Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[NH:13]1[CH:17]=[C:16]([CH:18]=[O:19])[N:15]=[CH:14]1.Cl>O1CCCC1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][CH2:3][CH:18]([C:16]1[N:15]=[CH:14][NH:13][CH:17]=1)[OH:19]
Reactant: O=Cc1c[nH]cn1
Reactant: Clc1ccccc1CCCBr
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCCc1ccccc1Cl)c1c[nH]cn1
Temperature: 25 °C

Procedure:
3.3 g of magnesium turnings are covered with 40 ml of dry tetrahydrofuran. To the mixture is added 32.0 g of 1-(3-bromopropyl)-2-chlorobenzene (prepared according to Baddar, F. G. et al., J. Chem. Soc., 1959, 1027) in 100 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. When the magnesium turnings have reacted the solution is cooled to room temperature. 4.3 g of imidazole-4-carbaldehyde in 40 ml of dry tetrahydrofuran is then added dropwise to the Grignard reagent and the reaction mixture is refluxed for one hour. The cooled reaction mixture is poured into a cold dilute hydrochloric acid solution. Tetrahydrofuran is distilled off under reduced pressure and the residue is cooled. The resulting precipitate is filtered and washed with water. The crude product is recrystallized from ethanol. The yield is 8.0 g. Melting point of the hydrochloride salt is 152-154° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[OH:19][C:20]1[C:44]([O:45][CH3:46])=[CH:43][C:23]2[C:24](=O)[N:25]3[CH2:41][CH2:40][CH2:39][C@H:26]3[C@H:27](O)[N:28](C(OCC[Si](C)(C)C)=O)[C:22]=2[C:21]=1[O:47][CH3:48].C1C[O:52]CC1>CCOC(C)=O>[CH3:46][O:45][C:44]1[C:20]([OH:19])=[C:21]([O:47][CH3:48])[C:22]2[N:28]=[CH:27][CH:26]3[CH2:39][C:40](=[O:52])[CH2:41][N:25]3[CH2:24][C:23]=2[CH:43]=1
Reactant: C1CCOC1
Reactant: COc1cc2c(c(OC)c1O)N(C(=O)OCC[Si](C)(C)C)[C@@H](O)[C@@H]1CCCN1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1O)N=CC1CC(=O)CN1C2
Temperature: 35 °C
Yield: 78 %

Procedure:
A solution of TBAF in THF (4.3 mL of a 1N solution, 4.3 mmol) was added to a rapidly stirred solution of 129 (0.37 g, 0.9 mmol) in THF (10 mL) and the reaction mixture heated to 35° C. for 2 h. The reaction mixture was diluted with EtOAc (50 mL), dried over anhydrous MgSO4, filtered and removal of excess solvent by rotary evaporation under reduced pressure afforded the product as a brown oil (0.18 g, 0.7 mmol, 78%). H1 NMR (CDCl3) mixture of C11/C11′R/S carbinolamine methyl ethers δ 7.08 (s, 1H), 4.43 (d, 1H, J=8.79 Hz), 4.05-3.23 (m, 12H), 2.3-1.48 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28]S(C)(=O)=O)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][O:28][C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1cccnc1
Reactant: COC(=O)CCCCCCCNC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c1ccc(Cl)cc1
Product: COC(=O)CCCCCCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 105 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-3-methanesulfonyloxy-N-(7-methoxycarbonylheptyl)propanamide (69.0 mg) was reacted with 3-hydroxypyridine to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(7-methoxycarbonylheptyl)-3-(pyridin-3-yloxy)propanamide (36.7 mg).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([N:18]2[CH2:22][CH2:21][CH2:20][S:19]2(=[O:24])=[O:23])[CH:9]=1>>[O:23]=[S:19]1(=[O:24])[CH2:20][CH2:21][CH2:22][N:18]1[C:10]1[CH:9]=[C:8]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C1CCCN1
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Product: COC(=O)c1ccc(N2CCCC2=O)cc1N1CCCS1(=O)=O
Yield: 71.8 %

