Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)(=[O:12])[CH3:11]>>[C:10]([NH:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[N+:1]([O-:4])=[O:2])(=[O:12])[CH3:11]
Reactant: COC(=O)c1ccc(CNC(C)=O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(CNC(C)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture (mixed acid) of fuming nitric acid (70 ml) and conc. sulfuric acid (70 ml) was added methyl 4-acetamidomethylbenzoate (54 g) at 7-15° C. for 1.5 hr. This reaction mixture was stirred at room temperature for 1 hr and poured into ice water (600 ml). The mixture was extracted with chloroform (300 ml×3). The extract was washed with water, saturated sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (75 g). The obtained yellow oil was crystallized from ethyl acetate (50 ml) and recrystallized from hexane/ethyl acetate (1:1, 600 ml) to give the title compound (45.5 g) as pale-yellow crystals.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C1(P(=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[O:1]1[CH2:2][C:3](=[CH:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:4]1
Reactant: O=C1COC1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: ClCCl
Product: O=C(C=C1COC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Under argon and at 0° C., 3.0 g (41.63 mmol) of oxetan-3-one (CAS Reg.-No. 6704-31-0) were dissolved in 50 ml of dichloromethane, and 18.8 g (45.79 mmol) of benzyl (triphenyl-λ5-phosphanylidene)acetate were then added. The reaction mixture was then slowly warmed to room temperature and stirred for another 15 minutes. The reaction solution was then concentrated to dryness. The residue was taken up in 25 ml of diethyl ether and stirred, and the mixture was kept at 4° C. for 12 h. The precipitated triphenylphosphine oxide was filtered off and the filtrate was concentrated to dryness. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→1:1). This gave 4.2 g (20.57 mmol, 49% of theory) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:7])[CH2:5][SH:6])C.CC([O-])(C)C.[K+].Cl[CH:15]=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17](=O)[CH:18]([CH3:20])[CH3:19]>C(O)C.C1COCC1.CCOCC>[CH2:22]([C:16]1[C:17]([CH:18]([CH3:20])[CH3:19])=[C:5]([C:4]([OH:3])=[O:7])[S:6][CH:15]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CCOC(=O)CS
Reactant: CC(C)CC(=CCl)C(=O)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CC(C)Cc1csc(C(=O)O)c1C(C)C
Temperature: 12.5 °C
Reaction time: 15 h
Yield: 1 %

Procedure:
Mercapto-acetic acid ethyl ester (9.86 g, 82.1 mmol) is slowly added to a solution of KOtBu (9.50 g, 84.7 mmol) in ethanol (50 mL) cooled to 10-15° C. The mixture is diluted with THF (100 mL) before a solution of the crude 1-chloro-2-isobutyl-4-methyl-pent-1-en-3-one (corresponds to 8.1 g, 43 mmol) in THF (50 mL) is added. The reaction mixture is stirred at 40° C. for 15 h, then at reflux for further 20 h, and at 35° C. for 48 h. The mixture is diluted with ether (300 mL) and washed with 1N aq. NaOH (3×100 mL), 1 M aq. KHSO4 (100 mL) and brine (100 mL). The organic phase is dried (Na2SO4), filtered and evaporated. The resulting residue is dissolved in ethanol (30 mL), 2 N aq. LiOH (30 mL) is added, and the mixture is stirred at reflux for 48 h. The mixture is extracted with diethyl ether, then the aq. phase is acidified with 25% aq. HCl and extracted with DCM. The organic extracts are dried (MgSO4), filtered and evaporated. The brown oil is diluted in acetonitrile (5 mL) and allowed to crystallize at 4° C. The crystalline material is collected, washed with acetonitrile and dried to afford pure 4-isobutyl-3-isopropyl-thiophene-2-carboxylic acid (98 mg) as pale yellow crystals; 1H NMR (CD3OD): δ 7.16 (s, 1H), 3.68 (hept, J=7.0 Hz, 1H), 2.48 (d, J=7.6 Hz, 2H), 1.84 (hept, J=7.0 Hz, 1H), 1.34 (d, J=7.0 Hz, 6H), 0.92 (d, J=6.4 Hz, 6H).
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[C:14]1[C:32](=[O:33])[N:31]([CH3:34])[C:17]2[N:18]([CH3:30])[C:19]3[C:24]([C:16]=2[CH:15]=1)=[CH:23][C:22]([C:25]1[NH:26][N:27]=[CH:28][CH:29]=1)=[CH:21][CH:20]=3.O>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:14]1[C:32](=[O:33])[N:31]([CH3:34])[C:17]2[N:18]([CH3:30])[C:19]3[C:24]([C:16]=2[CH:15]=1)=[CH:23][C:22]([C:25]1[NH:26][N:27]=[CH:28][CH:29]=1)=[CH:21][CH:20]=3
Reactant: COc1ccc(-c2cc3c4cc(-c5ccn[nH]5)ccc4n(C)c3n(C)c2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)c(-c2ccc(O)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reaction time: 16 h

