Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CS(=O)(=O)N(CCCNS(=O)(=O)c1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with benzenesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 596. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.0 (d, 1H) 7.5 (m, 3H) 7.3 (d, 2H), 7.2 (m, 4H), 6.7 (d, 4H), 4.4 (s, 2H), 4.2 (s, 2H), 3.6 (t, 2H), 3.2 (t, 2H), δ 2.9 (s, 3H), 2.7 (t, 2H), 2.7 (t, 2H), δ 1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][O:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][CH:24]([NH2:28])[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[CH:40](=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:40]([NH:28][CH:24]1[CH2:23][C:22]2[CH:21]=[N:20][C:19]3[N:15]([CH2:14][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:30][CH:29]=4)[N:16]=[CH:17][C:18]=3[C:27]=2[CH2:26][CH2:25]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(N)CC4)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(NCc2ccccc2)CC4)cc1
Temperature: 100 °C
Reaction time: 65 h

Procedure:
To a suspension of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-amine trifluoroacetate salt (0.094 g, 0.22 mmol) in toluene (3 mL) and ethanol (1 mL) was added Hunig's Base (0.11 mL, 0.66 mmol). The mixture was vortexed to ensure dissolution followed by the addition of benzaldehyde (22 μL, 0.22 mmol). The reaction mixture was heated at 100° C. for 2 hours followed by removal of solvent under reduced pressure. To the residue was added dichloromethane (10 mL), Hunig's Base (0.10 mL) followed by sodium triacetoxyborohydride (0.173 g, 0.66 mmol). The reaction mixture was shaken at room temperature for 65 hours. The reaction was quenched by addition of 1.5M NaOH (10 mL) and shaking it at room temperature for 1 hour. The organic layer was then separated, washed with brine (2×10 mL) and concentrated under reduced pressure to give the crude product. The crude product was purified by reverse phase HPLC to give the desired product, N-benzyl-3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-amine as a TFA salt and a pale yellow solid (0.045 g, 51%). Alternatively the crude product could be used in the next step without any further purification M.p.>178° C.; 400 MHz 1H NMR (DMSO-d6) δ: 9.07 (brs, 2H), 8.08 (s, 1H), 8.02 (s, 1H), 7.56-7.44 (m, 5H), 7.16 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 5.54 (s, 2H), 4.32 (t, J=6.0 Hz, 2H), 3.69 (s, 3H), 3.64 (m, 1H), 3.41 (m, 1H), 3.11 (m, 3H), 2.41 (m, 1H), 1.98 (m, 1H); LCMS [M+H]: 399.
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([CH3:20])=[C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:17][C:16]=2[C:27](N(OC)C)=[O:28])=[CH:11][CH:10]=1)(=[O:8])=[O:7])C.[CH2:33]1COC[CH2:34]1>>[CH3:20][C:19]1[C:15]([C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=2)=[C:16]([C:27](=[O:28])[CH2:33][CH3:34])[S:17][C:18]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Product: CCC(=O)c1sc(N2CCOCC2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 72.5 °C

Procedure:
To a stirred solution of 3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N,4-dimethyl-5-morpholinothiophene-2-carboxamide (compound 24f, 0.120 g, 0.25 mmol) in anhydrous THF (10 ml) at 25° C., Grignard reagent (ethyl magnesium bromide, 0.17 g, 1.25 ml, 1.25 mmol) was added dropwise and the reaction mixture was heated to 70-75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., reaction mixture was quenched by adding a saturated ammonium chloride solution (10 ml) and the resulting mixture was extracted with ethyl acetate (2×20 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent in the dried organic layer was evaporated under a reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 40-45% ethyl acetate in hexane as an eluent to obtain the title compound which was further purified by precipitation by dissolving 0.056 g of this compound in ethyl acetate (1.0 ml) and precipitating it by the slow addition of diisopropyl ether. The precipitate was filtered to obtain the title compound. (0.047 g, 48%).
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([NH2:24])[C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7](C3C(C)=CC(C)=CC=3C)[C:6]=2[N:23]=1.C(Cl)(=O)CC>ClC(Cl)C>[N:23]1[C:6]2=[N:7][C:8]3[C:13]([CH2:12][CH:11]=[CH:10][CH:9]=3)=[C:5]2[C:4]([NH2:24])=[CH:3][CH:2]=1
Reactant: Cc1cc(C)c(-n2c3c(c4c(N)cc(C)nc42)CCCC3)c(C)c1
Agent: CCC(=O)Cl
Solvent: CC(Cl)Cl
Product: Nc1ccnc2c1=C1CC=CC=C1N=2

