Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:14]=3)[N:9]=[C:8]([C:26]#[N:27])[C:7]=2[N:6]=[CH:5]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN(C=O)C.CO>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[N:9]=[C:8]([C:26]#[N:27])[C:7]3[N:6]=[CH:5][N:4]([CH2:3][CH2:2][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:12]=3[CH:11]=2)=[CH:14][C:15]=1[C:22]([F:25])([F:24])[F:23])[CH3:21]
Reactant: CCOc1ccc(-c2cc3c(ncn3CCBr)c(C#N)n2)cc1C(F)(F)F
Reactant: C1COCCN1
Solvent: CO
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2cc3c(ncn3CCN3CCOCC3)c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 66.3 %

Procedure:
1-(2-Bromo-ethyl)-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (92 mg, 0.21 mmol) was dissolved in DMF (2 ml) and morpholine (91 mg, 1.05 mmol) was added. The mixture was heated to 120° C. for 5 minutes in a Smith microwave. Mixture was diluted with methanol (5 ml) and passed through a 5 g SCX cartridge then eluted with 2M methanolic ammonia to afford 62 mg of 6-(4-ethoxy-3-trifluoromethyl-phenyl)-1-(2-morpholin-4-yl-ethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a clear oil. 1H NMR (CDCl3) δ 8.26-8.15 (m, 3H), 7.87 (s, 1H), 7.08 (d, 1H), 4.35 (t, 2H), 4.20 (q, 2H), 3.69 (m, 4H), 2.82 (t, 2H), 2.52 (m, 4H), 1.48 (t, 3H). MS m/z 446.4 (M+1).
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][C:6]1([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([N:31]6[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]6)[CH:26]=5)=[CH:23][CH:24]=[C:19]4[N:18]=[C:17]3[C:38]3[C:39]([NH2:44])=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl.CCOC(C)=O>[NH2:5][C:6]1([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20]4=[N:21][C:22]([C:25]5[CH:26]=[C:27]([N:31]6[CH2:32][CH2:33][CH:34]([NH:37][S:53]([CH3:52])(=[O:55])=[O:54])[CH2:35][CH2:36]6)[CH:28]=[CH:29][CH:30]=5)=[CH:23][CH:24]=[C:19]4[N:18]=[C:17]3[C:38]3[C:39]([NH2:44])=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCC(N)CC4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)CC1
Yield: 53.9 %

Procedure:
A solution of 3-{3-[4-(1-aminocyclobutyl)phenyl]-5-[3-(4-aminopiperidin-1-yl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine tetrahydrochloride (49 mg, 0.0731 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.061 mL, 0.439 mmol), then methanesulfonyl chloride (0.006 mL, 0.0804 mmol) at 0° C. and stirred at r.t for 3.5 hours. The mixture was diluted with AcOEt, washed with 0.5N NaOH, brine, dried over Na2SO4, then filtrated. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (CH2Cl2/MeOH=5:1) to afford desired product (24 mg, 54%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][OH:18])[N:8]2C2CCCCO2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:17][OH:18])[NH:8]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: OCc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: OCc1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: 50 °C
Yield: 100.4 %

Procedure:
(2-Chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)methanol (3.4 g, 0.0096 mol) in MeOH (20 mL) was treated with a catalytic amount of p-toluenesulfonic acid (0.25 g, 0.00144 mol). The reaction mixture was heated to 50° C. overnight and was then concentrated under reduce pressure. The residue was partitioned between water and EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to dryness to give (2-chloro-6-morpholino-9H-purin-8-yl)methanol (2.6 g, 100% yield). LC/MS (ESI+): m/z 271 (M+H)
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[C:7]1[CH2:12][CH:11]=[CH:10][C:9](=[CH:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]1Br)[CH2:4][CH3:5])[CH3:2].C([Li])CCC.[Cl-].[CH2:26]([In+:28][CH2:29][CH3:30])[CH3:27]>CCCCCC>[CH2:1]([N:3]([CH:6]=[C:7]1[CH2:12][CH:11]=[CH:10][C:9](=[CH:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:8]1[In:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CC[In+]CC
Reactant: CCN(C=C1C=CCC(=CN(CC)CC)C1Br)CC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCN(C=C1C=CCC(=CN(CC)CC)C1[In](CC)CC)CC