Procedure:
At −78° C., a 1M solution of BBr3 in CH2Cl2 (2.19 ml, 2.19 mmol) is added to a solution of compound E 3-(2-chloro-4-methoxyphenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one (306 mg, 0.73 mmol) in 3 ml of CH2Cl2. The mixture is stirred at AT for 16 h. H2O is added and the precipitate is filtered off. The solid is taken up in MeOH/CH2Cl2 and the product is adsorbed onto silica. Purification is carried out by column chromatography, elution being carried out with CH2Cl2/5% MeOH. The residue is taken up with MeOH, and the product is washed and filtered with MeOH.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]([NH:14][S@@](C(C)(C)C)=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[CH3:21].Cl>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C@H:9]([NH2:14])[C:10]([F:12])([F:13])[F:11])=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc([C@H](N[S@](=O)C(C)(C)C)C(F)(F)F)cc(C)c1Cl
Agent: Cl
Solvent: CO
Product: Cc1cc([C@H](N)C(F)(F)F)cc(C)c1Cl

Procedure:
A solution of intermediate INT 42 (860 mg, 2.52 mmol) in MeOH (40 mL) was treated with HCl (4 M in dioxane, 1.26 mL, 5.04 mmol) and stirred over the weekend. After evaporation of the solvents, a solid was obtained which was triturated with Et2O. The solid was then dissolved in water and the pH was adjusted to ˜9 using 10% sodium carbonate solution. It was extracted twice with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [C:1]1([CH2:7][C:8](OCC)=[S:9])C=CC=CC=1.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(S)C=C>CC[O-].[Na+]>[CH2:8]([S:9][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH2:1]
Reactant: CCOC(=S)Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C=CCS
Agent: CC[O-]
Agent: [Na+]
Product: C=CCSCC(=O)OCC

Procedure:
The procedure is as in Example 2 for the preparation of ethyl phenylthioacetate, starting with ethyl bromoacetate (16.7 g), a 2M ethanolic solution of sodium ethylate (50 cc) and allylmercaptan (7.7 cc). After purification by chromatography on a silica column with cyclohexane as eluent, ethyl (allylthio)acetate (3.1 g) is obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[C:24]([N+:31]([O-])=O)[CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]>CCO>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([NH2:31])[CH:23]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(N)c(N)c3)nc3ccccc3c2=O)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
3-(4-sec-butylphenyl)-2-(3,4-dinitrophenyl)quinazolin-4(3H)-one (0.240 g, 0.54 mmol) was dissolved in EtOH (20 mL) and flushed with N2 for 15 minutes. Pd/C (0.025 g, 10 wt %) was added, and stirred under 1 atmosphere of H2 overnight. After flushing with N2, the mixture was filtered through diatomaceous earth. The filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 0% to 10% MeOH in EtOAc, to afford 3-(4-sec-butylphenyl)-2-(3,4-diaminophenyl)quinazolin-4(3H)-one (0.130 g, 62%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[O:8])=[CH:5][NH:4][N:3]=1.F[C:10]1[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=1>>[CH:7]([C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:10]2[C:15]([C:16]#[N:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=1)=[O:8]
Reactant: Cc1n[nH]cc1C=O
Reactant: N#Cc1cccnc1F
Product: Cc1nn(-c2ncccc2C#N)cc1C=O
Yield: 23 %

