Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][NH:10]C(=O)OC(C)(C)C)[CH:6]=[N:7][CH:8]=1)#[N:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:10][CH2:9][C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)NCc1cncc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cncc(CN)c1
Reaction time: 1 h

Procedure:
To tert-butyl (5-cyanopyridin-3-yl)methylcarbamate in CH2Cl2 (10 ml), TFA (3 ml) was added. After 1 h, volatiles were removed on a rotavap under reduced pressure. Crude residue was dissolved in water, basified with 2N NaOH and extracted with CHCl3 (100 ml) to obtain 5-(aminomethyl)nicotinonitrile which was used without further purification.
Reaction SMILES: C(O[C:4]1[N:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1)C.[CH3:21][N:22](C)C1N=CC(C2SC3C=C(O)C=CC=3N=2)=CN=1.C([O-])(O)=O.[Na+]>>[S:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([NH:22][CH3:21])=[N:9][CH:8]=1
Reactant: CCOc1ccc(-c2nc3ccc(OC)cc3s2)cn1
Reactant: CN(C)c1ncc(-c2nc3ccc(O)cc3s2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Product: CNc1ccc(-c2nc3ccccc3s2)cn1

Procedure:
2-(6-Ethoxypyridin-3-yl)-6-methoxy-1,3-benzothiazole (23 mg, 80 μmol) was reacted according to the procedure used for the preparation of 2-[2-(dimethylamino)pyrimidin-5-yl]-1,3-benzothiazol-6-ol, with the following exceptions: The reaction mixture was allowed to reach rt on. sat. aq. NaHCO3 was added and the mixture was extracted with EtOAc. The organic phase was dried and concentrated under reduced pressure. Preparative HPLC of the residue gave the title compound (4 mg). 1H NMR (CHLOROFORM-d: CD3OD) δ 8.69 (d, 1H) 8.20 (dd, 1H) 7.79 (d, 1H) 7.29 (d, 1H) 6.99 (dd, 1H) 6.86 (d, 1H) 4.39 (q, 2H) 1.41 (t, 3H); MS m/z (M+H) 273.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH:5]([NH:13][C:14]([C:16]1[N:17]=[C:18]([Br:21])[S:19][CH:20]=1)=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[OH-].[Na+].O.Cl>CO>[Br:21][C:18]1[S:19][CH:20]=[C:16]([C:14]([NH:13][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4][C:3]([OH:22])=[O:2])=[O:15])[N:17]=1
Reactant: COC(=O)CC(NC(=O)c1csc(Br)n1)c1ccccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccccc1C(CC(=O)O)NC(=O)c1csc(Br)n1
Reaction time: 1 h

Procedure:
100 mg (0.26 mmol) 3-[(2-bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid methyl ester are dissolved in 10 ml MeOH, 0.55 ml of 1N NaOH solution (2.1 Eq NaOH) are added and the resulting mixture is stirred for 1 h. 10 ml of water are added and the pH of the resulting mixture is adjusted to 5.5 by addition of 10% HCl and the MeOH removed in vacuo. The remaining aqueous phase is extracted three times with 10 ml of CH2Cl2, the organic layer is collected, dried over Na2SO4 and the solvent removed in vacuo to deliver 3-[(2-Bromo-thiazole-4-carbonyl)-amino]-3-o-tolyl-propionic acid in yields below 90%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][OH:15])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:21][C:22]([CH3:24])([Si:25]([CH3:27])([CH3:26])[O:15][CH2:14][C@H:9]([C:10]([O:12][CH3:13])=[O:11])[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
To a solution of (R)-methyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (27.5 g, 0.126 mol) in DMF (250 mL) was added imidazole (25.7 g, 0.378 mol), followed by TBSCl (20.9 g, 0.139 mol) and the reaction mixture stirred for 4 h. The solvents were removed in vacuo and dissolved in EtOAc (300 mL). The solution was washed with saturated NH4Cl (2×100 mL), then with saturated NaHCO3 (100 mL), and brine (100 mL). The organic layer was then dried, filtered, and solvent removed in vacuo to give (R)-methyl 2,2,3,3,10,10-hexamethyl-8-oxo-4,9-dioxa-7-aza-3-silaundecane-6-carboxylate (40 g, yield 95%) as an oil that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.34 (brs, 1H), 4.35 (m, 1H), 4.05 (dd, J=13.2, 3.6 Hz, 1H), 3.82 (dd, J=14, 4.4 Hz, 1H), 1.45 (s, 9H), 3.73 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH2:12][C:8]1[N:9]=[CH:10][N:11]=[C:6]([O:5][C:4]2[CH:3]=[C:2]([NH:1][C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])[CH:28]=[CH:27][CH:26]=2)[C:7]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:18]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Agent: Cl
Product: CN(C)C/C=C/C(=O)Nc1cccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)c1
Yield: 22 %