Procedure:
2.4 g (7.3 mmol) of 2,6-bis(diethylaminomethylene)phenyl bromide in 40 ml of hexane, 4.6 ml of butyllithium (7.3 mmol; 1.6 mol/l in hexane) and 1.5 g (7.3 mmol) of diethylindium chloride in 20 ml hexane are reacted analogously to Example 1 to give [2,6-bis(diethylaminomethylene)phenyl]diethylindium, which is obtained as a colorless liquid, b.p. 115° C./0.04 mbar, by vacuum distillation.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:12]=[C:13]4[CH:19]=[CH:18][N:17](CC5C=CC(OC)=CC=5)[C:14]4=[N:15][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:12]=[C:13]4[CH:19]=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2ccc3cc(-c4nc5ccc(F)nc5o4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2nc(-c3cnc4[nH]ccc4c3)oc2n1
Temperature: 170 °C
Yield: 6 %

Procedure:
Crude 5-fluoro-2-[1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-oxazolo[5,4-b]pyridine from Step 2 was dissolved in TFA (0.5 mL) and heated by microwave to 170° C. for 25 min. The volatiles were then removed in vacuo and the resulting residue was purified by HPLC to afford 5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-oxazolo[5,4-b]pyridine (2.5 mg, 9.8 μmol, 6% yield). ES MS (M+H+)=255; 1H NMR δ (ppm) (DMSO-d6): 12.18 (1H, s), 9.04 (1H, d, J=2.10 Hz), 8.76 (1H, d, J=2.06 Hz), 8.44 (1H, dd, J=8.39, 7.10 Hz), 7.67 (1H, t, J=2.75 Hz), 7.31 (1H, d, J=8.40 Hz), 6.68 (1H, d, J=3.43 Hz); HRMS m/z 255.0675 (C13H7FN4O+H+ requires 255.0677).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C@H:8]([C:17]([O:19][CH3:20])=[O:18])[S:7][C@H:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:4].O1[CH2:32][CH2:31][CH2:30][CH2:29]1>CC1C=C(N=C=O)C=CC=1>[CH3:20][O:19][C:17]([C@@H:8]1[S:7][C@@H:6]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:3]([NH:5][C:9]2[CH:10]=[CH:32][CH:31]=[C:30]([CH3:29])[CH:8]=2)=[O:4])[C@H:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[O:18]
Reactant: COC(=O)[C@@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CN)[C@H]1c1ccccc1F
Reactant: C1CCOC1
Agent: Cc1cccc(N=C=O)c1
Product: COC(=O)[C@@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1F

Procedure:
The process is performed in a similar manner to that described in Example 1, but starting with 0.34 g of tert-butyl (2S,4S,5R)-3-(2-aminoacetyl)-5-methoxycarbonyl-4-(2-fluorophenyl)-2-thiazolidinecarboxylate dissolved in 10 ml of tetrahydrofuran and 106 μl of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (20/80 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After beating in diisopropyl ether, 0.17 g of tert-butyl (2S,4S,5R)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-(2-fluorophenyl)-2-thiazolidinecarboxylate is thus obtained in the form of a pale yellow foam, Rf=0.30, [ethyl/acetate cyclohexane (30/70 by volume); 1H NMR (250 MHz, (CD3)2SO, at a temperature of 363 K, δ in ppm): 1.53 (s, 9H: CH3 of the tert-butyl); 2.27 (s, 3H: ARCH3); 3.34 (s, 3H: COOCH3); from 3.60 to 3.80 and 4.06 (mt and dd respectively (J=17 and 5 Hz), 1H each: COCH2N); 4.33 (d, J=3 Hz, 1H: H at C5 of the ring); 5.74 (mt, 1H: H at C2 of the ring); 6.01 (d, J=3 Hz, 1H: H at C4 of the ring); 6.23 (t, J=5 Hz, 1H NHCO); 6.78 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.09 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3)); from 7.10 to 7.50 (mt, 5H: aromatic H); 8.03 (mt, 1H: aromatic H (H meta to the F)); 8.40 (s, 1H: ArNHCO).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](I)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[N:13]1C=CC=C[CH:14]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([C:14]#[N:13])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(I)nc1C
Reactant: c1ccncc1
Product: CCOC(=O)c1[nH]c(C#N)nc1C
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 1 g 2-Iodo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester in 3 ml pyridine 640 mg CuCN were added and the mixture stirred for 3 h at 110° C. Then the pyridine was removed under reduced pressure and the residue was directly purified by chromatography on silica eluting with DCM/MeOH 97:3. Yield: 494 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[O:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC1CCOCC1
Yield: 21.3 %

