Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])[CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>CO.[Pd]>[CH:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C4=CCCCC4)c3c2)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C4CCCCC4)c3c2)c1F
Yield: 25 %

Procedure:
N-(3-cyclohexenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (40 mg, 0.084 mmol) was dissolved in methanol (1 mL), and 10% Pd/C (40 mg, 1 eq.) was then added. This mixture was subjected to 45 psi of hydrogen for 16 hours and filtered through GF/F filter paper. The filtrate was then concentrated. The resulting solids were purified by preparative TLC (2×0.5 mm plates, 10% MeOH/DCM as the eluent) to give N-(3-cyclohexyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (10 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 10.82 (s, 1H), 9.79 (br s, 1H), 8.32-8.39 (m, 2H), 7.50-7.56 (m, 1H), 7.19-7.28 (m, 2H), 3.07-3.15 (m, 2H), 2.68-2.78 (m, 1H), 1.96-2.02 (m, 2H), 1.70-1.84 (m, 5H), 1.38-1.49 (m, 4H), 1.21-1.31 (m, 1H), 0.95-1.03 (m, 3H); m/z (APCI-neg) M−1=475.3, (APCI-pos) M+1=477.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12](Cl)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:32][OH:33]>>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][O:29][CH3:30])=[N:11][C:12]([O:33][CH3:32])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: COCOCCCCCCCCCCc1nc(Cl)nc(C)c1OCc1ccccc1
Agent: [Na]
Product: COCOCCCCCCCCCCc1nc(OC)nc(C)c1OCc1ccccc1

Procedure:
To a stirred solution containing 41.0 mg (0.09 mmol) of 5-(benzyloxy)-2-chloro-4-(10-(methoxymethoxy)decyl)-6-methylpyrimidine in 5 mL of anhydrous methanol were added 22 mg (0.94 mmol) of sodium. The mixture was then stirred at reflux for 16 h. The reaction was quenched with water and poured into 50 mL of water. The mixture was extracted with two 50-mL portions of ethyl acetate. The combined organic solution was washed with one 50-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (2×6 cm). Elution with 1:1 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 30 mg (74%); silica gel TLC Rf 0.65 (1:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.24 (br m, 12H), 1.55 (quint, 2H, J=6.8 Hz), 1.68 (quint, 2H, J=7.6 Hz), 2.37 (s, 3H), 2.65 (dd, 2H, J=7.6, 7.6 Hz), 3.33 (s, 3H), 3.48 (t, 2H, J=6.8 Hz), 3.93 (s, 3H), 4.59 (s, 2H), 4.83 (s, 2H) and 7.37 (m, 5H); 13C NMR (CDCl3) δ 19.21, 26.16, 27.85, 29.36, 29.40, 29.51, 29.53, 29.71, 31.71, 54.69, 55.02, 67.85, 75.80, 96.36, 127.49, 128.38, 128.38, 128.63, 128.63, 136.50, 145.14, 160.61, 162.38 and 165.87; mass spectrum (APCI), m/z (M+H)+431.2910 (C25H39N2O4 requires 431.2910).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH3:26])[C@@H:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14].CN>CO>[NH2:3][CH:12]([CH3:26])[C@@H:13]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CC([C@H](C)NC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CO
Product: CC(N)[C@H](C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
600 mg of benzyl [(2S)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butan-2-yl]carbamate (Example 137A, 1.7 mmol, 1 equivalent) were suspended in 10 ml of methanol, and 2.9 ml of 40% strength aqueous methylamine solution (2.6 g, 34 mmol, 20 equivalent) were added at RT. The mixture was allowed to stand at RT overnight, and Extrelut® was then added and the mixture was concentrated. The residue was purified on a silica gel cartridge (Biotage Isolera SNAP Cartridge KP-Sil 25 g, mobile phase: dichloromethane/methanol from 95:5 to 0:100). This gave 293 mg (43% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[N:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:31])(=[O:30])[N:21]=3)[C:10]2=[O:32])=[CH:4][CH:3]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[S:6][C:5]([CH2:7][NH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[S:22](=[O:30])(=[O:31])[N:21]=3)[C:10]2=[O:32])=[CH:4][CH:3]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccc(Cl)s1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 261A (0.048 g, 0.099 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.198 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.074 mL, 0.149 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 4.10 (s, 2 H) 6.24 (t, J=6.43 Hz, 1 H) 7.19 (m, 1 H) 7.30 (m, 3 H) 7.43 (d, J=8.46 Hz, 1 H) 7.56 (m, 3 H) 7.67 (d, J=8.09 Hz, 1 H) 8.12 (d, J=7.72 Hz, 1 H) 15.95 (s, 1 H). MS (ESI−) m/z 485 (M−H)−.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C:13](=[O:18])[CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:19](OCC)=O.[H-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1COCC1.O>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[CH2:19])[C:13](=[O:18])[CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC=O
