Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCN([CH2:10][C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][C:21]=3[C:32]3[CH:37]=[C:36]([C:38](=[O:51])[NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=4)[CH:35]=[CH:34][N:33]=3)=[O:18])[CH:14]=[CH:13][CH:12]=2)CC1)(=O)C.[N:52]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.N1(C(=O)C)CCNCC1>>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:17]([C:15]3[N:16]=[C:11]([CH2:10][N:55]4[CH2:56][CH2:57][CH2:58][N:52]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53][CH2:54]4)[CH:12]=[CH:13][CH:14]=3)=[O:18])=[C:21]([C:32]3[CH:37]=[C:36]([C:38](=[O:51])[NH:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=4)[CH:35]=[CH:34][N:33]=3)[CH:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(=O)N1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1

Procedure:
This compound was prepared using the procedure described for the preparation of 6-((4-acetylpiperazin-1-yl)methyl)-N-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)picolinamide 58, substituting tert-butyl 1,4-diazepane-1-carboxylate for -(piperazin-1-yl)ethanone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH:31][CH2:32][CH3:33])[CH3:30].CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[CH2:29]([N:31]([CH2:32][CH3:33])[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH3:30]
Reactant: CCNCC
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1cccc(Cl)n1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1cccc(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 160 °C
Yield: 4.3 %

Procedure:
To a microwave vial was added 2 ml of a solution of 6-chloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (350 mg, 0.90 mmol, prepared as described in Example 18) in DMSO (14 ml). Diethylamine (0.027 ml, 0.26 mmol) and DIPEA (0.113 ml) were added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Further diethylamine (0.027 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 2 h under microwave irradiation. Again, diethylamine (0.027 ml, 0.26 mmol) was added and the mixture was heated at 160° C. for 1 h under microwave irradiation. After this time, diethylamine (0.027 ml, 0.26 mmol) and DIPEA (0.113 ml) were both added to the mixture and it was heated at 160° C. for 2 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). Product-containing fractions were dried under a stream of nitrogen to afford the title compound (4.7 mg).
Reaction SMILES: [C:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:12])([OH:3])=[O:2].C(O[C:17](=O)[CH3:18])(=O)C.S(=O)(=O)(O)O.[C:25]([O-])(O)=O.[Na+]>CC(C)=O>[CH3:25][C:17]1([CH3:18])[O:2][C:1](=[O:3])[C:4]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[O:12]1
Reactant: O=C([O-])O
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1CCCCCCC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OC(=O)C2=C(CCCCCC2)O1
Reaction time: 1 h

Procedure:
To 2-carboxycyclooctanone of Preparation 86 (16.8 g) is added acetone (15 mL), acetic anhydride (20 mL) and sulfuric acid (0.8 mL, added dropwise) at 0° C. As soon as the sulfuric acid is added the solid dissolved and stirring continued for 1 hour at 0° C. and then the reaction is placed in the refrigerator (4° C.) overnight. The reaction is poured into NaHCO3 (500 mL) containing ice and then stirred for 1 hour at room temperature. The solid is collected on a filter and washed with water and air dried to yield 10.50 g of the product. Recrystallization from ether affords 8.9 g of the title product.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.Cl.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32][NH2:33]>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:33][CH2:32][CH2:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:13])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: NCCC1CCCCO1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Agent: Cl
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCCC4CCCCO4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.19 (m, 1 H) 1.31-1.43 (m, 3 H) 1.52 (d, J=12.9 Hz, 1 H) 1.58 (q, J=7.1 Hz, 2 H) 1.65-1.75 (m, 1H) 3.18-3.25 (m, 2 H) 3.29-3.38 (m, 2 H) 3.81 (m, J=2.0 Hz, 4 H) 7.34 (br. s., 1 H) 7.42 (d, J=5.1 Hz, 1 H) 7.98 (d, J=5.6 Hz, 1 H) 8.26-8.34 (m, 1 H) 8.37 (br. s., 1 H) 8.52 (br. s., 1 H) 8.59 (t, J=5.4 Hz, 1 H) 8.82 (s, 1 H) 13.45 (br. s., 1 H). MS m/z 424 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:10](=[O:23])[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH2:24])[CH:4]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: O=C(CCc1ccc(O)c([N+](=O)[O-])c1)CCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(CCC(=O)CCc2ccc(O)c(N)c2)ccc1O
Yield: 98 %