Procedure:
In a manner similar to the method described in example 4a, 5-chlorosalicylaldehyde (6 g, 39 mmol) (Aldrich) was reacted with methanesulfonic acid tetrahydropyran-4-yl ester (10 g, 46 mmol) prepared in Example 32a and K2CO3 in N,N-dimethylformamide to give 5-chloro-2-(tetrahydro-pyran-4-yloxy)-benzaldehyde as a yellow solid (Yield 2 g, 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([SH:24])=[N:14][C:15]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:16][CH:17]=1)=[O:11].II>>[N:18]1([C:15]2[N:14]=[C:13]3[S:24][N:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:10](=[O:11])[C:12]3=[CH:17][N:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(NCCc1ccccn1)c1cnc(N2CCCCC2)nc1S
Agent: II
Product: O=c1c2cnc(N3CCCCC3)nc2sn1CCc1ccccn1
Yield: 65.2 %

Procedure:
Using the procedure of Example 20, 33.0 g (96.2 mmol) of 4-mercapto-2-piperidin-1-yl-pyrimidine-5-carboxylic acid (2-pyridin-2-yl-ethyl)-amide were treated with 24.4 g (96.1 mmol) of iodine to give 21.4 g of the title compound after recrystallization from aqueous ethanol, mp 109°-110° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[C:3](OC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C@@H:2]([CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](N)CC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@H](CO)CC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −78° C., (2S)-methyl 2-amino-3-(tetrahydro-2H-pyran-2-yl)propanoate (1.84 g, 7.74 mmol) in THF (16 mL) was treated with lithium aluminum hydride (8 mL, 1 M in THF) at a rate such that the temperature remained below −65° C. The reaction was allowed to warm to rt. Upon completion, the reaction was cooled to 0° C. and quenched by dropwise addition of water, avoiding a rise in temperature above 2° C., the slurry was then stirred for an additional 1 h. The emulsion was dispersed by stirring with 1 M aq NaOH for 30 min, allowing warming to rt. Celite was added and stirred. The slurry was filtered through celite and washed several times with diethyl ether. The filtrate was concentrated to provide (2S)-2-amino-3-(tetrahydro-2H-pyran-2-yl)propan-1-ol as an oil and used without any further purification. A solution of (2S)-2-amino-3-(tetrahydro-2H-pyran-2-yl)propan-1-ol in THF (20 mL) and water (20 mL) was cooled to 0° C. Potassium carbonate (3.2 g, 23.2 mmol) was added, followed by di-tert-butyl dicarbonate (2.2 g, 10.06 mmol). The reaction was subsequently warmed to rt and stirred for 2 h. The aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and filtered. After solvent removal the crude material was purified by chromatography on silica gel (EtOAc/Hex) to afford tert-butyl (2S)-1-hydroxy-3-(tetrahydro-2H-pyran-2-yl)propan-2-ylcarbamate (1.41 g) as an oil. MS m/z 282 (M+Na).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:12])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:13]I.[Cl-].[Na+]>C(OCC)C.O1CCCC1>[F:12][C:7]1[CH:6]=[CH:5][C:4]([NH2:3])=[CH:9][C:8]=1[CH2:10][O:11][CH3:13]
Reactant: CI
Reactant: Nc1ccc(F)c(CO)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a round-bottomed flask, 374 mg of sodium hydride at 60% are introduced into 10 ml of tetrahydrofuran, 1 g of (5-amino-2-fluorophenyl)methanol and 0.441 ml of methyl iodide. After stirring at ambient temperature for one hour, a solution of sodium chloride and diethyl ether are added. The organic phase is extracted and then washed with water until pH=7. It is then dried over magnesium sulphate, filtered, and concentrated under reduced pressure. 900 mg of 4-fluoro-3-(methoxymethyl)aniline are obtained in the form of a black oil, which is used as it is in the next stage.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([CH:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]2([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=3)[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 50 °C

Procedure:
A mixture of rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-azepane-1-carboxylic acid tert-butyl ester (0.3 g, 0.82 mmol) (from Example 61b supra), 3-chlorobenzyl bromide (0.20 g, 0.97 mmol) (Aldrich), potassium iodide (0.16 g, 0.98 mmol) and potassium carbonate (0.24 g, 1.77 mmol) in acetone (5 mL) was heated at 50° C. for overnight The solvent was removed. The residue was purified by chromatography to give rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-azepane-1-carboxylic acid tert-butyl ester as white solid. (Yield 50 mg, 12.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][C:32](=O)[C:33]([OH:35])=[O:34])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:32]([C:33]([OH:35])=[O:34])[CH2:31][CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:9]([CH3:14])[N:8]=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN
Reactant: CN1CCN(CCCC(=O)C(=O)O)CC1
Product: CC1N=C(c2ccccc2)c2cc(Cl)ccc2N=C1NN=C(CCCN1CCN(C)CC1)C(=O)O

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-3-methyl-5-phenyl-3H-1,4-benzodiazepine can be stirred with 5-(4-methylpiperazino)-2-oxopentanoic acid at room temperature to give 7-chloro-2[[1-carboxy-4-(4-methylpiperazino)butylidene]hydrazino]-3-methyl-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [Ca].[C:2]1([C:8]2C=CC=C[C-]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C-:3]=1.[Li+].[Li+].[I-].[I-].[Ca+2].ClC1C=CC(C)=CC=1.[C:27]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1.O>[CH3:8][C:2]1[CH:7]=[CH:6][C:5]([C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: [c-]1ccccc1-c1[c-]cccc1
Agent: [Ca+2]
Agent: [Ca]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccc(Cl)cc1
Product: Cc1ccc(C2(O)CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
The following experimental procedure is representative of the reactions set forth below in Table I. Highly reactive calcium (3.07 mmol), prepared from lithium biphenylide (6.15 mmol) and excess CaI2 (4.91 mmol) in THF (30 mL), was cooled to -78° C. The color turned green upon cooling. An organocalcium reagent was prepared by adding p-chlorotoluene (324 mg, 2.56 mmol) to this mixture via a disposable syringe at -78° C. The reaction mixture was allowed to warm to -20° C. It was stirred at -20° C. for 30 minutes. The reaction mixture was then cooled to -35° C. A Grignard-type reaction was carried out by adding excess cyclohexanone (510 mg, 5.20 mmol) to the solution of the organocalcium reagent via a disposable syringe at -35° C. The resulting mixture was gradually warmed to room temperature and was stirred at room temperature for 30 minutes. The reaction mixture was again cooled to -35° C. Neutral H2O (distilled water, 20 mL) was added at -35° C. After being warmed to room temperature, the reaction mixture was filtered through a small pad of Celite™ filter agent (available from Aldrich Chemical Co., Milwaukee, Wis.) and was washed with Et2O (50 mL). The aqueous layer was extracted with Et2O (3×30 mL). The combined organic phases were washed with H2O (15 mL), and dried over anhydrous MgSO4. Removal of solvent and flash-column chromatography on silica gel (100 g, 230-400 mesh, available from EM Science; Gibbstown, N.J.) afforded 1-(p-methylphenyl)cyclohexanol (417 mg, 86% yield) as white crystals: mp 53°-55° C.; IR (KBr) 3419, 3030, 2935, 2843, 1514, 1446, 1392, 1134, 1036, 964, 810 cm-1 ; 1H NMR (200 MHz, CDCl3) δ 7.35-7.45 (m, 2 H), 7.10-7.20 (m, 2 H), 2.33 (s, 3 H), 1.55-1.85 (m, 11 H); 13C NMR (50 MHz, CDCl3) δ 146.5, 136.2, 128.9, 124.5, 72.9, 38.9, 25.5, 22.2, 20.9. Known compound: IR, see Sadtler 36367; 1H-NMR, see Sadtler 21529; 13C-NMR, see Sadtler 5269.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1>>[C:6]1([CH3:16])[CH:7]=[CH:8][C:9]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1.[Ca+2:5].[C:6]1([CH3:16])[CH:7]=[CH:8][C:9]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
240 ml of 0.01M p-toluenesulphonic acid was slowly added to 60 g of calcium carbonate (Polcarb 60S - English China Clay) and stirred for 1 hour so that only the surface of the calcium carbonate particles reacted with the p-toluenesulphonic acid and formed an insoluble coating of calcium p-toluenesulphonate. The solution was filtered at suction and 50 g of the solid was transferred to a 0.4M aniline solution (740 ml) and the solution was stirred for a further 1.5 hours after which p-toluenesulphonic acid (3M, 355 ml) was added slowly with continued vigorous stirring. Ammonium persulphate (1M, 300 ml) was then added over a 10 minute period. The reaction took approximately 15 minutes to go to completion when a dark green solution was produced The solution was filtered at suction, washed with 8 liters of deionised water and dried at 100° C. in vacuo (10-1 torr). The green powder (58.6 g) had a volume conductivity of 0.46±0.10 S cm-1.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][NH:9]1.[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[Cl:17][C:18]([Cl:23])([Cl:22])[C:19]([N:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8]1)=[O:20]
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N1Cc2ccccc2C1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Triethylamine (3.48 mL, 25.0 mmol) was added to a solution of isoindoline (4.98 g, 25.0 mmol) in chloroform (100 mL) at room temperature and the mixture was cooled in ice. Trichloroacetic acid chloride (2.79 mL, 25.0 mmol) was added dropwise thereto and the reaction mixture was warmed to room temperature and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to afford 2,2,2-trichloro-1-(1,3-dihydro-2 H-isoindol-2-yl)ethanone as a purple powder (6.59 g).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:11][S:12][CH2:13]Cl.C(N(CC)CC)C>>[C:1]([O:10][CH2:11][S:12][CH3:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting octanoic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 90° C./2 mm Hg, nD20 1.4577.
Reaction SMILES: [CH:1]12[CH2:10][CH2:9][CH:5]([NH:6][C:7]1=[O:8])[CH2:4][NH:3][CH2:2]2.Cl[C:12]1[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=1>>[O:8]=[C:7]1[CH:1]2[CH2:10][CH2:9][CH:5]([CH2:4][N:3]([C:12]3[N:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][N:13]=3)[CH2:2]2)[NH:6]1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C1NC2CCC1CNC2
Product: O=C1NC2CCC1CN(c1ncc(B(O)O)cn1)C2