Procedure:
The compound of Preparation 20 is essentially prepared as described in Preparation 19 by using 3-methyl-1H-pyrazole-4-carbaldehyde and 2-fluoropyridine-3-carbonitrile. The title compound is obtained with a yield of 23%. MS (m/z): 213 (M+1).
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH:21][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Product: O=C(Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2)C1CC1
Yield: 82.5 %

Procedure:
Prepared from N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 87) (142 mg, 0.50 mmol, HPLC 0.776 min) and cyclopropylcarbonyl chloride (53 ul, 0.55 mmol) according to the procedure described for Example 17. Obtained the title compound as a white solid (145 mg, 83%, HPLC 1.071 min), MS (ISP) m/e=352.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(C)CC5)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Yield: 53.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-(4-methylpiperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (74 mg, 0.119 mmol) was hydrolyzed by lithium hydroxide (50 mg, 1.19 mmol), THF/Methanol/water (12/6/3 ml) to yield 8 mg (30 mg 53.9% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.4 (b, 1H), 8.566-8.559 (d, 1H), 8.185-8.178 (d, 1H), 7.874 (s, 1H), 7.706 (s, 1H), 7.451-7.443 (d, 1H), 7.413-7.3 (m, 2H), 7.2-6.956 (m, 5H), 5.392 (s, 2H), 3.340-3.307 (m, 4H), 2.669-2.636 (m, 4H), 2.401 (s, 3H). MS: m/z=467.4 (M+1); HPLC: 98.239% in method B.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])(CC)C.[CH2:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]2)=[C:30]([F:41])[C:29]=1[F:42])[CH3:26].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1CCCCC1.CCCCCC>[F:18][C:14]1[C:13]([F:19])=[C:12]([CH:9]2[CH2:10][CH2:11][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)[CH:17]=[CH:16][C:15]=1[C:37]1([OH:40])[CH2:36][CH2:35][CH:34]([C:31]2[CH:32]=[CH:33][C:28]([O:27][CH2:25][CH3:26])=[C:29]([F:42])[C:30]=2[F:41])[CH2:39][CH2:38]1
Reactant: CCCCCC1CCC(c2cccc(F)c2F)CC1
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC1CCC(c2ccc(C3(O)CCC(c4ccc(OCC)c(F)c4F)CC3)c(F)c2F)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
4-Pentyl-(2,3-difluorophenyl)cyclohexane (10) (5.0 g) and THF (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. sec-Butyllithium (1.00 M, in a n-hexane and cyclohexane solution; 23.0 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the mixture was stirred for another 2 hours. 1-(4-Ethoxy-2,3-difluorophenyl)-cyclohexan-4-one (50) (4.8 g) dissolved in THF (150 ml) was slowly added dropwise thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to return to 25° C. The reaction mixture obtained was poured into a vessel containing an aqueous solution of ammonium chloride (3%; 500 ml) and toluene (300 ml) which had been cooled to 0° C., and mixed. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and extraction into an organic phase was carried out. The organic phase obtained was fractionated, washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 9.7 g of 1-(2,3-difluoro-4-(4-pentylcyclohexyl)phenyl)-4-(4-ethoxy-2,3-difluorophenyl)cyclohexanol (51). The compound (51) obtained was a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.S(Cl)(Cl)(=O)=O.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][C:2]1([C:22]2[CH:23]=[CH:24][C:19]([OH:25])=[CH:20][CH:21]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: Oc1ccccc1
Reactant: CC1Sc2ccccc2N(C)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: CN1C(=O)C(C)(c2ccc(O)cc2)Sc2ccccc21
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a stirred solution of 3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzothiazine (4.8 g) in methylene chloride (25 ml), sulfuryl chloride (3.5 g) is added under ice-cooling. The mixture is stirred for 30 minutes, and added into a solution of phenol (2.4 g) and aluminum chloride (3.3 g) in methylene chloride (20 ml) with stirring under ice-cooling. The mixture is stirred for 1 hour under ice-cooling, and washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The solution is dried over anhydrous sodium sulfate and concentrated in vacuo. A mixture of benzene and n-hexane (1:1) is added to the residue and the separated crystals are collected by filtration to give 6.4 g (90.2%) of the titled compound.
Reaction SMILES: [C@@H:1]1([N:10]2C=[N:16][C:14](N)=[N:13][C:11]2=[O:12])O[C@H](CO)[C@@H:4](O)[C@H:2]1O.C([O-])(=O)CCC.[Na+]>>[CH3:4][C:2]1[C:14]([NH2:16])=[N:13][C:11](=[O:12])[NH:10][CH:1]=1
Reactant: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: CCCC(=O)[O-]
Agent: [Na+]
Product: Cc1c[nH]c(=O)nc1N
Reaction time: 0 h

