Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:24]([C:27]1[NH:28][CH:29]=[CH:30][N:31]=1)(=[O:26])[NH2:25]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:28]1[CH:29]=[CH:30][N:31]=[C:27]1[C:24](=[O:26])[NH2:25])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: NC(=O)c1ncc[nH]1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1C(N)=O
Yield: 68 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methylsulfonyloxy-2-(2-methylsulfonyloxyethyl) pyrrolidine (21.5 g) and 2-carbamoylimidazole (7.07 g) were reacted in substantially the same manner as that of Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-{2-(2-carbamoylimidazol-1-yl) ethyl}-4-methylsulfonyloxypyrrolidine (15.2 g) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[N:8]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:7]2[NH:6][CH2:5][CH2:4]1.[C:28](Cl)(=[O:31])[CH:29]=[CH2:30]>C(Cl)Cl.CCN(CC)CC>[C:28]([NH:1][CH2:2][CH:3]1[N:8]2[N:9]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:11]([C:12]([NH2:14])=[O:13])=[C:7]2[NH:6][CH2:5][CH2:4]1)(=[O:31])[CH:29]=[CH2:30]
Reactant: C=CC(=O)Cl
Reactant: NCC1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)NCC1CCNc2c(C(N)=O)c(-c3ccc(Oc4ccccc4)cc3)nn21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a solution of 7-(aminomethyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (125 mg, 0.344 mmol) in 5 mL of DCM was added Et3N (four drops) and acryloyl chloride (46.5 mg, 0.52 mmol). After stirring at rt for 30 mins. The mixture was partitioned between water (10 mL) and DCM (5 mL). The organic layer was concentrated and purified by pre-TLC (DCM/MeOH=20/1) to give 40 mg (28%) of product. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.54-7.43 (m, 2H), 7.25 (t, J=7.6 Hz, 1H), 7.16-7.11 (m, 4H), 6.76 (s, 1H), 6.33 (dd, J=10.1, 17.0 Hz, 1H), 6.18 (dd, J=1.9, 17.0 Hz, 1H), 5.69 (dd, J=1.9, 10.1 Hz, 1H), 4.28-4.22 (m, 1H), 3.92-3.80 (m, 1H), 3.50-3.30 (m, 3H), 2.14-1.94 (m, 2H). MS (ESI) m/e [M+1]+ 417.9.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7]O[C:9]2=[O:12])=[CH:4][CH:3]=1.[NH2:13][C@@H:14]([CH2:22][CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15](=[O:16])[CH:14]([N:13]1[CH:7]([NH:13][CH:14]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:22][CH3:23])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]1=[O:12])[CH2:22][CH3:23])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=c1occc2ccc(Cl)cc12
Product: CCC(NC1Cc2ccc(Cl)cc2C(=O)N1C(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 64.2 %

Procedure:
A mixture of 7-Chloro-isochromen-1-one (10 g) and (S)-2-aminobutyric acid, tert-butyl ester (22 g) was heated at 85° C. for 24 hours. The mixture was then cooled and purified by flash chromatography (5-25% ethyl acetate/hexane) to afford the sub-title compound as a yellow oil (17.1 g, 64%): 1H NMR (400 MHz, CDCl3) δ 0.68-1.32 (6H, m), 1.50 (21H, m), 1.92 (1H, m), 2.15 (1H, m), 2.82-3.40 (3H, m), 4.41 (1H, m), 4.68 (1H, m), 7.11 (1H, m), 7.35-7.52 (1H, m), 8.05 (1H, m).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[C:7](=[S:10])([O-:9])[CH3:8].[K+].O>CN(C=O)C.[Br-].[Na+]>[C:7](=[O:9])([S:10][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])[CH3:8]
Reactant: CC([O-])=S
Reactant: CC(C)(O)CCl
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCC(C)(C)O
Temperature: 50 °C
Yield: 113.2 %

