Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=O)[CH2:8][CH2:7]1.[CH2:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1.C(=O)([O-])O.[Na+]>CC(O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9](/[CH:13]=[C:33]2/[C:29]([NH:28][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]azepane-4-carbaldehyde (156.5 mg) in 2-propanol (2.22 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (137 mg) and piperidinium acetate (64.3 mg). The reaction mixture was stirred at 60° C. overnight, allowed to cool to room temperature, poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to give the title compound (63.0 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][CH:16]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1)[CH:17]([OH:31])[C:18]([F:30])([F:29])[C:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C>C(O)=O>[NH2:8][C@H:9]([C:13]([NH:15][CH:16]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][N:42]2[CH2:43][CH2:44][O:45][CH2:46][CH2:47]2)=[CH:35][CH:34]=1)[CH:17]([OH:31])[C:18]([F:30])([F:29])[C:19]([NH:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc(OCCN2CCOCC2)cc1)C(O)C(F)(F)C(=O)NCc1ccccc1
Solvent: O=CO
Product: CC(C)[C@H](N)C(=O)NC(Cc1ccc(OCCN2CCOCC2)cc1)C(O)C(F)(F)C(=O)NCc1ccccc1

Procedure:
A solution of 4(N-tert-butoxycarbonyl-L-valyl)amino-2,2-difluoro-3-hydroxy-5[4(2-{N-Morpholinyl}Ethyloxy)Phenyl]N-benzyl pentanamide (0.19 g, 0.28 mmol) in formic acid (15 ml) was stirred at room temperature for 4 hours. After evaporation of the solvent in vacuo, the residue was diluted with ethyl acetate (50 ml) and washed three times with a saturated solution of sodium carbonate (3×10 ml) and brine (10 ml). The organic layer was dried over magnesium sulphate.
Reaction SMILES: [C:1](Cl)(C)=O.[CH3:5][C:6]1[N:10]2[C:11]3[CH:17]=[CH:16][NH:15][C:12]=3[N:13]=[CH:14][C:9]2=[C:8]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=2)[N:7]=1>CO>[CH3:5][C:6]1[N:10]2[C:11]3[CH:17]=[CH:16][NH:15][C:12]=3[N:13]=[CH:14][C:9]2=[C:8]([C:18]2[CH:19]=[N:20][N:21]([CH2:23][C:24]([O:26][CH3:1])=[O:25])[CH:22]=2)[N:7]=1
Reactant: Cc1nc(-c2cnn(CC(=O)O)c2)c2cnc3[nH]ccc3n12
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cn1cc(-c2nc(C)n3c2cnc2[nH]ccc23)cn1
Yield: 40 %

Procedure:
AcCl (20 mL) was added slowly with stirring to MeOH (100 mL) that was cooled in an ice bath. After about 1 h the solution was transferred to the 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)-1H-pyrazol-1-yl)acetic acid. The solvents were removed under reduced pressure and saturated Na2CO3 (25 mL) was added. The product was extracted with DCM (5×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel) and eluted with a gradient of 2-9% MeOH in DCM to give methyl 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)-1H-pyrazol-1-yl)acetate (0.109 g, 40%): LCMS (Table 2, Method b) Rt=1.46 min.; MS m/z: 311 (M+H)+. Syk IC50=B.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:4][CH2:3]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[C:12]([NH:14][C:15]2[CH:16]=[C:17]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[CH:26]=3)=[O:24])[CH:18]=[CH:19][C:20]=2[CH3:21])=[O:13])[CH2:4][CH2:3]1
Reactant: C1COCCN1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Solvent: O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CN2CCN(C)CC2)c1
Temperature: 110 °C

Procedure:
Using an analogous procedure to that described in Example 3, a mixture of N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-chloropyridine-4-carboxamide (0.5 g) and morpholine (5 ml) was stirred and heated to 110° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water and extracted with methylene chloride. The organic phase was evaporated and the residue was purified by column chromatography on an isolute SCX ion exchange column using a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound (0.023 g); Mass Spectrum: M+H+529.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[Cl:14][C:15]([Cl:25])([Cl:24])[CH2:16][O:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>C(Cl)Cl>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([NH:1][C:22]([NH:21][S:18]([O:17][CH2:16][C:15]([Cl:25])([Cl:24])[Cl:14])(=[O:19])=[O:20])=[O:23])[N:11]=1
Reactant: O=C=NS(=O)(=O)OCC(Cl)(Cl)Cl
Reactant: COc1nc(N)nc2nccnc12
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)OCC(Cl)(Cl)Cl)nc2nccnc12
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a suspension of 0.88 g (0.005 mol) of 2-amino-4-methoxypteridine in 40 ml of absolute methylene chloride were added with stirring to 1.35 g (0.053 mol) of 2,2,2-trichloroethoxysulfonyl isocyanate. After about 10 minutes, a clear solution had formed and it was heated to reflux. After 10 minutes, the mixture was evaporated to dryness and the residue was treated with diisopropyl ether and a little acetone. The mixture was vacuum filtered and the product was dried to obtain 2.05 g (95% of theory) of N-(4-methoxypteridin-2-yl)-N'-(2,2,2-trichloroethoxysulfonyl)-urea in the form of yellow crystals melting at 93° C. (decomp.).
Reaction SMILES: C(O[CH2:5][C:6]1[CH:14]=[CH:13][C:12]2[CH2:15][NH:16][C@@H:17]([CH:20]3[CH:25]4[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]4)[CH2:21]3)[C:18](=[O:19])[N:10]3[C:11]=2[C:7]=1[CH:8]=[CH:9]3)(=O)C.C(O)(=O)C>CO.[Pd]>[CH3:5][C:6]1[CH:14]=[CH:13][C:12]2[CH2:15][NH:16][C@@H:17]([CH:20]3[CH:25]4[CH2:24][CH2:23][N:22]([CH2:27][CH2:26]4)[CH2:21]3)[C:18](=[O:19])[N:10]3[C:11]=2[C:7]=1[CH:8]=[CH:9]3
Reactant: CC(=O)OCc1ccc2c3c1ccn3C(=O)[C@H](C1CN3CCC1CC3)NC2
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c3c1ccn3C(=O)[C@H](C1CN3CCC1CC3)NC2
Reaction time: 8 h

Procedure:
(S)-(1-Oxo-2-(quinuclidin-3-yl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)methyl acetate (124 mg, 0.34 mmol) from Step C above was dissolved in methanol (7 ml) and glacial acetic acid (3 ml). Excess 10% palladium on carbon was added and the suspension was stirred under an atmosphere of hydrogen (balloon pressure) overnight. The suspension was filtered through Celite and the filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) and preparative TLC (90:10:10 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-7-methyl-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one. This material was dissolved in methanol and treated with HCl (1.25 M solution in methanol) and the mixture was concentrated under reduced pressure. The residue was lyophilized from water to afford (S)-7-methyl-2-(quinuclidin-3-yl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-1(2H)-one hydrochloride (100 mg, 85%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.80 (d, J=4.0 Hz, 1H), 7.75 (d, J=3.8 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 4.90 (s, 1H), 4.22 (br s, 1H), 4.11 (br s, 1H), 3.77-3.72 (m, 2H), 3.48-3.29 (m, 6H), 2.35 (d, J=8.0 Hz, 1H), 2.21 (s, 3H), 2.06-1.96 (m, 4H); MS (ESI+) m/z 310 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][NH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=3)[CH:15]=2)[NH:10][N:9]=1)=[O:7].[OH-].[Na+].Cl>O1CCOCC1>[NH2:24][C:20]1[N:19]=[C:18]([NH:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][N:9]=[C:8]3[C:6]([NH:5][CH2:4][C:3]([OH:25])=[O:2])=[O:7])[CH:23]=[CH:22][N:21]=1
Reactant: COC(=O)CNC(=O)c1n[nH]c2ccc(Nc3ccnc(N)n3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc(Nc2ccc3[nH]nc(C(=O)NCC(=O)O)c3c2)n1
Yield: 7 %

Procedure:
A solution of {[5-(2-amino-pyrimidin-4-ylamino)-1H-indazole-3-carbonyl]-amino}acetic acid methyl ester (was prepared from Example N.2.8, B, 0.014 g, 0.043 mmol) and 2M aqueous NaOH solution (1.0 mL, 2.0 mmol) in 1,4-dioxane (2 mL) was stirred at ambient temperature for about 30 minutes. The reaction mixture was acidified with 1M aqueous HCl solution until pH 3. The white precipitation was filtered off, washed with water (3 mL) and dried under reduced pressure to give {[5-(2-amino-pyrimidin-4-ylamino)-1H-indazole-3-carbonyl]-amino}-acetic acid (0.001 g, 0.003 mmol); RP HPLC (Table 1, Method a) Rt=0.42 min; m/z: (M+H)+ 328.2.
Reaction SMILES: FC1C=C2C(=CC=1F)N([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])C=C2I.[I:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=2)[NH:25][CH:24]=1>>[I:22][C:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([F:33])([F:35])[F:34])=[CH:29][CH:30]=2)[N:25]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:24]=1
Reactant: FC(F)(F)c1ccc2c(I)c[nH]c2c1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)c(F)cc21
Product: O=S(=O)(c1ccccc1)n1cc(I)c2ccc(C(F)(F)F)cc21
Yield: 45 %

Procedure:
Following the general method as outlined in Intermediate 28, starting from 3-iodo-6-(trifluoromethyl)-1H-indole (Intermediate 39; 1.60 g; 5.14 mmol), 1.06 g (45%) of the title compound was obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[NH3:40]>>[NH2:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=S1(=O)CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Product: Nc1nccc(-c2sc(N3CCS(=O)(=O)CC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1
Yield: 38 %

Procedure:
Following a procedure analogous to Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dioxido-4-thiomorpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.30 g, 0.487 mmol) and 7 M ammonia (20 mL) the title compound was obtained (0.11 g, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (br. s., 1H), 7.85 (d, J=5.3 Hz, 1H), 7.63-7.75 (m, 1H), 7.42 (td, J=7.5, 1.7 Hz, 1H), 7.19-7.36 (m, 4H), 6.60 (br. s., 2H), 5.68 (d, J=5.1 Hz, 1H), 3.97 (br. s., 4H), 3.29 (br. s., 4H). m/z (ES+): 597 [M+H]+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([O:20][NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:34](=[O:35])[C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=2[O:31][C:30]2[CH:40]=[CH:41][CH:42]=[CH:43][C:29]1=2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)=O>C1COCC1.C(OCC)(=O)C>[CH2:13]([O:20][N:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:34](=[O:35])[C:33]2[CH2:36][CH2:37][CH:38]=[CH:39][C:32]=2[O:31][C:30]2[CH:40]=[CH:41][CH:42]=[CH:43][C:29]1=2)[CH:1]=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2Oc2ccccc2N1CCCCCCNOCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CN(CCCCCCN1C(=O)C2=C(C=CCC2)Oc2ccccc21)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
1,1′-Carbonyldiimidazole (1.26 g, 7.8 mmol) was dissolved in THF (15 mL) and the mixture was cooled at 0° C. Title compound 402 (0.646 g, 1.56 mmol) and formic acid in solution in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours then diluted in ethyl acetate. The organic phase was washed with a saturated aqueous solution of bicarbonate, water and brine, then evaporated. The residue was purified by flash chromatography (30-50% ethyl acetate in hexanes) to afford title compound 403 (348 mg, 50%) as a colorless oil. MS (m/z): 445.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(N(CC)CC)C.C(O)=O.C(OCC)(=O)C>[C].[Pt].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9]
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pt]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(Br)c(N)c1
Reaction time: 12 h
Yield: 98.9 %

Procedure:
4-Bromo-3-nitrotoluene (60.35 g, 279 mmol), 5% by weight platinum carbon (1.09 g, 0.28 mmol) and triethylamine (112.93 g, 1116 mmol) were stirred under heating at 100° C., to which formic acid (99%) (42.39 g, 921 mmol) was added dropwise over 20 minutes. After stirring for 12 hours, it was brought back to room temperature, and then 100 ml of ethyl acetate and 100 ml of water were added thereto. After stirring well, it was filtered through celite to remove platinum carbon. By further adding 200 ml of ethyl acetate and 100 ml of water, it was extracted, the organic phase was washed with water (300 ml×3 times), and dried on magnesium sulfate. The solvent was evaporated to obtain 2-bromo-5-methylaniline (51.30 g, 276 mmol). The yield was 99%.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([CH2:40][CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[CH:47]([NH:54]C(OC(C)(C)C)=O)[CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:32]2)[CH:18]=1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]([CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]([CH2:40][CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[CH:47]([NH2:54])[CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:32]2)[CH:18]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCCC1Cc1cn(CCOCCn2cc(CC3CCCN3C(=O)C(NC(=O)OC(C)(C)C)C3CCCCC3)c3ccccc32)c2ccccc12)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(C(=O)N1CCCC1Cc1cn(CCOCCn2cc(CC3CCCN3C(=O)C(N)C3CCCCC3)c3ccccc32)c2ccccc12)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.5 %

Procedure:
A solution containing 48 (0.085 g, 0.08 mmol) in DCM (8 mL) was cooled to 0° C. Trifluoroacetic acid (2 mL) was added and the reaction mixture was maintained at 0° C. for 30 min. An additional portion of TFA (1 mL) was added and the reaction mixture was stirred for 1 h at 0° C. The reaction was quenched by the careful addition of saturated aqueous NaHCO3 and the product was extracted with EtOAc. The combined organic extracts were washed with aq. NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.068 g of 49 as a pale yellow oil. The crude product was used directly in the next reaction. 1H NMR (CDCl3, 300 MHz) δ7.90 (d, J=7.6 Hz, 2H), 7.31-7.12 (m, 6H), 6.84 (app t, J=14 Hz, 2H), 4.47 (m, minor rotomer), 4.15 (m, 4H), 3.66-3.36 (m, 8H), 2.80 (m, 2H), 2.42 (m, 2H), 2.04-0.83 (m, 30H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:22]2[CH:27]=[CH:26][C:25](C=O)=[CH:24][CH:23]=2)=[C:13](\[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[C:30]([OH:36])(=[O:35])[CH2:31][C:32](O)=O.N1C=CC=CC=1.C(O)(=O)C>CC#N.O.CCCCCCC.N1CCOCC1>[C:16]1(/[C:13](/[CH2:14][CH3:15])=[C:12](/[C:22]2[CH:27]=[CH:26][C:25](/[CH:32]=[CH:31]/[C:30]([OH:36])=[O:35])=[CH:24][CH:23]=2)\[C:9]2[CH:10]=[CH:11][C:6]([O:5][C:1](=[O:4])[CH2:2][CH3:3])=[CH:7][CH:8]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CC(=O)O
Reactant: CCC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(C=O)cc2)cc1
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: O
Product: CCC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 5 °C
Yield: 80.3 %

Procedure:
To a mixture of 11 (20.0 g, 52 mmol) and malonic acid (8.10 g, 100 mmol) was added, sequentially, CH3CN (100 mL), pyridine (2.1 mL, 30 mmol) and morpholine (0.09 mL, 1.0 mmol). The mixture was then heated to reflux and the solvent distilled. The volume of the reaction was maintained constant by addition of fresh CH3CN until ˜30 volumes of solvent were distilled. The reaction was then cooled to 5° C. and a solution of acetic acid (2.08 mL, 36 mmol) in CH3CN (20 mL) added. The precipitated solid was filtered, washed with cold CH3CN (40 mmol) and H2O (40 mL) then slurried overnight in heptane (150 mL) at 35° C. The solid was filtered, rinsed with heptane (40 mL) and dried overnight in vacuo to yield 17.8 g (80%) of the title compound 7 as a white solid. 1HNMR (DMSO-d6): δ 0.26 (s, 6H), 0.83 (t, J=7.5 Hz, 3H), 0.94 (s, 9H), 2.35 (q, J=7.5 Hz, 2H), 6.39 (d, J=8.4 Hz, 2H), 6.53 (d, J=16 Hz, 1H), 6.58 (d, J=8.4 Hz, 2H), 7.06-7.18 (m, 5H), 7.2 (d, J=8 Hz, 2H), 7.59 (d, J=16 Hz, 1H), 7.69 (d, J=8 Hz, 2H), 9.19 (s, 1H); MS, m/z 485 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH3:15][C:16](OC(C)=O)=[O:17].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:16]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@H:2]([CH3:1])[CH2:7]1)(=[O:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(C(=O)OC(C)(C)C)[C@H](C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-tert-butyl 2-methylpiperazine-1-carboxylate (4.8 g, 23.97 mmol), Ac2O (3.39 mL, 36.0 mmol) and pyridine (3.88 mL, 47.9 mmol) in DCM (30 mL) was stirred at rt for 30 min. Reaction was diluted with EtOAc, washed with diluted HCl, brine and sat NaHCO3, brine, and dried over Na2SO4, concentrated. Resulting residue was treated with 1N NaOH in ether, extracted with ether, washed with brine, dried over Na2SO4, concentrated and purified by FCC (0-10% MeOH in DCM) to give (R)-tert-butyl 4-acetyl-2-methylpiperazine-1-carboxylate. 1H NMR (400 MHz, CD2Cl2) δ ppm 4.14-4.46 (m, 2 H) 3.74-3.91 (m, 1 H) 3.46-3.72 (m, 1 H) 2.92-3.35 (m, 2 H) 2.56-2.91 (m, 1 H) 2.05 (d, J=16.67 Hz, 3 H) 1.44 (s, 9 H) 1.03-1.18 (m, 3 H). MS (ESI+) m/z 243.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[C:32]1([CH3:41])[CH:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:38](=[O:39])[C:35]3[CH:36]=[CH:37][C:32]([CH3:41])=[CH:33][CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and p-toluoyl chloride (0.43 g, 2.8 mmol). The mixture was then stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and washed with H2O (40 mL), 1N HCl (40 mL) and brine (40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting mixture was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methyl-benzamide as a white solid (0.5 g, 61%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.3 (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.36 (s, 3H), 2.54-2.64 (m, 2H), 2.85-2.93 (m, 1H), 4.94 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 9.07 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 20.93, 31.97, 30.92, 38.26, 48.85, 121.81, 127.08, 127.30, 128.87, 131.11, 131.51, 132.98, 134.77, 139.47, 141.35, 166.47, 166.97, 167.54, 169.83, 172.74. Anal Calcd for C22H19N3O5: C, 65.18; H, 4.72; N, 10.36. Found: C, 64.78; H, 4.72; N, 10.07.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[OH-].[K+].[C:14]([O:18][C:19](=O)[O:20]C(C)(C)C)([CH3:17])([CH3:16])[CH3:15].CO>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:14]([O:18][C:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=Cc1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Indole-3-carboxaldehyde (4.53 g, 30 mmol) was dissolved in tetrahydrofuran (100 mL) (dissolved at about 40° C.). Aqueous potassium hydroxide (1N, 30 mL) and tetrabutylammonium bromide (0.97 g, 3 mmol) were added. Then di-t-butylcarbonate (7.2 g, 33 mmol) was added (the temperature should not rise about 25° C.). The resulting mixture was stirred at room temperature until the starting material was not detected by TLC (CH2CL2 /CH3OH 9:1). The reaction mixture was separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was dried with MgSO4 and evaporated to give crude product. The product was recrystallized from methylene chloride/hexane (20 mL/100 mL) to obtain needle crystals (7.19 g, 97.7%). m.p. 124°-125° C.