Procedure:
(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide was prepared from 6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride using Method E (22% yield). HPLC: 98%, RT=3.556 min. MS: m/z=482 [M+H]+, RT=3.53 min. 1H-NMR (DMSO-d6) δ 10.34 (s, 1H), 9.73 (s, 1H), 8.04 (s, 1H), 7.45 (s, 1H), 7.41-7.36 (m, 5H), 7.29 (t, 1H), 7.15 (t, 1H), 7.09-7.06 (m, 4H), 6.78 (d, 1H), 6.74-6.68 (m, 1H), 6.50 (broad s, 2H), 6.41 (d, 1H), 3.93-3.92 (m, 2H), 2.78 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=O)[CH3:14].C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[N:22][OH:23])[CH3:14]
Reactant: CC(=O)c1nc(-c2ccncc2)[nH]c1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)c1nc(-c2ccncc2)[nH]c1C
Temperature: 25 °C

Procedure:
To a 1.0 g (0.005 mole) amount of 1-[5-methyl-2-(4-pyridinyl)-1H-imidazol-4-yl]ethanone (prepared as described in Example 24) dissolved in 200 ml of boiling water were added 1.0 g (0.012 mole) of sodium acetate and 0.7 g (0.01 mole) of hydroxylamine hydrochloride. The mixture was stirred and heated for 2 hours, then cooled to room temperature. The resulting precipitate was collected by filtration and when dried at 60° C. for 18 hours gave 0.7 g of the product of the Example as white crystals, mp 253°-255° C. (dec.).
Reaction SMILES: [NH2:1][C@H:2]([CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[C:8]([Cl:14])[CH:7]=1)=[O:4].[CH:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.CCCCCC>[C:17]([C@@H:20]1[N:5]([C:6]2[CH:7]=[C:8]([Cl:14])[C:9]([F:13])=[C:10]([Cl:12])[CH:11]=2)[C:3](=[O:4])[C@@H:2]([CH3:15])[NH:1]1)([CH3:19])([CH3:18])[CH3:16]
Reactant: C[C@@H](N)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Reactant: CC(C)(C)C=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@H]1N[C@H](C(C)(C)C)N(c2cc(Cl)c(F)c(Cl)c2)C1=O
Temperature: 50 °C
Reaction time: 22 h
Yield: 59.2 %

Procedure:
To a solution of (R)-2-amino-N-(3,5-dichloro-4-fluoro-phenyl)-propionamide (149 g crude, max 594 mmol) in toluene (743 mL) at 40° C., was added pivalaldehyde (67.1 mL, 618 mmol) in one portion. The reaction was stirred at 50° C. for 22 h and then all volatiles were removed in vacuo to give a viscous brown oil. Hexane (500 mL) was added and the resulting suspension was stirred at room temperature for 30 min. The mixture was filtered and the solids rinsed with cold hexane. The filtrate was concentrated in vacuo and reprocessed in a similar manner to obtain additional precipitate. The remaining filtrate was diluted with hexane until a black oil separated from the solution. The hexane layer was decanted from this black oil and concentrated in vacuo. The residue was re-dissolved in warm diethyl ether (300 mL) and stored in the freezer for 1.5 h over which time crystal growth was observed. The solids were filtered, and the filtrate reprocessed in a similar manner to obtain additional crystals. All of the collected solids were combined to give 112.2 g of (2S,5R)-2-tert-butyl-3-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-imidazolidin-4-one as a tan solid. To a solution of this solid in toluene (639 mL) at 0° C. was added triethylamine (73.5 mL, 527 mmol) in one portion. Trifluoroacetic anhydride (58.6 mL, 422 mmol) was added to the reaction mixture over 1 h at a rate to keep the internal temperature below 5° C. The reaction mixture was stirred at 0° C. for 1 h and then warmed to 20° C. over 1 h. The mixture was then cooled to 10° C. and water (1.2 L) was added. The layers were separated and the organic layer was washed with water (1.2 L and then 0.6 L). The combined aqueous layers were extracted with toluene (0.6 L). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give 149.4 g of the title compound as a tan solid, m/z 456.4 [M+MeCN+H]+.
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[O:17]([CH2:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:25](=[O:26])[CH2:24][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)COc2ccccc2)c(O)c1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and phenoxyacetyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(phenoxyacetoxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with methanesulfonic acid there is obtained the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(phenoxyacetoxy)-alpha-(isopropylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: CCn1nccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC

Procedure:
A neat solution of 5-amino-1-ethylpyrazole (20.0 g, 180 mmol) and diethyl ethoxymethylenemalonate (42.8 g, 198 mmol) was heated at 120° C. for 5 h. This material was used directly without further purification. If needed, the product can be distilled at 154-160° C. (0.1 mm Hg) to afford the title compound as a liquid which solidified to afford the title compound as a pale colored solid: mp 50-53° C.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1.[CH3:22][S:23]([Cl:26])(=[O:25])=[O:24]>N1C=CC=CC=1>[ClH:26].[CH3:22][S:23]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[CH:14][C:15](=[O:21])[NH:16]3)[CH:8]=[CH:9][CH:10]=1)(=[O:25])=[O:24]
Reactant: Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(-c2nccc3[nH]c(=O)ccc23)c1
Reaction time: 0.5 h

Procedure:
To a mixture containing 6.57 g of 5-(3-aminophenyl)-1,6-naphthyridin-2(1H)-one dihydrochloride monohydrate and 64 ml of pyridine was added dropwise with stirring 2.9 ml of methanesulfonyl chloride and the reaction mixture was stirred for about 30 minutes. The reaction mixture was concentrated on a rotary evaporator and to the residual oily material was added water whereupon a solid separated and then dissolved. To the solution was added about 10 ml of acetic acid and the mixture allowed to stand overnight. The solution was concentrated on a rotary evaporator and to the residue was added ethanol whereupon on standing crystallization resulted. The crystalline material was collected, washed with ethanol and dried in a vacuum oven at 90° C. to yield 6.0 g of 5-(3-methanesulfonylaminophenyl)-1,6-naphthyridin-2(1H)-one monohydrochloride, m.p. 258° C. with decomposition.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][NH2:26]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:25][NH2:26])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reactant: NN
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN)cn1
Temperature: 90 °C
Yield: 76.4 %

Procedure:
A mixture of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (1.0 g, 3 mmol), hydrazine (3.09 g, 62 mmol) and ethanol (1 mL) was heated at 90° C. for 5 h. The mixture was cooled and concentrated to give a white residue that was triturated with chloroform and filtered. The filtrate was concentrated to afford the title compound (743 mg, 49%) as a white solid. MS: m/e=325.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=O.[C:12]1([PH:18](=[O:20])[OH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[O:3]=[C:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([P:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:19])[OH:20])[O:7]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: O=[PH](O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C1OC(P(=O)(O)c2ccccc2)c2ccccc21
Yield: 58 %

Procedure:
Into a suspension of 30.1 grams (0.2 moles) of 2-carboxybenzaldehyde in 240 mL of toluene is added 28.4 grams (0.2 moles) of phenylphosphinic acid. The resultant mixture is heated to reflux and 3.8 mL of water is collected by azeotropic distillation using a Dean-Stark receiver. Upon cooling the reaction mixture, the precipitated white solid is collected by filtration and dried. The crude solid is recrystallized from 240 mL of methanol to give 31.8 grams (58% yield) of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)-phenyl-phosphinic acid as white crystals, mp 230-233° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:52]([O:56][C:57]([NH:59][CH2:60][C:61](O)=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:25][CH2:26][N:27]([C:61](=[O:62])[CH2:60][NH:59][C:57](=[O:58])[O:56][C:52]([CH3:53])([CH3:54])[CH3:55])[CH2:28][CH2:29]4)[N:20]=3)[CH2:17][CH2:18]2)=[O:12])=[N:2]1
Reactant: O=C(Nc1noc2ccccc12)N1CCN(c2nc(N3CCNCC3)ns2)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 74 %

Procedure:
A solution of N-1,2-benzisoxazol-3-yl-4-(3-piperazin-1-yl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide (100 mg, 0.241 mmol), 1-hydroxybenzotriazole (32.5 mg, 0.241 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92.5 mg, 0.482 mmol) and N-(tert-butoxycarbonyl)glycine (42.3 mg, 0.241 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 12 hours. The reaction mixture was poured to water, and a solid was separated by filtration, which was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to give 102 mg (73.9%) of the desired product as a solid.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[N:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:15]1([N:13]2[C:12](=[O:21])[C:6]3=[CH:7][NH:8][C:9]4[CH:10]=[CH:11][C:2]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[N:3][C:4]=4[C:5]3=[N:14]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Reactant: C1CNCCN1
Product: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Yield: 84 %