Procedure:
The slides produced with cells grown in presence of either Cd+Cr+H2O2 or 5-azacytidine, or sodium butyrate are incubated overnight at 4° C. in the presence of 30 μl of an anti-5 methylcytosine sheep antibody (Abcam, Ab1884) diluted 1/100 in PBS. The slides are washed once in PBS and then incubated for 15 seconds in the presence of 30 μl of NaOH 7×10−5 N. After washing with PBS, the slides are finally incubated 30 minutes in the presence of a donkey anti-sheep IgG antibody (southern Biotechnology Associates, Inc) diluted at a concentration of 0.1 μg 1 1×106 cells in PBS.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[CH3:1][C:2]1[C:14]2[N:13]([CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:14])[CH:11]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)CCBr
Reactant: Cc1nccc2c1[nH]c1cc(O)ccc12
Product: Cc1nccc2c3ccc(OCCC(C)C)cc3n(CCC(C)C)c12
Yield: 69 %

Procedure:
The title compound was synthesized from 1-methyl-7-hydroxy-β-carboline (1.504 g, 4.770 mmol) in presence of 1-bromo-3-methylbutane (1.440 g, 9.520 mmol) as described here above.
Reaction SMILES: CC1(C)CC2C=C3N(CCNC3=O)C=2C1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:34][CH2:33][N:32]3[C:25](=[CH:26][C:27]4[CH2:28][C:29]([CH3:36])([CH3:35])[CH2:30][C:31]=43)[C:24]2=[O:37])[C:18]=1[CH:38]=[O:39].[BH4-].[Na+].B(O)(O)[B:43]([OH:45])[OH:44].CC([O-])=O.[K+]>CO.C(Cl)Cl.CCO.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:34][CH2:33][N:32]3[C:25](=[CH:26][C:27]4[CH2:28][C:29]([CH3:36])([CH3:35])[CH2:30][C:31]=43)[C:24]2=[O:37])[C:18]=1[CH:38]=[O:39].[CH3:35][C:29]1([CH3:36])[CH2:28][C:27]2[CH:26]=[C:25]3[N:32]([CH2:33][CH2:34][N:23]([C:19]4[C:18]5[CH2:38][O:44][B:43]([OH:45])[C:17]=5[CH:22]=[CH:21][N:20]=4)[C:24]3=[O:37])[C:31]=2[CH2:30]1
Reactant: OB(O)B(O)O
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc2c1COB2O)C3=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
4-Chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 107e was prepared following the procedures for intermediate 108a in U.S. Pat. No. 8,716,274, Example 108, Figure 8, and from 4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one from U.S. Pat. No. 8,729,072, Example 103e. To a solution of 107e (12.0 g, 35.0 mmol) in MeOH (40 mL) and DCM (40 mL) was added NaBH4 (1.83 g, 38.4 mmol) in batches at 0° C. The reaction mixture was stirred at 0° C. for 1 h, quenched with water and concentrated. The residue was partitioned between EA and brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude product 4-Chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbinol 107f was used in next step without further purification (9.6 g, 80%). A mixture of compound 107f (9.6 g, 27.8 mmol), tetrahydroxydiborane, hypodiboric acid (7.43 g, 83.5 mmol), Xphos-Pd-G2 (218 mg, 0.278 mmol), Xphos (321 mg, 0.556 mmol) and KOAc (6.85 g, 83.5 mmol) in EtOH (200 mL) was heated to 80° C. for 1 h and concentrated. The residue was dissolved in sat. K2CO3 (100 mL) and extracted with DCM 4 times. The organic phase was discarded and the aqueous layer was neutralized with conc. HCl. White precipitate evolved and the suspension was extracted with DCM. The organic layer was combined, dried over Na2SO4, filtered and concentrated to give 107g as a gray solid (6.21 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([NH:22][CH2:19][CH2:20][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Yield: 91.1 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (10 