Procedure:
Using pyrrolidin-2-one (432 mg) and methyl 4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (1.54 g) described in Preparation Example 13 and by the reaction and treatment in the same manner as in Example 1, methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was obtained. The obtained methyl 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoate (1.12 g) was dissolved in a solution of methanol (5 mL) and tetrahydrofuran (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated from the reaction mixture, and the mixture was neutralized with 1N hydrochloric acid, and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated to give 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (720 mg). A mixture of the obtained 2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-4-(2-oxopyrrolidin-1-yl)benzoic acid (250 mg), 1-(2,4-dimethylphenyl)piperazine (154 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (242 mg) was dissolved in ethanol (3 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated from the reaction mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (330 mg).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([CH2:37][O:38][CH2:39][CH3:40])[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:2].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[CH2:39]([O:38][CH2:37][CH:5]([CH2:4][O:3][CH2:1][CH3:2])[O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:24]([F:35])[CH:23]=3)[CH:15]=2)=[C:9]([CH3:36])[CH:8]=1)[CH3:40]
Reactant: CCOCC(COCC)Oc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OCC)c(F)c3)c2)c(C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOCC(COCC)Oc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)O)c(F)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
To a mixed solution of ethyl 3-[4-({4′-[2-ethoxy-1-(ethoxymethyl)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2-fluorophenyl]propanoate (0.665 g, 1.20 mmol) in ethanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at room temperature for 72 hrs. Water was added to the reaction mixture and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (0.588 g, yield 93%) as a colorless viscous oil.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][C:9](=O)[CH2:10][S:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][C:9]1[CH2:10][S:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: O=C1CSC=C(c2ccccc2)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1=CC(c2ccccc2)=CSC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
This compound was prepared as shown in Scheme 25. Thus, to 0.96 g (5 mmol) of 5-phenyl-3-thiopyranone (P. T. Lansbury, et al., J. Am. Chem. Soc. 1970, 92, 5649) in 50 mL of anhydrous methanol was added 7.7 g (100 mmol) of ammonium acetate and 6.5 g of 3A molecular sieves. After stirring 30 minutes at room temperature, 1.25 g (20 mmol) of sodium cyanoborohydride was added portionwise. After stirring 16 hours, the mixture was gravity filtered, and the methanol was evaporated under vacuum. The residue was partitioned between ice/HCl and ether. The acidic aqueous phase was extracted twice more with ether, then it was made basic with ice and 50% NaOH aqueous. The mixture was extracted with CH2Cl2, dried (MgSO4), and evaporated to give 0.19 g (20%) of the title compound. GC/MS showed 100% purity with a molecular ion of 193.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1)=[O:6].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1>C(OCC)(=O)C>[CH3:15][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:2]([NH:1][C:29]([NH:28][C:24]3[CH:23]=[C:22]([CH3:21])[CH:27]=[CH:26][CH:25]=3)=[S:30])[CH:3]=2)[CH:13]=[CH:12][C:11]=1[CH3:14]
Reactant: COc1ccc(C(=O)Nc2ccc(C)c(C)c2)cc1N
Reactant: Cc1cccc(N=C=S)c1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccc(C)c(C)c2)cc1NC(=S)Nc1cccc(C)c1
Yield: 52.4 %