Procedure:
Compound 5a was stirred with excess of piperazine at 175° C. for 24 hours. The precipitates were collected by filtration and washed with ethyl acetate and purified using column chromatography to obtain title compound in 84% yield. 1H-NMR (DMSO-d6) δ (ppm): 2.88 (4H, brm), 3.64 (4H, brm), 7.11 (2H, tt, J=7.42, 1.10 Hz), 7.23 (1H, d, J=9.34 Hz), 7.41 (2H, m), 7.84 (1H, d, J=9.06 Hz), 8.22, (2H, m), 8.51 (1H, s). m/z 347.4 (MH+).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:13]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[CH2:23]([S:22][C:13]1[C:12]([NH:11][CH:1]=[O:2])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=CO
Reactant: COC(=O)c1cccc(N)c1SCc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc(NC=O)c1SCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
27.0 g (0.586 mol) of formic acid are added dropwise to 48.6 g (0.476 mol) of acetic anhydride at 0° C. After the mixture has been stirred at 50°-60° C. for 2 h it is cooled to 0° C. and a solution of 50.0 g (0.183 mol) of methyl 3-amino-2-benzylmercaptobenzoate in 150 ml of THF is added. The reaction solution is then stirred at room temperature for 4 h. The mixture is concentrated under reduced pressure (60° C., 0.1 torr). The resulting oily residue (61.77 g) is employed in subsequent reactions without further purification (cf. Example e)).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:25][C:26]#[N:27])[C:17]([NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18].[Cl:28][C:29]1[C:30]([CH:51]=O)=[C:31]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:32]2=[N:33][CH:34]=1>C(Cl)Cl>[Cl:28][C:29]1[C:30]([CH2:51][NH:15][C@H:16]([CH2:25][C:26]#[N:27])[C:17]([NH:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])=[C:31]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:42])=[O:43])[C:32]2=[N:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)c(Cl)cnc32)cc1
Reactant: N#CC[C@@H](N)C(=O)NC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@H](CC#N)C(=O)NC4CCCC4)c(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of sodium triacetoxyborohydride (26.5 mg, 0.125 mmol) and (R)-2-amino-3-cyano-N-cyclopentylpropanamide (22.70 mg, 0.125 mmol) in DCM (1 mL) was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. A solution of 5-chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (30 mg, 0.063 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at 0° C. for 20 min and then concentrated to afford the title compound. [M+H] calc'd for C26H28ClN5O5S, 544; found, 544.2.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]=[CH:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N:27]2[CH2:32][CH2:31][CH:30]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[CH:9][CH:10]=[C:11]5[C:16]=4[N:15]=[CH:14][CH:13]=[CH:12]5)[CH2:2][CH2:3]3)[CH2:29][CH2:28]2)[CH:20]=[CH:19][CH:18]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1cnc2c(N3CCC(N4CCN(c5cccc6cccnc56)CC4)CC3)cccc2c1

Procedure:
Using the synthetic methods described in previous examples, 8-(piperazin-1-yl)quinoline (Oruz et al., J. Med. Chem. 45:4128 (2002)) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a light yellow solid; MP. 194-196° C.; MS (ES) m/z (relative intensity) 424 (M+H)+ (100).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH2:16])=O)[CH:3]=1.ClCCl.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>>[Cl:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]#[N:16])[CH:3]=1
Reactant: NC(=O)c1ccccc1-c1cc(Cl)c2cccnc2n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: N#Cc1ccccc1-c1cc(Cl)c2cccnc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a slurry of 970 mg (3.42 mmol) 2-(4-chloro-[1,8]naphthyridin-2-yl)-benzamide in 10 ml dichloromethane 2.85 g (12.0 mmol) 1.26 g (5.27 mmol) methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt, (Burgess reagent) was added. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was crystallized from isopropanol yielding 2-(4-chloro-[1,8]naphthyridin-2-yl)-benzonitrile as colourless crystals; HPLC-MS: 1.94 min, [M+H] 266.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([OH:12])=[O:11].[CH3:18]O>>[CH3:18][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([NH2:6])[CH:8]=1
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(N)c1

Procedure:
Concentrated H2SO4 (9 mL) was added in portions to a stirred solution of -3-amino-4-methoxybenzoic acid (20.06 g, 110.4 mmol) in methanol (280 mL).