Procedure:
2-Methyl-6,7,8,9-tetrahydro-9-(2,4,6-trimethylphenyl)-5H-pyrido[2,3-b]indol-4-amine (1b (470 mg) dissolved in 10 mL dichloroethane is refluxed for 3 hours with propionyl chloride (0.5 mL). The residual reagents are evaporated under reduced pressure. The crude product is partitioned between aqueous sodium carbonate solution and dichloromethane. The organic extract is dried over sodium sulfate and concentrated. The solid, diacylated product is triturated with hexanes and collected by filtration to afford N,N-Dipropionyl-2-methyl-6,7,8,9-tetrahydro-9-2,4,6-trimethyl phenyl)-5H-pyrido[2,3-b]indol-4-amine 1c as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)[N:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[BH3-]C#N.[Na+].O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)[N:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Oc2ccc3[nH]ccc3c2)ncn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Oc2ccc3c(c2)CCN3)ncn1
Reaction time: 1 h

Procedure:
A solution of 6.21 g (21.9 mMol) 6-(1H-indol-5-yloxy)-pyrimidine-4-carboxylic acid ethyl ester in 70 ml acetic acid is cooled in an ice bath. Then 6.88 g (109 mMol) NaBH3CN are added and stirring is continued for 1 h. After addition of 17 ml water, the mixture is concentrated in vacuo. The resulting brown oil is re-dissolved in EtOAc and a 1:1 mixture of water and sat. NaHCO3, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to the crude title compound: MS: [M+1]+=286.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11](OC)=[O:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[F:23])([CH3:4])[CH3:3].C1COCC1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[F:23])([CH3:1])[CH3:3]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C(C)(C)C)c1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a cooled solution of 8.8 (0.85 g, 2.69 mmol) in dry THF (10.0 mL, 2.69 mmol) at 0° C., was added LAH (1.0 M solution in THF (6.0 mL, 6.0 mmol)). Upon complete addition, the reaction was allowed to warm to room temperature and monitored by TLC and LCMS. Upon completion, 1N NaOH (5 mL) was carefully added to quench the reaction. The resulting solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-40% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 8.9 as a colorless oil (0.56 g, 72%). MS ESI (pos.) m/e: 311.2 (M+Na)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34](Cl)[CH:33]=1)#[N:31]>>[C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]4[CH3:29])=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:33]=1)#[N:31]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: N#Cc1ccnc(Cl)c1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(C#N)ccn2)C3)cc1

Procedure:
Compound ei was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 4-cyano-2-chloropyridin. LC-MS: m/z=+499 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:8]3=1.[H-].[Na+].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24]Cl>CN(C)C=O>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][N:10]1[C:11]2[C:7](=[C:6]3[C:2]([CH3:1])=[CH:3][S:4][C:5]3=[CH:13][CH:12]=2)[C:8]2[CH2:17][NH:16][CH2:15][CH2:14][C:9]1=2
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc2ccc3c(c4c(n3CCCN(C)C)CCNC4)c12

Procedure:
The compound is formed analogously to that described in Example 31, from 4.8 g of 1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, 1.0 g of a dispersion of NaH and 2.4 ml of 3-dimethylaminopropyl chloride in dimethylformamide. Melting point: 92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1>[Ni].CO>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Nc2cccc(F)c2)cn1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Nc2cccc(F)c2)cn1
Yield: 98.4 %

Procedure:
This compound was easily prepared from N-(3-fluorophenyl)-6-nitro-3-pyridinamine 210 mg, 0.9 mmol) by catalytic hydrogenation (Raney nickel at atmospheric pressure) in methanol to give the desired product (180 mg, 98%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.CO>[ClH:38].[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccc(F)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(F)c1
Yield: 42 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 42% of theory, C28H29FN6O3 (516.6); Rf value: 0.31 (silica gel; dichloromethane/methanol 5:1); EKA mass spectrum: (M+H)+=517; (M+H+Na)++=270.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][CH:14]=[CH:15][N:16]=2)=[CH:8][CH:7]=1)=[N+]=[N-].[H][H]>CCO.[Pd]>[NH:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:11][CH:10]=1
Reactant: [N-]=[N+]=NCCc1ccc(-c2ncc[nH]2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCCc1ccc(-c2ncc[nH]2)cc1
Reaction time: 5 h

