Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:25]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][N:28]=1>>[Cl:26][C:27]1[N:28]=[CH:29][C:30]([C:31]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][C:7]=3[S:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:16]=2)=[O:32])=[CH:34][CH:35]=1
Reactant: COc1ccc2cc(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: COc1ccc2c(C(=O)c3ccc(Cl)nc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Yield: 51 %

Procedure:
The title compound was prepared from 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Example 1, Part B) and 6-chloronicotinic acid in 51% yield (based on 6-methoxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene) by essentially following the procedures described in Example 1, Part C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15]>C1COCC1>[CH3:11][C:12]([CH3:17])=[CH:13][C:14]([O:10][C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][CH:6]=1)=[O:15]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice bath cooled solution of 1.66 g (69.2 mmol) of NaH (60% suspension in mineral oil) in 25 ml of dry THF was added slowly under argon a solution of 10.0 g (57.8 mmol) of 4-bromophenol in 50 ml of dry THF. The mixture was stirred at 0 degrees C. for 30 minutes and then treated with a solution of 6.85 g (6.44 ml, 57.8 mmol) of dimethylacryloyl chloride in 25 ml of dry THF. The cooling bath was then removed and the mixture allowed to warm to room temperature. The organic layer was separated and the aqueous layer was washed with 2×25 ml of ether. The combined organic layers were washed with 2×50 ml of water, brine and dried (MgSO4). The solvent was removed in-vacuo and the residue purified using flash chromatography (SiO2 ; 5% ethyl acetate in hexanes) to give the title compound as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH:3]=[CH:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCc2cc(C=CCCl)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C=CCN3CCN(Cc4ccccc4)CC3)ccc2N1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2.3 Grams of 6-(3-chloro-1-propenyl)-3,4-dihydrocarbostyril, 2.0 g of 4-benzylpiperazine and 2.0 ml of triethylamine were mixed in 50 ml of dimethylformamide and the mixture was stirred at 50° C. for 3 hours. The reaction mixture was poured into a mixture of 50 ml of a sturated sodium chloride aqueous solution with 50 ml of 5% of sodium hydrogencarbonate aqueous solution, and the organic layer was extracted with chloroform. The coloroform layer was washed with water and dried, then chloroform was removed by distillation to obtain a residue. The residue was recrystallized from ethanol-water to obtain 2.1 g of 6-[3-(4-benzylpiperazinyl)-1-propenyl]-3,4-dihydrocarbostyril, having the melting point of 151°-153° C. in colorless needle-like crystals. Then 2.1 g of 6-[3-(4-benzylpiperazinyl)-1-propenyl]-3,4-dihydrocarboxtyril, 0.2 g of platinum balck and 2 ml of concentrated hydrochloric acid were mixed with 100 ml of ethanol and the mixture was subjected to catalytic reductin under 3 kg/cm2 of hydrogen gas at a room temperature for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated to obtain a residue. The residue was recrystallized from methanol to obtain 1.8 g of 6-(3-piperzinopropyl)-3,4-dihydrocarbostyril dihydrochloride in colorless needle like crystals. Melting point: 275°-278° C. (decomposed).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].C([Li])CCC.[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19].[Cl-].[NH4+]>O1CCCC1>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:3])[CH3:2]
Reactant: C=CCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A solution of (4S)-4-isopropyl-1,3-oxazolidin-2-one (26 g, 0.2 mol) in anhydrous tetrahydrofuran (600 ml) was cooled to −78° C. under a nitrogen atmosphere and treated with n-butyl lithium, 2.5M in hexanes (80 ml, 0.2 mol) keeping the temperature below −65° C. Once the addition was complete the reaction mixture was allowed to warm to −55° C. and stirred at this temperature for 30 minutes. The mixture was cooled back down to −78° C. and treated dropwise with a solution of 4-pentenoyl chloride (23.7 g, 0.2 mol) in anhydrous tetrahydrofuran (100 ml). After stirring at −78° C. for 30 minutes the reaction mixture was allowed to warm to room temperature. Saturated aqueous ammonium chloride solution (1 L) was added and the mixture was extracted with ethyl acetate (2×). The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 (pentane:ethyl acetate) gradually changing to 70:30 (pentane:ethyl acetate) to afford the title compound as a yellow oil (36.3 g).
Reaction SMILES: Br[CH:2]1[CH2:20][CH2:19][C:5]2=[CH:6][C:7]3[C:8]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=4[CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[C:3]1=[O:21].[C:22]([O:26][C:27]([N:29]1[C@@H:33]([CH3:34])[CH2:32][CH2:31][C@H:30]1[C:35]([OH:37])=[O:36])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[CH3:34][C@@H:33]1[N:29]([C:27]([O:26][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:28])[C@H:30]([C:35]([O:37][CH:2]2[CH2:20][CH2:19][C:5]3=[CH:6][C:7]4[C:8]5[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:9]=5[CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[C:3]2=[O:21])=[O:36])[CH2:31][CH2:32]1
Reactant: O=C1c2cc3c(cc2CCC1Br)-c1ccc(Cl)cc1CO3
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@@H](C(=O)OC2CCc3cc4c(cc3C2=O)OCc2cc(Cl)ccc2-4)N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 82.1 %