Procedure:
A solution of 8.2 g of 1,5-bis(4-hydroxy-3-nitrophenyl)pentan-3-one in 50 ml of methanol and 150 ml of ethyl acetate was placed in a Parr hydrogenator with 300 mg of 10% Pd/C. After 3 hours the solution was filtered and evaporated to dryness to give 6.7 g of product of m.p. 131°-133° C. Anal. calcd. for C17H20N20. Calcd C, 67.98; H, 6.71; N, 9.32. Found C, 66.91; H, 6.62; N, 8.64.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([C:7](OC)=[O:8])[C@H:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:8][CH2:7][C@@H:5]1[CH2:6][C:2](=[CH2:1])[CH2:3][C@H:4]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C1C[C@@H](C(=O)OC)[C@H](c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of methyl (+−)-trans-4-methylene-2-phenylcyclopentanoate (5.0 g, 23 mmol) from Step A in THF (30 mL) under nitrogen was added dropwise over 10 min 1M lithium aluminum hydride (LAH) in THF (23 mL). After 2 h at rt, the excess LAH was quenched by dropwise addition of ethyl acetate and the reaction was then poured into dilute aq. HCl. The mixture was extracted twice with ether and the organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (20-30% ethyl acetate in hexanes) to afford the title product (4.5 g) as a white solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(O)C>C(Cl)(Cl)Cl>[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:9])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)sc1ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=S1c2ccccc2-c2ccccc21
Temperature: -35 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of mCPBA (8.27 g, 36.9 mmol) in 71 mL chloroform was added dropwise over 30 minutes to a solution of dibenzothiophene in 89 mL chloroform at −35° C. The reaction mixture was stirred at −35° C. for 1 hour and then warmed up to room. The reaction was quenched with saturated sodium bicarbonate aqueous solution. The organic layer was washed with saturated sodium bicarbonate solution twice and dried over MgSO4, concentrated down to give an off-white solid. The solid was dissolved in refluxing ethanol and slowly cooled to room temperature to give a white crystalline solid Dibenzothiophene 5-oxide (5.65 g, 76%). LCMS-ESI″: calc'd for C12H8OS: 200.26. Found: 200.9 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[C:10]([NH2:12])=[O:11].[C:14]([O-:17])(=[O:16])[CH3:15].[K+].CN(C)C=O.C(OCC)(=O)C>[I-].[K+].CCOCC>[C:14]([O:17][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:13])[C:10]([NH2:12])=[O:11])(=[O:16])[CH3:15]
Reactant: NC(=O)C(=O)c1ccccc1CCl
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)OCc1ccccc1C(=O)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 2-(2-chloromethylphenyl)-2-oxoacetamide (3.41 g), potassium acetate (2.03 g), potassium iodide (0.14 g) and N,N-dimethylformamide (35 ml) was stirred at room temperature for 24 hours. To the reaction mixture was added a mixed solution (about 300 ml) of ethyl acetate and ether in a mixing ratio of about 1:1. The mixture was washed with water twice and saturated brine once. The resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product (3.55 g). The crude product was recrystallized from ethyl acetate-hexane, the resulting mother liquor was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to give the title compound (2.62 g in total, yield: 68.6%, white crystals).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH2:26][C:27]#[N:28])[C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([N:18]([CH2:26][C:27]#[N:28])[C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CCN(Cc1ccccc1)[C@@H]1CCCC[C@H]1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCN(Cc1ccccc1)[C@@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To oxalyl chloride (1,842 ml, 3.68 mmol) in CH2Cl2 (12.300 ml) at −78° C. was added DMSO (0.523 ml, 7.37 mmol). The reaction mixture was stirred for 10 min and then {benzyl[(1R,2R)-2-hydroxycyclohexyl]amino}acetonitrile (2-1) (300 mg, 1.228 mmol) in 2 ml of CH2Cl2 was added. The reaction mixture was stirred at −78° C. for 1 hr before triethylamine (2.054 ml, 14.73 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min and then warm gradually to 0° C. After another 30 min the reaction was quenched by H2O. The reaction mixture was diluted with aqueous potassium carbonate (saturated, 20 mL) and extracted with dichloromethane (3×30 mL). The combined organic fractions were washed with brine (saturated, 30 mL), dried, filtered. The organic phase was concentrated and the residue was diluted with dry THF, filtered with 0.25 uM filter and concentrated to give the title compound. LRMS m/z (M+H) Calcd:243.1. found: 243.3.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([C:19](OCC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CO.[BH4-].[Li+].O>C1COCC1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([CH2:19][OH:20])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (60.43 g, 174 mmol) in dry THF (300 mL) was added dry methanol (28.3 mL) followed by the addition of lithium borohydride (2M in THF, 262 mL, 523 mmol) over 30 mins. The mixture was heated to reflux. After 1 h additional methanol (14.1 mL) was added. After a further 30 mins additional methanol (14.1 mL) was added. After a further 30 mins the mixture was cooled in an ice bath and treated with methanol (100 mL) followed (cautiously) with water (1,000 mL). The mixture was stirred for 1 h and then extracted with dichloromethane (1,500 mL total). The combined organics were washed with water, then brine, dried and evaporated to dryness to afford 49.84 g of the title compound. LC-MS m/z 305 (M+H)+, 1.79 min (ret time).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][C:5]1([O:17][CH2:18][C:19]([OH:21])=[O:20])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16].[CH:23]1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.CO>[CH3:23][O:20][C:19](=[O:21])[CH2:18][O:17][C:5]1([CH2:4][CH2:3][CH:2]([CH3:22])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: CC(C)CCC1(OCC(=O)O)C(=O)CC(=O)c2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)COC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Yield: 90.4 %