Procedure:
The title compound was prepared from 3,6-diazabicyclo[3.2.2]nonan-7-one and (2-chloropyrimidin-5-yl)boronic acid in accordance with General Method C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>CO>[CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][N:3]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC1CC(=O)CCN1C(=O)OCc1ccccc1
Solvent: CO
Product: C[C@H]1CC(=O)CCN1C(=O)OCc1ccccc1

Procedure:
The crude Racemic benzyl 2-methyl-4-oxopiperidine-1-carboxylate was dissolved in MeOH and chromatographed on a 10 cm Chiralpak AD column eluting with 100% MeOH in 2.5 g injections to give the two separated enantiomers. The desired enantiomer eluted first, 95% ee.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14]C)=[O:13])=[N:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O.CCOC(C)=O.Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=[O:13])=[N:3][CH:2]=1
Reactant: COC(=O)c1ncoc1-c1ccncn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncoc1-c1ccncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl 5-(pyrimidin-4-yl)oxazole-4-carboxylate (179 mg, 0.80 mmol) in THF/H2O (1:1, 6 mL) was treated with LiOH (60 mg, 1.43 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 min, then diluted with EtOAc and 1N aq. HCl-solution was added (to reach pH=1). The layers were separated and the aq. layer extracted with EtOAc (2×), EtOAc/MeOH 4:1 then DCM/MeOH 4:1. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a solid which was used without further purification. LC-MS conditions A: tR=0.56 min, [M+H]+=192.47.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([NH:21][C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][N:27]2[CH2:28][CH2:29][CH:24]([C:22](=[O:23])[NH:21][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:25][CH2:26]2)[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(C=O)cs1
Reactant: O=C(NC1CCCC1)C1CCNCC1
Product: CC(C)(C)OC(=O)Nc1nc(CN2CCC(C(=O)NC3CCCC3)CC2)cs1

Procedure:
The title compound is prepared according to the reactions described above starting from (4-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester and piperidine-4-carboxylic acid cyclopentylamide J-4 yielding after reductive amination [4-(4-cyclopentylcarbamoyl-piperidin-1-ylmethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester; LC-MS A: tR=0.66 min; [M+H]+=409.13.