Procedure:
A solution of 3-amino-N-(3,4-dimethylphenyl)-4-methoxy-benzamide from Example 6 (0.541 g, 2.00 mmol) and 3-methylphenyl isothiocyanate (0.28 mL, 2.07 mmol) in ethyl acetate (35 mL) was boiled until nearly all the solvent had evaporated. Filtration after 2 days at room temperature afforded the product (0.44 g) in two crops; m.p. 155-160° C.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[C:23]=4[CH:41]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:42]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:23]=4[CH:41]=3)=[O:42])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OO
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc2C(C2CCCCC2)(C2CCCCC2)O1
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:26][C@@H:27]1[CH2:32][C@@H:31]2[CH2:33][C@@H:29]([C:30]2([CH3:35])[CH3:34])[C@H:28]1[CH3:36].FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:26][C@@H:27]1[CH2:32][C@@H:31]2[CH2:33][C@@H:29]([C:30]2([CH3:35])[CH3:34])[C@H:28]1[CH3:36]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NC[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(=O)c1Br)C2(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NC[C@H]3CCNC3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
t-Butyl (3S)-3-[({[5-bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]pyrrolidine-1-carboxylate (72.5 mg, 0.13 mmol) in dichloromethane (2 mL) was mixed with trifluoroacetic acid (19.7 μL, 0.26 mmol) at room temperature and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=20/1) to give the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:8][CH2:7][C@@H:6]([OH:9])[C@H:5]([NH:10][C@H](C2C=CC=CC=2)C)[CH2:4][O:3]1>C(O)(C)C.[Pd]>[NH2:10][C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:19])[O:8][CH2:7][C@H:6]1[OH:9]
Reactant: C[C@H](N[C@@H]1COC(C)(C)OC[C@H]1O)c1ccccc1
Agent: [Pd]
Solvent: CC(C)O
Product: CC1(C)OC[C@@H](N)[C@H](O)CO1
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To (5S,6R)-2,2-dimethyl-6-((S)-1-phenylethylamino)-1,3-dioxepan-5-ol (500 mg, 1.88 mmol) in iso-propanol (5 ml) was added 10% Pd—C (100 mg). The mixture was stirred at 50° C. under an atmospheric pressure of H2 overnight. Then the solution was filtered on a pad of Celite and the pad washed with MeOH (20 ml). The filtrate was evaporated to dryness to give (5S,6R)-6-amino-2,2-dimethyl-1,3-dioxepan-5-ol (300 mg, 1.86 mmol, 99% yield) as a white solid. 1H NMR (CDCl3) 1.03 (3H, s), 1.06 (3H, s), 2.61 (1H, d, OH), 2.75 (1H, m), 3.38 (1H, m), 3.46 (1H, dd, J 5.3 and 12.5 Hz), 3.57 (1H, dd, J 5.9 and 12.5 Hz), 3.75 (1H, dd, J 2.3 and 12.5 Hz), 3.80 (1H, dd, J 1.8 and 12.5 Hz). 13C NMR (CDCl3) 25.0, 25.1, 56.1, 61.6, 62.8, 74.6, 101.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH:21][C:22](=O)OC(C)(C)C)[CH2:14]1.Cl.C(N(CC)CC)C.[O:37]=[C:38]1[CH2:43][S:42][C:41]2[CH:44]=[CH:45][C:46](C=O)=[N:47][C:40]=2[NH:39]1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O1CCOCC1.CO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:18][CH2:19][CH2:20][NH:21][CH2:22][C:46]2[CH:45]=[CH:44][C:41]3[S:42][CH2:43][C:38](=[O:37])[NH:39][C:40]=3[N:47]=2)[CH2:14]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(N3CCC(SCCNC(=O)OC(C)(C)C)C3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2nccc(N3CCC(SCCNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl [2-({1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-3-pyrrolidinyl}thio)ethyl]carbamate (210 mg, 0.52 mmol) was dissolved in a minimum amount of chloroform and treated with 4N HCl in dioxane (2 mL). After stirring 2 h, the reaction mixture was concentrated to dryness and azeotroped with toluene. The resulting HCl salt of the free amine was dissolved in methanol/dichloromethane (4 mL, 1:3) and treated with triethylamine (0.36 mL, 2.6 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (101 mg, 0.52 mmol) and stirred for 12 hours. The solution was diluted with a small amount of methanol and treated with sodium borohydride (19 mg, 0.52 mmol.) After stirring 90 minutes, the reaction mixture was diluted with chloroform and poured into saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, concentrated and chromatographed in chloroform/methanol/ammonia. The resulting solid was converted to an HCl salt of the title compound as a yellow solid (85 mg, 34%): LC-MS m/z 483 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.27-8.31 (m, 1H), 8.18-8.22 (m, 1H), 7.82-7.86 (m, 1H), 7.35-7.41 (m, 1H), 7.16-7.19 (m, 1H), 6.89-6.94 (m, 1H), 7.39-7.42 (m, 2H), 4.2-4.27 (m, 1H), 4.14 (s, 3H), 3.84-3.98 (m, 3H), 3.69-3.75 (m, 1H), 3.55 (s, 2H), 3.42-3.50 (m, 2H), 3.16-3.26 (m, 2H), 2.55-2.63 (m, 1H), 2.18-2.22 (m, 1H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2)c2c(N)ncnc21

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (3,5-difluorophenyl)acetic acid (76 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. LCMS indicated partial conversion, with a mixture of starting material, desired product and bis-acylated material, so the reaction mixture was poured into water (10 mL), and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water (10 mL), and dried at the pump for an hour. The beige solid was adsorbed onto silica, and purified by flash chromatography (0-10% methanol in DCM, 12-g column) to afford a pale yellow solid which showed presence of bis-acylated material. The product was adsorbed onto silica and purified by flash chromatography (100% EtOAc-10% MeOH in EtOAc, then 10% MeOH in DCM, 24-g column) to afford 5-{1-[(3,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (92 mg, 49.5% yield) as a white solid. LC-MS (ES) m/z=420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.21-3.28 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.24 (t, J=8.34 Hz, 2H), 6.04 (br. s., 2H), 7.06 (d, J=6.57 Hz, 2H), 7.14 (t, J=9.60 Hz, 1H), 7.21-7.29 (m, 2H), 7.33 (s, 1H), 8.07-8.21 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12].O>C(O)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)c1ccccc1O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc([N+](=O)[O-])ccc1O
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 2-isopropylphenol (4.1 ml) in acetic acid (30 ml) was added 69% nitric acid (4 ml) in an ice bath and the mixture was stirred at the same temperature for 30 minutes. After addition of iced water, the reaction mixture was extracted with t-butyl methyl ether. The extractant was washed with water and brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (2.66 g, yield 49%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[O:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:15][CH2:14]1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([N:22]2[CH2:21][CH2:20][N:19]([CH:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)[CH2:24][CH2:23]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Product: N#Cc1cc(N)ccc1N1CCN(C2CCOCC2)CC1
Yield: 66.9 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (10 g) and 4-(3,4,5,6-tetrahydro-2H-pyran-4-yl)piperazine (27 g), the title compound (10.5 g) was obtained. melting point: 162° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:13]=3[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:13]=3[CH:14]=2)=[CH:8][CH:9]=1
Reactant: COc1cccc2sc(-c3ccc([N+](=O)[O-])cc3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc2sc(-c3ccc(N)cc3)cc12

Procedure:
2-(4-Nitrophenyl)-4-methoxybenzothiophene (1-1, 200 mg, 0.71 mmol) obtained in Example 1 and 10% palladium on charcoal (Pd/C, 5 mg) were added to a round bottom flask containing anhydrous methanol (10 mL) and sealed with a septum. Then, the flask is filled with hydrogen gas, provided with a hydrogen balloon and stirred at room temperature for 12 hours. Then, the resulting product was filtered using celite, and a methanol solvent was removed under reduced pressure to give the target compound 2-(4-aminophenyl)-4-methoxybenzothiophene (1-7, 151 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][OH:18])[CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[C@H:12]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCN(CCc2ccc(F)cc2)C[C@H]1COS(C)(=O)=O

Procedure:
A solution of trans-{1-[2-(4-fluorophenyl)ethyl]-4-methylpiperidin-3-yl}-methanol (251 mg, 1.0 mmol) in dichloromethane (10 mL) was treated with triethylamine (280 μL, 2.0 mmol) and stirred on an ice-acetone bath. Methanesulfonyl chloride (85 μL, 1.1 mmol) was added dropwise, and the resulting solution was stirred at room temperature for 1.5 hours. The solution was concentrated under vacuum, and the residue was taken up in ethyl acetate and filtered. The filtrate was concentrated under vacuum to provide an orange gum (342 mg, quantitative) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ7.16 (m, 2H), 6.98 (t, J=9 Hz, 2H), 4.30 (dd, J=10, 3 Hz, 1H), 4.18 (dd, J=10, 7 Hz, 1H), 3.13 (dm, J=10 Hz, 1H), 3.02 (s+m, 4H), 2.83 (m, 2H), 2.66 (m, 2H), 2.07 (m, 2H), 1.76 (m, 2H), 1.43 (m, 2H), 1.02 (d, J=6, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]2[NH:27][C:11]3=[CH:12][C:13]4[C:14](=[O:26])[N:15]([C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)[C:16](=[O:19])[C:17]=4[CH:18]=[C:10]3[N:9]=2)=[C:6]([NH:28][C@@H:29]([CH3:41])[CH2:30][C:31]2[C:36]([F:37])=[C:35]([F:38])[CH:34]=[C:33]([F:39])[C:32]=2[F:40])[CH:5]=[CH:4][NH:3]1>C(O)(=O)C.[Zn]>[OH:26][CH:14]1[C:13]2[CH:12]=[C:11]3[NH:27][C:8]([C:7]4[C:2](=[O:1])[NH:3][CH:4]=[CH:5][C:6]=4[NH:28][C@@H:29]([CH3:41])[CH2:30][C:31]4[C:32]([F:40])=[C:33]([F:39])[CH:34]=[C:35]([F:38])[C:36]=4[F:37])=[N:9][C:10]3=[CH:18][C:17]=2[C:16](=[O:19])[N:15]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(c1cccnc1)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@@H](Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(O)N(c1cccnc1)C3=O
Yield: 32.6 %

Procedure:
Compound (S)-2-(2-oxo-4-((1-(2,3,5,6-tetrafluorophenyl)propan-2-yl)amino)-1,2-dihydropyridin-3-yl)-6-(pyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.46 g, 0.82 mmol) and zinc powder (1.23 g, 18.8 mmol) were suspended in acetic acid (30 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 50 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (150 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a white solid product, 0.15 g, 32.6% yield. MS: 563.0 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.21-13.19 (m, 1H), 11.30-11.29 (m, 1H), 11.13-11.09 (m, 1H), 9.08 (s, 1H), 8.41 (d, 1H, J=3.5 Hz), 8.26 (d, 1H, J=7.0 Hz), 8.11 (s, 0.5H), 7.98 (s, 0.5H), 7.90 (s, 0.5 Hz), 7.78-7.73 (m, 1.5H), 7.52-7.50 (m, 1H), 7.41-7.38 (m, 1H), 6.93-6.90 (m, 1H), 6.67-6.64 (m, 1H), 6.20-6.17 (m, 1H), 4.26-4.25 (m, 1H), 3.19-3.14 (m, 2H), 1.41 (d, 3H, J=5.0 Hz).