Procedure:
To a solution of 2-[4-(2-azidoethyl)phenyl]-1H-imidazole (120 mg, 0.56 mmol) in EtOH, Pd/C (6 mg, 0.06 mmol) was added. A hydrogen balloon was placed over the reaction and the reaction was complete after approximately five hours. Reaction mixture was filtered through a pad of celite and concentrated to give 2-[4-(1H-imidazol-2-yl)phenyl]ethanamine which was used without further purification. LCMS (ES) m/z 188.4 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)(C)(C)C.Cl>O1CCOCC1>[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:14][C@@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[CH2:7][C:6]([OH:30])=[O:5])=[CH:21][CH:20]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)CN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To the product from step 1 (55 mg, 0.127 mmol) in 1,4-dioxane (2 mL) was added 12N HCl (1.7 mL) and the resulting mixture was stirred at 55° C. for 5 h. The solvent was removed in vacuo to obtain the product as a solid. The oil was triturated with diethyl ether (4 mL) to obtain the title product as a white solid (27 mg, 52%): MS; m/z 374 (M−H): LCMS (UV) 94%; 1H NMR (400 MHz, DMSO-d6) δ 1.49-1.54 (m, 1H), 1.74-1.83 (m, 4H), 1.93-1.96 (m, 1H), 3.30-3.36 (m, 2H), 3.44-3.47 (m, 1H), 3.82-3.84 (m, 1H), 4.02-4.06 (m, 1H), 4.17-4.20 (m, 2H), 4.29-4.33 (dd, 1H J1=6.8 Hz, J2=10.8 Hz), 6.93-6.95 (m, 2H) 6.95-6.98 (m, 2H), 7.00-7.07 (m, 2H), 7.39-7.41 (m, 2H).
Reaction SMILES: Cl.[CH:2]1([C:6]2[CH:45]=[CH:44][C:9]3[NH:10][C:11]([CH2:13][CH2:14][CH:15]4[CH2:18][CH:17]([N:19]([CH2:23][C@@H:24]5[C@H:28]6[O:29]C(C)(C)[O:31][C@H:27]6[C@H:26]([N:34]6[CH:42]=[N:41][C:40]7[C:35]6=[N:36][CH:37]=[N:38][C:39]=7[NH2:43])[O:25]5)[CH:20]([CH3:22])[CH3:21])[CH2:16]4)=[N:12][C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3]1.N>CO>[NH2:43][C:39]1[N:38]=[CH:37][N:36]=[C:35]2[C:40]=1[N:41]=[CH:42][N:34]2[C@H:26]1[C@H:27]([OH:31])[C@H:28]([OH:29])[C@@H:24]([CH2:23][N:19]([CH:17]2[CH2:18][CH:15]([CH2:14][CH2:13][C:11]3[NH:10][C:9]4[CH:44]=[CH:45][C:6]([CH:2]5[CH2:5][CH2:4][CH2:3]5)=[CH:7][C:8]=4[N:12]=3)[CH2:16]2)[CH:20]([CH3:22])[CH3:21])[O:25]1
Reactant: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCc2nc3cc(C4CCC4)ccc3[nH]2)C1
Agent: Cl
Agent: N
Solvent: CO
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C4CCC4)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12N HCl (24 mmol, 2 ml) was added dropwise to a solution of 9-[(3aR,4R,6R,6aR)-6-[({3-[2-(5-cyclobutyl-1H-1,3-benzo diazol-2-yl)ethyl]cyclobutyl}(propan-2-yl)amino)methyl]-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-amine (120 mg, 0.164 mmol) in MeOH (2 ml) at 0° C. whilst stirring. This was then allowed to warm to RT and continued for 6 hours. The reaction mixture was cooled to 0° C. and basified with 7N NH3 in MeOH (10 ml). This was then evaporated in vacuo. The crude product was absorbed onto silica gel (1 ml), placed onto an isolute flash Si cartridge (10 g) and purified, eluting with 7N NH3 in MeOH:DCM (1:9) to give a white solid, 36 mg (38%); MS (ESI+) for C30H40N8O3 m/z 561.45 [M+H]+; HPLC purity 100% (ret. time, 1.13 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.29 (d, J=4.6 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.50-7.18 (m, 2H), 7.06 (ddd, J=8.3, 4.6, 1.3 Hz, 1H), 6.01-5.90 (m, 1H), 4.73 (dd, J=9.8, 5.1 Hz, 1H), 4.26 (q, J=5.4 Hz, 1H), 4.14-4.03 (m, 1H), 3.60-3.15 (m, 2H), 3.07-2.86 (m, 2H), 2.84-2.67 (m, 3H), 2.42-2.31 (m, 2H), 2.25-2.11 (m, 4H), 2.10-1.95 (m, 2H), 1.92-1.74 (m, 4H), 1.57 (dd, J=12.2, 6.2 Hz, 1H), 1.02 (dd, J=6.6, 4.0 Hz, 3H), 0.95 (dd, J=6.6, 2.3 Hz, 3H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCCC>[Br:18][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reaction time: 20 h