Procedure:
To a solution of 9-bromo-3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.41 g, 3.88 mmol) in MeCN (17 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (980 mg, 4.27 mmol) and DIPEA (1.49 mL, 8.54 mmol). After stirring for 18 h at 50° C., the solution was diluted with EtOAc and washed successively with 1N HCl, saturated aqueous NaHCO3 and brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 30% EtOAc/hexanes) to afford (2S,5S)-1-tert-butyl 2-(3-chloro-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylate (1.63 g, 81%).
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].[NH2:11][C:12]1[C:25]2[N:24]([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:7]([NH:11][C:12]1[C:25]2[N:24]([CH3:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:14][CH:13]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Cl
Reactant: Cn1c2ccccc2c(=O)c2c(Oc3ccccc3)ccc(N)c21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc(Oc2ccccc2)c2c(=O)c3ccccc3n(C)c12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 ml (16 mmol) of pyridine and 0.28 (4 mmol) of acetyl chloride are added to a solution of 0.7 g (2 mmol) of 4-amino-N-methyl-1-phenoxyacridone in 20 ml of chloroform, and the mixture is stirred at room temperature for 6 hours. The solution is washed with hydrochloric acid (18%), water and saturated aqueous sodium chloride solution, dried using sodium sulphate and evaporated. The residue is washed with diethyl ether nad filtered off. Yield: 0.6 g (83%) melting point: 252°-254° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][O:13][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)cc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a solution of 1.49 g (6.3 mmoles) of 3-bromo-1-(hydroxymethyl)-naphthalene in 25 ml anhydrous CH2Cl2 were added sequentially N,N-dimethyl-4-aminopyridine (76.8 mg, 0.63 mmoles), t-butyldimethylchlorosilane (1.23 g, 8.2 mmoles) and triethylamine (1.22 ml, 8.8 mmoles). The resulting solution was stirred at room temperature for 2 hours under a N2 atmosphere and then partitioned between EtOAc and ice/H2O. The organic phase was separated, washed with brine, dried with anhydrous Na2SO4, filtered and concentrated under vacuum to provide a pale yellow liquid. The crude reaction residue was purified by column chromatography (44 g silica gel, packed and eluted with 9:1 hexanes: CH2Cl2) to provide 2.19 g of the title compound as a clear liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:20]([O:23][CH2:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:26]=1[N:40]1[CH2:45][CH2:44][C:43]2[C:46]3[CH2:52][CH2:51][CH2:50][CH2:49][C:47]=3[S:48][C:42]=2[C:41]1=[O:53])(=[O:22])[CH3:21]>>[C:20]([O:23][CH2:24][C:25]1[C:26]([N:40]2[C:41](=[O:53])[C:42]3[S:48][C:47]4[CH2:49][CH2:50][CH2:51][CH2:52][C:46]=4[C:43]=3[CH2:44][CH2:45]2)=[CH:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH2:16][O:17][CH3:18])[N:13]([CH3:19])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:22])[CH3:21]
Reactant: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Product: COCc1cc(Nc2cc(-c3cccc(N4CCc5c(sc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nn1C
Yield: 69.9 %