Procedure:
A solution of Example 40B (20 mg, 0.066 mmol), 1,3-dicyclohexylcarbodiimide (20 mg, 0.1 mmol) in tetrahydrofuran (2 mL) and methanol (0.5 mL) was stirred at 25° C. for 16 hours. The solution was and concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound (19 mg, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.37-0.47 (m, 1H), 0.68 (dd, J=13.24, 6.62 Hz, 6H), 0.76-0.91 (m, 1H), 1.15-1.34 (m, 1H), 1.81-1.98 (m, 1H), 2.05-2.22 (m, 1H), 3.40 (d, J=15.08 Hz, 1H), 3.57 (s, 3H), 3.76 (d, J=15.07 Hz, 1H), 5.75 (s, 1H), 7.43-7.57 (m, 1H), 7.55-7.70 (m, 2H), 7.89 (d, J=7.72 Hz, 1H), 11.94 (br. s, 1H); MS (ESI) m/z 319.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OCC)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
To a solution of Ethyl 4-[5-(4-n-pentyloxyphenyl)-isoxazol-3-yl]benzoate (6.33 g) in ethanol 60 ml) and tetrahydrofuran (90 ml) was added 2N sodium hydroxide aqueous solution (12.5 ml) at 80° C. The mixture was refluxed for 1 hour and poured into ice-water. The suspension was adjusted to pH 2.0 with 1N HCl. The precipitate was collected by filtration, washed with water and dried to give 4-[5-(4-n-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (5.80 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].[S:27](=O)(=[O:30])([OH:29])[OH:28]>CO>[S:27]([O:18][C:13]1([C:12]#[C:11][C:9]2[N:8]=[C:7]3[C:3]([N:4]=[C:5]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[N:6]3[CH3:19])=[C:2]([NH2:1])[N:10]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1)([OH:30])(=[O:29])=[O:28]
Reactant: O=S(=O)(O)O
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Solvent: CO
Product: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(OS(=O)(=O)O)CCCC3)nc21
Yield: 92.5 %