mg, 0.385 mmol) and propylamine (228 mg, 3.85 mmol) in methanol (50 ml) were heated at 120° C. for 10 hours in autoclave. The reaction mixture was condensed in vacuo and to the residue was added 5N aqueous sodium hydroxide, followed by extraction with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (99 mg, yield 91%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]([CH3:20])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH:32]=O)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26].C([BH3-])#N.[Na+]>CO>[CH3:21][O:22][C:23]1[CH:30]=[C:29]([CH2:31][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:12]([C:3]3[CH:4]=[CH:5][C:6]4[C:7](=[O:11])[O:8][CH2:9][C:10]=4[C:2]=3[CH3:1])[CH3:20])[CH2:15][CH2:16]2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: COc1cc(CC=O)ccc1C#N
Reactant: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CC(C)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 4-methyl-5-[1-(piperazin-1-yl)propan-2-yl]-2-benzofuran-1(3H)-one (25 mg, 0.080 mmol) and 2-methoxy-4-(2-oxoethyl)benzonitrile (17 mg, 0.097 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (7 mg, 0.113 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 434.3 [M+1]+. (0.17 μM)
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17](=[O:38])[NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])(C)(C)C>C(Cl)Cl.CN(C=O)C>[ClH:1].[NH2:14][CH2:15][CH2:16][C:17]([NH:18][CH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29])=[O:38]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NCCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 168 h
Yield: 74 %

Procedure:
4N HCl/dioxane (3.4 mL) was added to a stirred solution of (2-{[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-carbamoyl}-ethyl)-carbamic acid t-butyl ester (1.5 g, 3.4 mmol) in CH2Cl2 (50 mL) and DMF (25 mL). The mixture was stirred at room temperature for 7 days. The mixture was filtered to give 3-amino-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-propionamide hydrochloride (1.0 g, 74%) as a white solid: mp 249-251° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.37-2.65 (m, 4H, 2CH2), 2.86-2.99 (m, 3H), 4.34-4.57 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.8 and 13.1 Hz, 1H, CH), 7.46-7.64 (m, 3H, Ar), 8.02 (s, 3H, NH3), 8.78 (t, J=5.3 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.17, 31.94, 35.09, 39.02, 46.21, 51.57, 121.71, 128.27, 130.81, 131.65, 134.28, 140.14, 167.99, 169.47, 170.96, 172.83; Anal. calcd. for C17H21N4O4Cl: C, 52.38; H, 5.69; N, 14.37; Cl, 9.09. Found: C, 52.31; H, 5.56; N, 14.19; Cl, 9.01.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][C@@H:30]([NH2:33])[CH2:29]1)[CH3:27]>CS(C)=O.CO>[CH2:26]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: CCN1CC[C@@H](N)C1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CS(C)=O
Solvent: CO
Product: CCN1CC[C@H](Nc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Temperature: 120 °C
Yield: 65.4 %

Procedure:
A solution of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.13 g) and (R)-1-ethylpyrrolidin-3-ylamine (Intermediate 193, 1.22 g) in DMSO (0.7 mL) was stirred and heated in a sealed vessel at 120° C. for 22 hours. After cooling, the mixture was diluted with methanol and concentrated under vacuum. The residue was purified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-yl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.107 g) as a white solid.