Reactant: CCCCCCCCc1ccc2c(c1)CC(=O)C2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C=C1C(=O)Cc2cc(CCCCCCCC)ccc21
Temperature: 25 °C

Procedure:
5-Octyl-2-indanone, 2A (5.00 g, 20.5 mmol) and ethyl formate (3.70 g, 50 mmol) are dissolved in toluene (40 mL). Sodium hydride (1.15 g, 50 mmol) is added and the reaction brought to reflux for 6 hours with continuous removal of water. The reaction mixture is cooled to room temperature and p-toluenesulfonyl chloride (3.75 g, 21.0 mmol) dissolved in THF (20 mL) added. The reaction mixture is maintained under inert atmosphere for 12 hours and filtered. The solvent is removed in vacuo to yield a viscous liquid residue. The crude reaction mixture is used without purification in the next step.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].CO[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]2[C@@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]2[C@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([N:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]5)=[O:21])[CH:15]=4)[C:32]3=[O:40])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(I)c1
Product: CS(=O)(=O)N1CCN(C(=O)c2cccc(N3C(=O)[C@]4(C[C@@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 85 starting from 1-Methanesulfonyl-piperazine, methyl-3-iodobenzoate (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C28H26ClN3O4S: 535, observed (M+H)+: 536.2 1H NMR (400 MHz, MeOD-d4) ppm 2.32 (dd, J=8.97, 4.93 Hz, 1 H) 2.43 (dd, J=8.72, 4.93 Hz, 1 H) 2.86 (s, 3 H) 3.20 (br. s., 4 H) 3.38 (t, J=8.84 Hz, 1 H) 3.71 (br. s., 4 H) 6.96 (d, J=7.83 Hz, 1 H) 7.14-7.24 (m, 2 H) 7.24-7.36 (m, 5 H) 7.46 (s, 1 H) 7.47-7.53 (m, 2 H) 7.64 (t, J=7.83 Hz, 1 H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21][CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[C:1]1([S:7]([C:10]2[C:15](=[N:16][C:29](=[O:31])[CH3:30])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[S:21][CH3:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1nc2ccccn2c(=NC(C)=O)c1S(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
3-Benzenesulfonyl-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine (100 mg, 0.30 mmol) was dissolved in anhydrous methylenechloride (2 ml) to which pyridine (48 mg, 0.6 mmol) was added. Acetylchloride was then added at room temperature and the reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NaHCO3, extracted with methylene chloride, and purified by flash chromatography to yield 79 mg of a yellow solid product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=5)[CH:18]=[C:17]([C:31]([O:33]C)=O)[C:13]=4[NH:14][C:15]=3[CH:16]=2)[CH2:5][C@@H:4]([CH3:35])[O:3]1.[NH3:36]>CO>[CH3:35][C@H:4]1[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:12]4[N:20]=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=5)[CH:18]=[C:17]([C:31]([NH2:36])=[O:33])[C:13]=4[NH:14][C:15]=3[CH:16]=2)[CH2:7][C@@H:2]([CH3:1])[O:3]1
Reactant: N
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3C[C@@H](C)O[C@@H](C)C3)ccc12
Solvent: CO
Product: C[C@@H]1CN(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(-c4cccc(C(F)(F)F)c4)nc23)C[C@H](C)O1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
A suspension of methyl 7-((2S,6R)-2,6-dimethylmorpholino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (16 mg, 0.033 mmol) in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated at 80° C. for 48 hr. Removal of the solvent followed by preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=75:25 to A:B=25:75 [A=95% H2O:5% MeOH:0.1% TFA; B=5% H2O:95% MeOH:0.1% TFA] over 20 min) followed by SCX capture and release with 2 N NH3 in MeOH afforded 7-((2S,6R)-2,6-dimethylmorpholino)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (12.9 mg, 0.026 mmol, 79% yield) as an orange solid. MS (ESI) m/z 469.28 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.47 (1H, s), 8.39 (1H, t, J=4.27 Hz), 8.23 (1H, d, J=8.55 Hz), 8.20 (1H, s), 7.72(2H, d, J=4.27 Hz), 7.07-7.11 (1H, m), 7.01-7.08 (1H, m), 3.80-3.91 (2H, m), 3.70-3.76 (2H, m), 2.43-2.53 (2H, m), 1.29 (6H, d, J=6.41 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[N:24]([CH2:25][CH2:26]OS(C)(=O)=O)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[N:24]([CH2:25][CH2:26][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCOS(C)(=O)=O)CC1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCn2ccnn2)CC1