Procedure:
1-{2-(6-Amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol (1.59 g) was suspended in 10 mL of methanol and 1 mL of a methanol solution of 440 mg of concentrated sulfuric acid was added dropwise thereinto at room temperature. The resulting solution was evaporated until the amount of the solution became about one half followed by adding 4 mL of ether thereto. The resulting crystals were collected by filtration, washed with ether and dried to give 1.79 g of the sulfate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[NH:25][C:26]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.CCOCC>CCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:33][C:31]1[CH:30]=[CH:29][C:27]2[N:28]=[C:24]([S:23][CH2:22][CH2:21][N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[NH:25][C:26]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCSc2nc3ccc(F)cc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: CCOCC
Product: Fc1ccc2nc(SCCN3CCNCC3)[nH]c2c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
While trifluoroacetic acid (17 mL) was stirred under cooling with ice, 1-tert-butoxycarbonyl-4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine (6.50 g, 17.08 mmol) was added to the acid over 30 minutes and dissolved thereto. The temperature of the mixture was allowed to room temperature, and the mixture was stirred for 30 minutes. Thereafter, ether and hexane were added thereto, and the formed solid was collected through filtration. The collected product was washed with ether, to thereby yield 1-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (10.50 g, yield 99%) as a brown powder.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=2[F:19])[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[ClH:27]>C(Cl)Cl.CCOCC>[ClH:27].[CH:1]1([C:4]2[CH:5]=[C:6]([CH2:7][NH2:8])[CH:16]=[CH:17][C:18]=2[F:19])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(C2CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: NCc1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 3-cyclopropyl-4-fluorobenzylcarbamate (0.220 g, 0.829 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL, 64.9 mmol). The solution was stirred at room temperature for 1 h. To the solution was added 2M HCl in Et2O (5 mL). The solids were collected via filtration to give the title compound as a white solid (0.154 g, 92% yield). 1H NMR (400 MHz, MeOD) δ: 7.21-7.33 (1 H, m), 7.03-7.16 (2 H, m), 4.06 (2 H, s), 2.06-2.18 (1 H, m), 0.99-1.09 (2 H, m), 0.74-0.86 (2 H, m). 13C NMR (500 MHz, MeOD) δ: 162.09 (1C, d, J=245.84 Hz), 131.64 (1C, d, J=14.64 Hz), 128.98 (1C, d, J=3.08 Hz), 127.33 (1C, d, J=8.48 Hz), 126.78 (1C, d, J=4.62 Hz), 115.15 (1C, d, J=23.12 Hz), 42.43 (1C, s), 8.03 (1C, d, J=5.39 Hz), 7.04 (1C, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]([CH2:18][OH:19])[CH2:5]2.[H-].[Na+].[CH3:22]I.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:6]([CH2:18][O:19][CH3:22])[CH2:5]2
Reactant: CC(C)(C)OC(=O)N1c2ccc(Cl)cc2CC1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1Cc2cc(Cl)ccc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, to a solution of 700 mg of tert-butyl 5-chloro-2-(hydroxymethyl)-2,3-dihydro-1H-indole-1-carboxylate in 14 mL of tetrahydrofuran was added portionwise 197 mg of 60% sodium hydride under ice-cooling, followed by warming to room temperature and stirring for 4 hours. After ice-cooling again, 462 μL of methyl iodide was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. Water was added thereto, followed by extraction with chloroform, and then the obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 230 mg of tert-butyl 5-chloro-2-(methoxymethyl)-2,3-dihydro-1H-indole-1-carboxylate as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH2:31][S:32]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39](=[O:44])[CH2:38]2)(=[O:34])=[O:33].N1CCCCC1>C(O)C>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[CH2:31][S:32]([C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][C:39](=[O:44])/[C:38]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1])(=[O:33])=[O:34].[CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][CH:3]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 368.3 %

Procedure:
3-Methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c (100 mg, 0.325 mmol) and 5-(2,6-dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one 64c (104 mg, 0.293 mmol) were dissolved in 3 ml of ethanol, and added with 52 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-2-(5-(2,6-dichlorobenzylsulfonyl)-2-oxoindolin-3-yl idene)methyl)-3-methyl-5-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 64 (166 mg, yield 88%) as an orange solid.
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]([C:7]12[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:14][CH2:13][C:12](=NN)[CH:11]1[CH2:10][N:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8]2)=[O:6].C(OCC)(=O)C>O1CCCC1>[CH3:3][O:4][C:5]([C:7]12[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:14][CH:13]=[C:12]([I:1])[CH:11]1[CH2:10][N:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8]2)=[O:6]
Reactant: II
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1OC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1OC
Yield: 48.5 %

Procedure:
106.1 g (0.418 mol) of iodine in 1.1 dm3 of tetrahydrofuran were added dropwise to a solution of 85 g (0.209 mol) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate in 2 dm3 of tetrahydrofuran. After addition of 2 dm3 of ethyl acetate, the organic phases were washed with two times 1 dm3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 1 dm3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture, 51 g (48%) of methyl(3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were obtained in the form of a brown oil, the characteristics of which were as follows: