Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#N)[CH2:10][CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.C([Li])(C)(C)C.C1C[O:24]CC1>>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([CH2:6][C:7]3([CH2:10][CH2:9][CH2:8]3)[C:11]2=[O:24])=[CH:4][CH:3]=1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CCC1
Reactant: C1CCOC1
Agent: [Li]C(C)(C)C
Product: O=C1c2cc(Br)ccc2CC12CCC2
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
A dried flask charged with 1-(4-bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37, 2.60 g, 6.91 mmol), was dissolved in dry THF (100 mL) under an argon atmosphere. The resulting mixture was cooled to −78° C. and then was tert-butyllithium (1.7 M in pentane, 8.13 mL, 13.83 mmol), added dropwise. The reaction was stirred for 1.5 h at −78° C. and then the reaction was quenched with MeOH (0.5 mL), followed by aq. hydrochloric acid (2M, 10 mL). The resulting solution was concentrated to remove the organic solvent and then partitioned between DCM and water. The organic phase was dried over MgSO4 and concentrated to give a crude product which was purified by flash chromatography (eluent: heptane/EtOAc20:1-15:1-10:1) to afford the title compound (1.1 g, 63% yield): 1H NMR (500 MHz, CDCl3) δ ppm 1.97-2.13 (m, 3 H), 2.13-2.24 (m, 1 H), 2.45-2.60 (m, 2 H), 3.24 (s, 2 H), 7.31 (d, 1 H), 7.67 (dd, 1H), 7.88 (d, 1 H); GC MS (EI) m/z 250 M
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:2]([OH:1])(=[O:38])[C:27]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:26]=1.[C:31]([OH:38])(=[O:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1
Reaction time: 24 h

Procedure:
2.5 g of 1α,24-dihydroxycholesterol was mixed with 2.10 g of benzoyl chloride and 40 ml. of pyridine, and the mixture was allowed to stand for one day at 20° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[F:34][C:35]1[CH:36]=[C:37]([S:41]([N:12]2[C:6]3[CH:7]=[N:8][C:9]4[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]=3[N:14]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:19][CH:20]=3)[C:13]2=[O:26])(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2ncc3c(c2c1)n(-c1ccc(C(C)(C)C#N)cc1)c(=O)n3S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added 3-fluorobenzene-1-sulfonyl chloride (84 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 20 mg (14%); 1H NMR (DMSO-d6, 300 MHz): δ 9.341 (s, 1H), 8.039-8.059 (d, 2H, J=6 Hz), 7.939-7.967 (d, 1H, J=8.4 Hz), 7.683-7.811 (m, 6H), 7.469-7.499 (d, 1H, J=9 Hz), 6.433 (s, 1H), 2.112 (s, 3H), 1.780 (s, 6H); MS: m/z 501 (M+).
Reaction SMILES: COC1C=C(C=CC=1C1SC=CC=1)[NH2:6].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.O>C(O)(=O)C>[C:18]1(=[O:19])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[NH:6]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1cc(N)ccc1-c1cccs1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)c2ccccc21

Procedure:
A stirred mixture of 5.1 g (0.025 mole) of 3-methoxy-4-(thien-2-yl)aniline (prepared in Example 4) and 4.1 g (0.03 mole) of phthalic anhydride in 20 ml of glacial acetic acid was heated at reflux for approximately 18 hours. The hot reaction mixture was poured into 700 ml of distilled water forming a precipitate. The precipitate was collected by filtration and the filter cake dissolved in methylene chloride. The methylene chloride solution was washed first with a 10% aqueous potassium carbonate solution and then with an aqueous sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate by evaporation under reduced pressure to yield 8.2 g of 2-[4-thien-2-yl)-3-methoxyphenyl]-1H-isoindol-1,3-(2H)-dione as a solid (mp 153°-155° C.).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.CS(O[CH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)(=O)=O.C(=O)([O-])O.[Na+]>CC(=O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: CS(=O)(=O)OCc1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2cnccn2)C[C@H]1OC

Procedure:
4.7 Parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide were dissolved in 160 parts of 2-propanone. Then there were added successively 3.2 parts of [(2-pyrazinyl)methyl] methanesulfonate (ester) and 1.7 parts of sodium hydrogen carbonate. The whole was stirred and refluxed for 18 hours while nitrogen gas was introduced. The precipitated product was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized twice from acetonitrile, yielding 1.16 parts of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(2-pyrazinylmethyl)-4-piperidinyl]-benzamide; mp. 203.5° C. (compound 144).
Reaction SMILES: [CH2:1](O)CCCCO.C(O)C(O)CCCC.N1CCCC1=O.CCCCC([CH2:29][CH2:30][CH:31]([O:36]S([O-])(=O)=O)[CH2:32][CH:33]([CH3:35])[CH3:34])CC.[Na+]>O>[CH3:35][CH:33]([CH2:32][C:31]([OH:36])([C:30]#[CH:29])[CH3:1])[CH3:34]
Reactant: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Reactant: OCCCCCO
Agent: CCCCC(O)CO
Agent: O=C1CCCN1
Agent: [Na+]
Solvent: O
Product: C#CC(C)(O)CC(C)C
Yield: 188.1 %

Procedure:
Ink I-1 containing inventive Dye 1 was prepared by dissolving 0.57 g dye, 1 g 1,5-pentanediol, 0.2 g 1,2-hexanediol, 0.6 g 2-pyrrolidinone, 0.04 g Tergitol 15-S-9 and 0.03 g Surfynol 465® (Air Products Co.) in enough water to give a total weight of 10 g. Ink I-2 was made in the same way except 0.52 g of inventive Dye 2 was used.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[NH:4][C:3]1=[O:16].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12](=[O:14])[CH3:13])[C:6]=2[C:5](=[O:15])[N:4]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[CH3:23])[C:3]1=[O:16]
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(=O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCCCn1c(=O)c2c(ncn2CC(C)=O)n(C)c1=O

Procedure:
22.2 g (0.1 mol) of 3-methyl-7-(2-oxopropyl)-xanthine from Example 7a are stirred together with 14.8 g (0.11 mol) of 1-chloro-5-hexanone and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide at 110° C. for 1.5 hours. The mixture is then allowed to cool slowly, with further stirring, and filtered, the salt on the suction filter is rinsed thoroughly with dimethylformamide, the solution is concentrated under reduced pressure, the residue is taken up in 200 ml of methanol, 50 ml of water and 2 ml of concentrated sulfuric acid are added and the mixture is boiled under reflux for one hour. After removal of the methanol in vacuo, the residue is rendered alkaline with 33% strength sodium hydroxide solution and the mixture is extracted thoroughly by shaking with chloroform. The combined chloroform extracts are washed with a little water until neutral and dried over sodium sulfate and the solvent is distilled off in vacuo, whereupon 25.8 g of solid crude product (80.5% of theory) are obtained and are recrystallized from ethanol, with the addition of petroleum ether, at the boiling point.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH+:9]([O-])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:3][CH:2]=1.C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:22]([C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][N:1]=1)#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)[NH+]([O-])CCc1ccncc1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCc1ccnc(C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.1 %

Procedure:
tert-Butyl 2-(4-pyridyl)ethylcarbamate N-oxide (7.4 g, 31 mmol) was dissolved in nitroethane (100 ml), and trimethylsilyl cyanide (9.2 g, 92 mmol) and N,N-dimethylcarbamoyl chloride (6.7 g, 62 mmol) were added thereto. The mixture was stirred at room temperature for 10 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (6.6 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:17])[C:3]=1[OH:18].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-:27].[K+].[K+]>C(#N)C>[F:16][C:13]([F:14])([F:15])[C:8]([C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([CH3:17])[CH:5]=1)([OH:27])[C:9]([F:10])([F:11])[F:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(C(F)(F)F)C(F)(F)F)cc(C)c1O
Reactant: CCOC(=O)CBr
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reaction time: 5 h

Procedure:
To 2,6-dimethyl-4-(hexafluoro-2-propyl)phenol [Farah, et al, J. Org. Chem., 30, 1003 (1965)], (10.0 g=35 mmol) in 100 ml acetonitrile add ethyl bromoacetate (6.9 g=42 mmol) and potassium carbonate (9.7 g=69 mmol). Stir 5 hours, filter and concentrate. Partition between ether and 1.0 N HCl. Dry and concentrate the ether extract. Recrystallize from ether-hexane to obtain, as white crystals, m.p. 99°-101° C., ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]4[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[CH2:25][C@H:14]34)=[O:12])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2ncsc2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 36 %

Procedure:
The title compound is prepared from benzothiazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 36% of theory; LC (method 4): tR=1.94 min; Mass spectrum (ESI+): m/z=335 [M+H]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([C:14](OCC)=[O:15])[CH:11]=[C:10]([CH3:19])[N:9]=1.C(O)(=O)C>C1COCC1>[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH3:19])[N:9]=1
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(CO)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.7 %

Procedure:
Lithium aluminium hydride (350 mg, 9.26 mmol) was added in portions to a solution of ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (1.85 g, 9.26 mmol) in THF (40 ml) cooled at 0° C. The mixture was stirred for 15 minutes at 0° C. and acetic acid (2 ml) was added. The mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7.5 with 5 % aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (35/65) to give 2-chloro-4-hydroxymethyl-6-methylpyridine (1.28 g, 88%). 1H NMR Spectrum: (CDCl3) 1.92(t, 1H); 2.53(s, 3H); 4.70(d, 2H); 7.06(s, 1H); 7.16(s, 1H) MS-ESI: 157 [MH]+
Reaction SMILES: C([O:3][C:4](=[O:38])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Li+]>C(O)C.O.C(OCC)(=O)C>[C:7]([NH:6][C@H:5]([C:4]([OH:38])=[O:3])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:20][CH:21]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCSCCOc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSCCOc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a suspension of N-benzoyl-O-dodecanylthioethyl-L-tyrosine ethyl ester (4.2 g, 7.75 mmol) in ethanol (50 ml) was added a solution of lithium hydroxide (0.42 g, 10.08 mmol) in water (5 ml). The solution was stirred at room temperature for 4 hours and then diluted with ethyl acetate and washed with 1N hydrochloric acid and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (3.84 g, 96%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([C:24]#[CH:25])[CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:27]1CCOCC1.ClC(OCC(C)C)=O.N.Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([C:24]#[CH:25])[CH2:22][CH2:21][C@H:17]1[C:18]([NH2:27])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of N-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-proline (2.83 mmol) and N-methyl morpholine (0.39 mL, 3.50 mmol) in THF (15 mL) was added isobutyl chloroformate (0.42 mL, 3.25 mmol). The resulting cloudy white mixture was stirred at 0° C. for 30 minutes followed by the addition of a solution of ammonia (0.5 Min dioxane, 10.0 mL, 5.0 mmol). The solution was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted by the addition of 1 M HCl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:13]2[CH2:15][CH2:14]2)[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]#[N:12].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([CH:13]2[CH2:15][CH2:14]2)[C:2]=1[NH:1][C:16](=[O:18])[CH3:17])#[N:12]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1c2c(n(C3CC3)c1N)CCCC2
Product: CC(=O)Nc1c(C#N)c2c(n1C1CC1)CCCC2
Yield: 71.5 %

Procedure:
A solution of 2-amino-1-cyclopropyl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile (3 g, 14.91 mmol) in acetic anhydride (24 ml, 254 mmol) was stirred at rt for 2.5 hours. The precipitate was filtered, washed with Ac2O, and dried to give N-(3-cyano-1-cyclopropyl-4,5,6,7-tetrahydro-1H-indol-2-yl)acetamide (2.5948 g, 10.66 mmol, 71.5% yield) as white solid. The filtrate was concentrated, suspended with Et2O, stirred, and filtered to give additional product (690 mg, 2.84 mmol, 19.03% yield) as light brown solid: 1H NMR (400 MHz, CHLOROFORM-d) δ=7.22 (br. s., 2 H), 2.98-2.86 (m, 1 H), 2.56 (t, J=5.9 Hz, 2 H), 2.49 (t, J=5.9 Hz, 2 H), 2.22 (s, 3 H), 1.88-1.65 (m, 4 H), 1.01-0.89 (m, 2 H), 0.88-0.76 (m, 2 H).
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].CCN(CC)CC.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[N+:30]([O-:32])=[O:31]>CC(C)=O>[N+:27]([C:24]1[CH:23]=[C:22]([N+:30]([O-:32])=[O:31])[CH:21]=[CH:26][C:25]=1[O:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])([O-:29])=[O:28]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=[N+]([O-])c1ccc(Br)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a suspension of 2-hydroxyisoindoline-1,3-dione (20.0 g, 0.12 mol) in acetone (400 mL) was added Et3N (14.9 g, 0.15 mol), the mixture was stirred at room temperature until it became a homogeneous solution, then 1-bromo-2,4-dinitrobenzene Y-1 (30.2 g, 0.12 mol) was added. The reaction was stirred at room temperature for 3 h, then poured into ice-water, the resulting precipitate was filtered and washed three times with cold MeOH, dried in vacuum to afford the title compound (38.1 g).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.Cl.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].CS(C)=O.C(N(CC)CC)C>CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: COC(=O)CCCN
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: COC(=O)CCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.142 g (0.925 mmol) of gamma amino butyric acid, methyl ester hydrochloride were placed into a 10 ml round bottom flask with a magnetic stirring bar and 2 ml dimethylsulfoxide. To this solution was added 0.100 g (0.988 mmol) of triethylamine. The solution immediately turned green and was stirred at room temperature for one hour. Then 5 ml of acetone was added and the solution was filtered. The mother liquor was treated with ether (approximately 35 ml) to precipitate the product. Upon filtration and washing with ether, 232 mg of a white solid 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]butanoic acid, methyl ester (AIT-0092) was obtained. Yield: 83%.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]C1.[I-].[K+].Cl[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19].[CH3:21][C:22](C)=O>>[N:11]1([CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])[C:6]2[C:7](=[CH:8][CH:9]=[C:10]3[O:1][CH2:3][CH2:4][C:5]3=2)[CH2:22][CH2:21]1
Reactant: Nc1cccc2c1CCCO2
Reactant: CC(C)=O
Reactant: CC(=O)NCCCl
Agent: [I-]
Agent: [K+]
Product: CC(=O)NCCN1CCc2ccc3c(c21)CCO3

Procedure:
A mixture of Intermediate 4 (50 mg), potassium iodide (1 g) and N-(2-chloroethyl)acetamide (96 mg) in acetone (5 ml) was heated to reflux for 2 days. The cooled mixture was partitioned between water and ethyl acetate. The extracts were dried, and evaporated, and the residue chromatographed on silica gel. Elution with CH2Cl2 :EtOH:NH3 ; 400:8:1 gave a sample of desired material (69 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCCCC)CCC.[Cu]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([NH:1][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1N
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 160 °C

Procedure:
A mixture of 1-(2-amino-4-chlorophenyl)-ethanone (1.85 g), copper powder (140 mg), KI (360 mg), K2CO3 (3.06 g) and iodobenzene (4.8 mL) in dibutyl ether (40 mL) was heated at 160° C. (oil bath temperature) overnight. More copper powder (140 mg), KI (360 mg), K2CO3 (3.06 g) and iodobenzene (4.8 mL) were added and the reaction mixture was heated at reflux overnight. The resulting mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane) to afford 2.2 g of 1-(4-chloro-2-phenylamino-phenyl)-ethanone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl-].[CH3:11][NH2+:12][CH3:13].[CH2:14]=O>C(O)CCC>[CH3:11][N:12]([CH2:14][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:13]
Reactant: C[NH2+]C
Reactant: c1cnc2[nH]ccc2c1
Reactant: C=O
Agent: [Cl-]
Solvent: CCCCO
Product: CN(C)Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 67.1 %

Procedure:
7-azaindole (5.0 g, 17 mmole), dimethylammonium chloride (3.76 g), and paraformaldehyde (1.40 g) were dissolved in n-butanol (30 mL). The reaction was refluxed for 1 hour where upon cooling to room temperature fluffy white needles crystalized out. These were filtered and washed with butanol (10 mL). The solid was dried in vacuo to a white crystalline solid massing 6.1 g. A portion of this material (2.0 g) was converted to the free base by dissolving in 20 mL water. Upon the addition of ammonium hydroxide (aqueous, 30%) (2 mL) a white precipitate formed, was filtered, washed with water (5 mL), and dried in vacuo to yield 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (2.0 g, 27% yield). δH (300 MHz CDCl3) 2.27 (6H, s), 3.61 (2H, s), 7.09 (1H, dd, J=4.5 and 8.0), 7.28 (1H, s), 8.04 (1H, dd, J=1.2 and 8.1), 8.32 (1H, dd, J=1.2 and 4.7), ESMS 176 (MH+)