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.76 g, 25.0 mmol) was dissolved in dry tetrahydrofuran (100 mL) and carbon tetrabromide (9.12 g, 27.5 mmol). A solution of triphenyl phosphine (6.62 g, 25.3 mmol) in dry tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred for 20 hours. The reaction was diluted with n-hexane (100 mL) and washed with a saturated NaHCO3 solution, water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes 1:4 gave the title compound. MS (DCI) m/z 295 (M+H)+.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.O[CH:9]([C:21]1[O:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:24][CH:25]=1)[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.O>C(#N)C>[F:34][C:32]([F:33])([F:35])[C:28]1[CH:27]=[C:26]([C:23]2[O:22][C:21]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=3)=[CH:25][CH:24]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc(C(O)c2ccc(-c3cccc(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(Cc2ccc(-c3cccc(C(F)(F)F)c3)o2)cc1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Sodium iodide (0.49 g) was suspended in acetonitrile (2 mL), and the suspension was cooled in an ice bath. Chlorotrimethylsilane (0.42 mL), and then a solution of the compound (0.26 g) obtained in Example 222b in acetonitrile (2 mL) were added. The reaction mixture was stirred at the same temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.22 g) as an oil.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[N:15]=[CH:16][N:17](C)[C:7]=2[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[CH2:20](N1C2N=CC=CC=2C2N=CNC=2C1=O)[CH2:21]CC>>[C:1]1([N:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:8]3[N:15]=[CH:16][NH:17][C:7]=3[C:6]2=[O:19])[CH:2]=[CH:3][CH:4]=[CH:21][CH:20]=1
Reactant: CCCCn1c(=O)c2c(ncn2C)c2cccnc21
Reactant: CCCCn1c(=O)c2[nH]cnc2c2cccnc21
Product: O=c1c2[nH]cnc2c2cccnc2n1-c1ccccc1
Yield: 72 %

Procedure:
Compound 28 was obtained according to the same procedure as in Example 4 except that Compound 27 obtained in Example 27 was used instead of Compound 3 (yield 72%).
Reaction SMILES: [F:1][C:2]1([F:15])[C@@H:7]2[C@H:3]1[C@@H:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C@H:6]2[NH2:8].CCN(C(C)C)C(C)C.O=C1CCC(=O)N1[O:32][C:33]([NH:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[N:39][N:40]2C(OC)=O)=O.[OH-].[Na+]>CCOC(C)=O.CO.CN(C=O)C>[F:1][C:2]1([F:15])[C@@H:7]2[C@H:3]1[C@@H:4]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:5][C@H:6]2[NH:8][C:33]([NH:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:37]=1[CH:38]=[N:39][NH:40]2)=[O:32]
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: N[C@@H]1C[C@H](c2ccccc2)[C@@H]2[C@H]1C2(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2[nH]ncc12)N[C@@H]1C[C@H](c2ccccc2)[C@@H]2[C@H]1C2(F)F
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
An orange solution of Example 54C (77 mg, 0.368 mmol), DMF (0.8 mL), i-Pr2NEt (0.135 mL, 0.773 mmol), and methyl 4-((2,5-dioxopyrrolidin-1-yloxy)carbonylamino)-1H-indazole-1-carboxylate (128 mg, 0.386 mmol) was stirred at ambient temperature. After 15 minutes, MeOH (1.60 mL) and sodium hydroxide (50 wt % in water, 0.058 mL, 1.1 mmol) were added. After 20 minutes of stirring, the mixture was diluted with EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (75-100% EtOAc/hexanes, gradient elution) to provide the title compound (117 mg, 0.318 mmol, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.72 (s, 1H), 8.03 (s, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.47-7.30 (m, 4H), 7.30-7.14 (m, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.48 (d, J=6.1 Hz, 1H), 4.30 (s, 1H), 3.54 (d, J=6.6 Hz, 1H), 2.64-2.50 (m, 3H), 1.81 (d, J=13.8 Hz, 1H). MS (DCI) M/Z 369 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH3:61])[CH2:56][CH2:55]2)[CH2:51]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:50]4[CH2:53][CH:52]([N:54]5[CH2:59][CH2:58][N:57]([CH2:60][CH3:61])[CH2:56][CH2:55]5)[CH2:51]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1CCN(C2CNC2)CC1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: CN1CCCC1=O
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: O
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(CC)CC5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (397 mg, 0.689 mmol) described in Production Example 1-1-6 and NMP (10 mL) was added a mixture (1.16 g) of 1-(azetidin-3-yl)-4-ethylpiperazine and benzylbenzene described in Production Example 1-3-2 at room temperature. The resultant mixture was irradiated with a microwave at 140° C. for 12 hours. The reaction mixture was cooled to room temperature, water was then added thereto, then the resultant solution was extracted with ethyl acetate, and an organic layer was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (methanol) and then further purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (402 mg, yield: 80%).