Procedure:
Prepare by the method of Preparation 28 using triazole (0.045 g, 1.13 mmol) and 1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.33 g, 0.75 mmol) to give 1-(t-butoxycarbonyl)-4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.32 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]([OH:35])[CH2:10][NH:11][C@H:12]([CH2:33][OH:34])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)=[O:22])=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+:37]>CO>[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:9]([OH:35])[CH2:10][NH:11][C@H:12]([CH2:33][OH:34])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:27]([O-:29])=[O:28])=[CH:31][CH:32]=3)=[O:22])=[CH:18][CH:19]=2)[CH:6]=[CH:7][CH:8]=1.[Na+:37]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of methyl 4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]-phenyl]amino]carbonyl]benzoate hydrochloride (101 mg) in methanol (4.0 ml) was added 1N sodium hydroxide solution (486 μl) and the mixture was refluxed for 90 minutes. After cooling to room temperature, the solvent was removed by evaporation. The residual solid was applied on a solid phase extraction cartridge (BOND ELUT C18, 20 ml, VARIAN) and eluted with water and methanol successively. The eluents containing the target compound were combined and concentrated in vacuo to give sodium 4-[[[4-[(2S)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-3-hydroxypropyl]-phenyl]amino]carbonyl]benzoate (66.7 mg) as an off-white solid.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.C1CCN2C(=NCCC2)CC1.[C:30]([O:34][C:35](=[O:41])[NH:36][CH2:37][CH2:38][CH2:39]Br)([CH3:33])([CH3:32])[CH3:31].CCN(C(C)C)C(C)C.C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=[C:2]1[S:1][CH2:39][CH2:38][CH2:37][NH:36][C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:41])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(SCCCNC(=O)OC(C)(C)C)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A solution of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 502 mg, 1.9 mmol) and DBU (289 mg, 284 μl, 1.9 mmol) in THF (1 ml) is added onto a solution of (3-bromo-propyl)-carbamic acid tert-butyl ester (407 mg, 1.71 mmol) in THF (1 ml). The resulting solution is stirred at rt for 2 h. It becomes slowly turbid and the undesired solid is filtered on a fritted funnel. The solution is diluted with THF (2 ml) and DIPEA (491 mg, 650 μl, 3.8 mmol) is added. The mixture is poured onto a suspension of 2-chlorotrityl chloride resin (200-400 mesh), 1% DVB (1.0-1.6 mmol/g, 475 mg, 0.76 mmol) in THF (1 ml) and allowed to stir for 3 h. The resin is filtered and rinsed with THF. The solvent is removed in vacuo and the residue diluted with dichloromethane (5 ml). This organic phase is washed with an aqueous citric acid solution (pH=4) and with water. The solvent is evaporated under reduced pressure. The same purification process is repeated using dichloromethane instead of THF as the solvent. The obtained organic phase is washed with a saturated aqueous KH2PO4 solution and water. Evaporation of the solvent in vacuo affords a residue that is purified by flash chromatography on silica-gel (AcOEt/heptane, 1:2), yielding the title compound (587 mg) in 73% as a colourless oil: tR=2.41 min (LC-2), ESI-MS (pos.): m/z 422.50 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.37 (s, 9H, tBu), 1.39 (s, 9H, tBu), 1.74 (quint. 2H, CH2CH2N), 3.20 (dd, 2H), 3.38 (t, 2H), 4.67 (s, 2H, CH2CO2), 5.82 (br. s, 1H, NH), 7.10-7.29 (m, 3Harom), 7.65 (m, 1Harom).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([OH:17])=[C:11]([CH3:18])[C:10]=2[CH3:19])[CH:6]=[CH:7][CH:8]=1.CC1C=CC(S(O[CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:19][C:10]1[C:11]([CH3:18])=[C:12]([O:17][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Reactant: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Temperature: 90 °C
Reaction time: 12 h
Yield: 63.9 %

Procedure:
To a solution of 3′-(hydroxymethyl)-2,3,5,6-tetramethylbiphenyl-4-ol (0.616 g, 2.40 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (1.05 g, 3.60 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.597 g, 4.32 mmol), and the mixture was stirred at 90° C. for 12 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.577 g, yield 85%) as colorless crystals.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[N:5]([N:6]=[C:7]3[C:12]=2[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[ClH:17].[C:27]1([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:2]3[CH2:3][CH2:4][N:5]4[N:6]=[C:7]5[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]5)=[C:13]4[C:1]3=[O:14])[CH2:26][CH2:25]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Reactant: O=C1NCCn2nc3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cl
