and the activated carbon was filtered off, and washed with methanol (2 mL). The filtrate and washing were concentrated under reduced pressure. Methanol (1 mL), ethyl acetate (5 mL), and THF (10 mL) were added to the residue, and the mixture was washed twice with 10% sodium chloride-containing 5 w/v % aqueous sodium bicarbonate solution (15 mL). The separated organic layer was concentrated under reduced pressure to give 6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (135.4 mg, 0.44 mmol). yield 44%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16]([CH3:19])([CH3:18])Cl)[CH:2]=[CH2:3].[CH3:20][N:21]([CH3:30])[C:22]1([Li])[CH:26]=[C:25]([CH3:27])[C:24]([CH3:28])=[CH:23]1>C1(C)C=CC=CC=1.O1CCCC1>[CH3:20][N:21]([CH3:30])[C:22]1[CH:26]([Si:16]([C:6]2[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([C:11]([CH3:13])([CH3:14])[CH3:12])[C:5]=2[O:4][CH2:1][CH:2]=[CH2:3])([CH3:19])[CH3:18])[C:25]([CH3:27])=[C:24]([CH3:28])[CH:23]=1
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Reactant: [Li]C1(N(C)C)C=C(C)C(C)=C1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1C(N(C)C)=CC(C)=C1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.7 %

Procedure:
A solution of (2-allyloxy-3-tert-butyl-5-methylphenyl)dimethylchlorosilane (7.0 mmol) in toluene (12.1 mL) was added dropwise to a solution of 1-dimethylamino-3,4-dimethylcyclopentadienyllithium (7.0 mmol) in tetrahydrofuran (10.5 mL) and the mixture was stirred at room temperature for 6 hours. After the solvent was distilled off under reduced pressure, dehydrated pentane was added and a precipitated solid was filtered off. The filtrate was concentrated to obtain the title compound (2.86 g, 100%) as an oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[C:10](Cl)[CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].C(N(CC)CC)C>CO.[H][H].[Pd]>[C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1cc(Cl)cc(C#N)c1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)c1cccc(C#N)c1F

Procedure:
Reduction of 3-acetyl-5-chloro-2-fluorobenzonitrile in methanol using H2 /Pd-C for 3 h under 45 p.s.i.g. of H2 in the presence of triethylamine affords 3-acetyl-2-fluorobenzonitrile, which is the starting material.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:14])[N:4]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:3]=[C:2]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(-n2cc(Br)c3cc(OC)ccc3c2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-n2cc(-c3ccccc3)c3cc(OC)ccc3c2=O)cc1
Yield: 98 %

Procedure:
4-Bromo-6-methoxy-2-(4-methoxyphenyl)-isoquinolin-1(2H)-one (0.52 g, 1.44 mmol), tetrakis(triphenylphosphine)palladium (83 mg, 0.07 mmol), potassium carbonate (0.22 g, 1.00 mmol) and phenylboronic acid (0.21 g, 1.73 mmol) were placed in a dry and argon flushed 150 mL three-necked round-bottomed flask fitted with a stirring bar and reflux condenser. 1,2-Dimethoxyethane (10 mL) and water (3 mL) were added via a syringe under argon atmosphere. The reaction solution was stirred and heated to reflux for 20 hours. The reaction was quenched by adding 30 mL of water at room temperature. The mixture was extracted with ethyl acetate (3×20 mL). The extracts were combined, washed with brine (2×10 mL) and dried over anhydrous MgSO4 and 2 g of 3-(diethylenetriamino)propylfunctionalized silica gel followed by filtration and concentration to give a yellow residue. The yellow residue was purified by flash column chromatography (silica-gel, hexanes/ethyl acetate=2/3 v/v) to give a white solid product, 0.50 g, 98.0% yield. MS: m/z 358.3 [M+H]+. 1H NMR (DMSO-d6, 300 MHz) (8.30 (d, 2H, J=9.0 Hz), 7.55-7.40 (m, 8H), 7.29 (s, 1H), 7.21 (dd, 1H, J1=9.0 Hz, J2=2.4 Hz), 7.05 (d, 2H, J=9.0 Hz), 6.94 (d, 1H, J=2.4 Hz), 3.81 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:30])=[CH:24][CH:23]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(OC)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).