Procedure:
Following Example 176d, 327 mg of 5-bromo-3-(5-(methoxymethyl)-1-methyl-1H-pyrazol-3-ylamino)-1-methylpyridin-2(1H)-one 176b and 481 mg of 111a were reacted to give 177a as a yellow solid (420 mg, 70%). LCMS: [M+H]+ 602
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Mg].CON(C)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[F:8])[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Br)cc1Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccc(F)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.2 %

Procedure:
A solution of 4-bromo-2-chloro-1-fluoro-benzene (31.3 g, 0.15 mol) in anhydrous THF (150 mL) was added dropwise to Mg (4.8 g, 0.2 mol) in THF (50 mL) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr at which time most of the magnesium was consumed. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (27.2 g, 0.1 mol) in anhydrous THF (300 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-chloro-4-fluorobenzoyl)piperidine-1-carboxylate (31.5 g, 92%), which was used immediately for next step without purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([O:15]C)[C:4]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].Br>C(O)(=O)C>[C:18]1([CH3:23])[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:4]1[C:5]([OH:15])=[C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(-c2cccnc2)c(OC)c1-c1ccccc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccccc1-c1c(O)ccc(-c2cccnc2)c1O
Yield: 88.1 %

Procedure:
1,3-Dimethoxy-2-(tol-2-yl)-4-(pyrid-3-yl)-benzene 3 (3.5 g, 11.46 mmol), acetic acid (30 ml), and hydrobromic acid (48%) (15 ml) were refluxed for 24 hr. After cooling the reaction mixture, most of the reagent was removed under reduced pressure; the residual acid was removed by mixing the concentrate with sodium bicarbonate solution (5%) (100 ml). The product was extracted into ethylacetate (100 ml), washed with water (100 ml×2) and brine (100 ml), and the ethyl acetate was evaporated. The crude product was purified by silica-gel chromatography eluting with dichloromethane and acetone (0% to 10% acetone) yielding 2.8 g (90%) of 4.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][O:14][CH2:15][C:16]1[CH:24]=[N:23][CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C=O)C>[OH:12][C:3]1[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[CH:22][N:23]=[CH:24][C:16]=2[CH2:15][O:14][CH3:13])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1
Reactant: COCc1cnccc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cnc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1cnccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A mixture of 0.51 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 0.48 g of 3-methoxymethyl isonicotinic acid, 1.65 g of BOP reagent, 0.38 g of triethylamine and 6 ml of DMF was stirred at room temperature for one hour, and further stirred while heating at 50° C. for two hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.58 g of N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]-3-(methoxymethyl)isonicotinamide.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C@:15]1([CH3:22])[C@H:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[OH:14][C@@:15]1([CH3:22])[CH2:16][C:17](=[O:21])[N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C@H:19]1[CH3:20]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: C[C@@H]1NC(=O)C[C@]1(C)O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C[C@]1(C)O