Product: O=C1c2c3ccccc3nn2CCN1CCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
A solution of 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one (375 mg; 2.0 mmol) in a mixture of tetrahydrofuran:dimethylformamide (DMF) in a ratio of 1:1 (4 ml) was added drop wise to a suspension of NaH 55% in mineral oil (104 mg; 2.4 mmol) in anhydrous tetrahydrofuran (THF), kept stirred at room temperature under argon atmosphere. The mixture was kept under stirring at the same temperature under inert atmosphere for 1 h; then, a solution of 1-(3-chloropropyl)-4-phenylpiperidine (4.4 g; 0.015 mol) in DMF (25 ml) was slowly added. Once the additions were over, the mixture was heated at the reflux temperature for 6 h. The reaction was then stopped by cooling the mixture to room temperature and by adding ethyl acetate (10 ml). The mixture was then filtered through a silica gel pad, then the solvent was removed by evaporation at reduced pressure. The residue was purified by flash chromatography on silica gel, using a mixture of chloroform:methanol in a ratio of 9:1 as eluent. The product thus purified was dissolved in a mixture of diethyl ether:ethanol in a ratio of 10:1 (10 ml) and processed at room temperature with 3M HCl in ethanol (0.33 ml). The solid thus formed was filtered and crystallized from a mixture of isopropanol:diisopropyl ether in a ratio 1:1. Thus, 197 mg of 2-[3-(4-phenylpiperidin-1-yl)propyl]-3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one hydrochloride were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.[Br:21][CH:22](O)[CH3:23]>>[Br:21][CH2:22][CH2:23][N:8]1[CH2:7][C:6]2[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[S:9]1(=[O:19])=[O:18]
Reactant: CC(O)Br
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Product: O=S1(=O)N(CCBr)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 68.8 %

Procedure:
In an analogous manner to Example 11 step 4, a solution of 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (1.01 g, 3.4 mmol) was reacted with bromoethanol (0.95 mL, 13.4 mmol) to afford 3-(2-bromoethyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.943 g, 69%) as white solid:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](C(OC)=O)=[CH:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[CH:9][C:8]=2[CH:16]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc2cc(C(C)=O)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc2occc2c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5-Acetyl-2-methoxycarbonyl-1-benzofuran [Ramachandra P. K., Cheng T., Horton W. T., J. Org. Chem. 28 2744 (1963)] (795 mg, 3.64 mmol) was dissolved in methanol (7 mL), and 20% sodium hydroxide (7 mL) was added to the solution. The mixture was stirred for one hour at 60° C., followed by concentrating under reduced pressure. Subsequently, the reaction mixture was acidified with hydrochloric acid. The formed precipitates were collected through filtration, washed with water and dried, to thereby yield 667 mg of a carboxylic acid product. The product was heated with quinoline (3.3 g) and copper powder (133 mg) at 200° C. for six hours in a nitrogen atmosphere. After cooling, the mixture was dissolved in ethyl acetate, followed by washing sequentially with diluted hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. The mixture was dried over sodium sulfate anhydrate, and the solvent was removed through distillation, to thereby yield 517 mg of the title compound as a blackish brown powder (88.7%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH2:47][NH2:48].C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:48][CH2:47][C:46]2[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN)cc1OC
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (1.0 g, 4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (920 mg, 4.8 mmol), 1-hydroxybenzotriazole hydrate (600 mg, 4.4 mmol), 3,4-dimethoxybenzylamine (730 mg, 4.4 mmol) and N-ethyldiisopropylamine (2.5 ml, 14 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate. This solution was washed with 1N hydrochloric acid (2×), sodium bicarbonate solution (2×) and sodium chloride solution. The solution was dried over magnesium sulphate and evaporated under reduced pressure to afford the title compound as a colourless solid, 1.6 g.