Procedure:
Using 4-iodo-2-(trifluoromethyl)benzonitrile (958 mg), (4S,5S)-4-hydroxy-4,5-dimethylpyrrolidin-2-one (500 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (286 mg), tris(dibenzylideneacetone)dipalladium(0) (148 mg) and cesium carbonate (1.55 g), and in the same manner as in Example 62, the title compound was obtained as colorless crystals (yield: 508 mg, 52%).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:45])[CH:40]=[CH:39]2)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:37]=[C:38]5[C:42](=[CH:43][CH:44]=4)[N:41]([CH3:45])[CH:40]=[CH:39]5)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cn1ccc2cc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)ccc21
Agent: Cl
Product: Cn1ccc2cc(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5[nH]cnc45)c3F)ccc21
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-methyl-1H-indole-5-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(Cl)(Cl)Cl.C(#N)C>O.[Ru](Cl)(Cl)Cl>[CH2:7]([O:14][C:15]([NH:17][CH2:18][C:19]([CH3:23])([CH3:22])[C:20]([OH:2])=[O:21])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(CO)CNC(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to a solution of 4.6 g of 3-benzyloxycarbonylamino-2,2-di(methyl)propanol obtained in Reference Example (2a) (19.4 mmol) in a mixed solvent of carbon tetrachloride (40 ml), acetonitrile and water (40 ml), and the mixture was stirred at room temperature for 16 hours. 11.6 g of sodium periodate (54.2 mmol) and 0.2 g of ruthenium trichloride (0.96 mmol) were added to the reaction mixture, and the mixture was further stirred at room temperature for three days. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 3.16 g of crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid. 3.0 g of 1,1′-carbonylbis-1H-imidazole (18.5 mmol) was added to a solution of 3.1 g of the crude 3-benzyloxycarbonylamino-2,2-di(methyl)propionic acid obtained above (12.3 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for one hour. 20 ml of a 28% ammonia aqueous solution (914 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for one hour. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. Then, the organic layer was washed with a 1 M hydrochloric acid aqueous solution and brine and dried over magnesium sulfate. After filtration, 300 ml of a saturated potassium carbonate aqueous solution was added to the residue, followed by washing with ethyl acetate. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate/n-hexane=2/1-3/1) to obtain 2.54 g of the title compound (yield: 54%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16][C:15]=3[CH:22]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:23](O)[CH3:24]>S(=O)(=O)(O)O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([C:19]([O:21][CH2:23][CH3:24])=[O:20])[CH2:16][C:15]=3[CH:22]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2ccc3c(c2)CC(C(=O)O)O3)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1Cc2cc(-c3ccc(NC(C)=O)cc3)ccc2O1
Reaction time: 4 h

Procedure:
5 drops of concentrated sulfuric acid was added to a mixture of 3.2 g of 7C and 150 ml of ethanol. The mixture was heated under reflux, using a Soxhlet extractor filled with molecular sieve (3A). After 4 hours, the solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with saturated sodium bicarbonate solution, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dry column chromatographed over silica gel, using chloroform as eluent. The product was extracted with tetrahydrofuran and the solvent was evaporated under reduced pressure. The residue was stirred in ether. The solid was collected and refluxed in ether. The solid was collected and dried under reduced pressure to give ethyl 5-(4-(acetylamino)phenyl)-2,3-dihydro-2-benzofurancarboxylate (7D), mp: 164°-166° C.
Reaction SMILES: Br[C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:20][C:21]1[N:30]=[C:29]([C:31]([N:33]2[CH2:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:34]2)=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[N:22]=1>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:20][C:21]1[N:30]=[C:29]([C:31]([N:33]2[CH2:34][C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:41]2)=[O:32])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:2]3[C:3]([CH:11]=[O:12])=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=3)[CH:27]=2)[N:22]=1
Reactant: CC1(C)OB(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)OC1(C)C
Reactant: O=Cc1cc2c(cc1Br)OCO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc4c(cc3C=O)OCO4)ccc2n1
Temperature: 120 °C

Procedure:
280 mg of 6-bromo-1,3-benzodioxole-5-carbaldehyde, 331 mg of potassium carbonate, 22 μl of water and 49 mg of [1,1′-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride are added to a solution of 500 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 50 ml of ethanol under argon. The mixture is heated at 120° C. for 4 h; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated. The residue obtained was triturated with 2 ml of acetonitrile, and the precipitate formed was filtered off with suction.