Procedure:
To a mixture of 1-chloro-2-methylpropan-2-ol (2.2 g, 20.26 mmol) and potassium ethanethioate (6.94 g, 60.8 mmol) in DMF (20 mL) was added 100 mg of sodium bromide and the resulting mixture was heated at 50° C. for 18 hours. The mixture was then poured into water and extracted with EtOAc. The acetate layer was washed with water, brine, dried with MgSO4 and concentrated under reduced pressure to provide 3.4 g of the title compound.
Reaction SMILES: N[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+].[Cl-].[Na+]>S(=O)(=O)(O)O.O>[OH:11][C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](O)C(=O)O
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a cooled solution (0-5° C.) of D-leucine (200 g, 1.5 mol) in sulfuric acid (3 L, 1 M) was added dropwise a solution of sodium nitrite (240 g, 3.5 mol) in water (1 L) while maintaining the temperature between 0-5° C. The reaction mixture was stirred at room temperature overnight. The solution was saturated with sodium chloride and extracted with tert-butyl methyl ether (3×). The combined organic layers were dried over Na2SO4 and filtered, and the solvent was removed in vacuo. (R)-α-hydroxyisocaproic acid was isolated as a white solid in a yield of 67% (132 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][CH:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[CH2:15][O:14]1)CCC)[C:2]1C=CC=C[CH:3]=1.CC(O)=O>[Pd].CCO>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[CH2:15][O:14][CH:13]([CH2:12][NH:8][CH2:1][CH2:2][CH3:3])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: CCCN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 68 %

Procedure:
(−)-N-benzyl-N-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methyl}propan-1-amine (0.25 g, 0.67 mmol), palladium on carbon (10%, 30 mg), concentrated AcOH (0.1 ml) and EtOH (15 ml) was hydrogenated at 40 psi for 1 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness. The crude product was dissolved in EtOAc (100 ml) and basified with Na2CO3 (10%, 50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2×75 ml). The combined organic layers were collected, dried (Na2SO4), filtered and evaporated to dryness (0.32 g). Purification by flash chromatography (EtOAc/MeOH 10:1) afforded the pure title compound (0.13 g, 71%, >95% e.e.). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/MeOH/DEE. M.p. 235° C. [α]DMeOH=−80°. 1H-NMR (400 MHz, MeOH): δ 7.49 (1H, dd, J1 8.0 Hz J2 2.0 Hz), δ 7.41 (1H, d, 2.0 Hz), δ 7.30 (1H, d, J 8 Hz), δ 5.25 (1H, t, J 5.2 Hz), δ 5.02 (2H, dd, J1 50 Hz, J2 16 Hz), δ 3.1 (3H, s), δ 2.97 (2H, m), δ 2.65 (2H, t, J 7.2 Hz), δ 1.56 (2H, m), δ 0.95 (3H, t, J 7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:3]=1[F:28].Cl.[N:30]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[F:28][C:3]1[C:2]2[N:1]=[N:30][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[F:27]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1F
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-fluoro-phenyl)amino)benzoate (2.07 g, 5.17 mmol) in acetic acid (60 mL) was added HCl (con., 8 mL) and water (6 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO2 (0.43 g, 6.21 mmol) in water (10 mL) was added dropwisely at 0° C. within 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO3 (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic extract was washed with water (30 mL×3) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.53 g, 92.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.65 (s, 1H), 8.48 (s, 1H), 7.00-6.90 (m, 4H), 3.94 (s, 3H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH3:18])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH:19]([C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[CH:25]=[C:24]([OH:36])[N:23]=1)([CH3:21])[CH3:20].[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:2].[ClH:1].[CH2:17]([NH:16][C:5]1[C:4]([CH2:3][C:25]2[C:26]3[C:31](=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=3)[C:22]([CH:19]([CH3:20])[CH3:21])=[N:23][C:24]=2[OH:36])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[N:6]=1)[CH3:18]
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(C(C)C)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
To a stirred solution of 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride (250 mg, 0.87 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (215 mg, 0.87 mmol) followed by a 2 N aq. LiOH solution (0.87 mL, 1.74 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation and drying, 38 mg of 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.70 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-1-isopropyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 47 as a yellow solid (24 mg, 5% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Ic1ccc(OCCN2CCOCC2)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
A resealable tube was charged with 4-iodophenol 99b (2.50 g, 11.4 mmol), 4-(2-chloroethyl)morpholine hydrochloride (2.14 g, 11.5 mmol), potassium carbonate (7.88 g, 57.0 mmol), and acetonitrile (50 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at 85° C. for 20 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford a pale orange oil. This oil was purified via column chromatography (eluting with 0-100% ethyl acetate-hexane) to afford 4-[2-(4-iodo-phenoxy)-ethyl]-morpholine 100b as a pale yellow oil. MS (MH+) 334.0; Calculated 333 for C12H16INO2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][CH2:11][CH2:10][S:9]2)=[CH:4][N:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:12][CH2:11][CH2:10][SH:9])=[CH:4][N:3]=1
Reactant: Clc1ccc(C2NCCS2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: SCCNCc1ccc(Cl)nc1
Yield: 82.2 %

Procedure:
A solution composed of 6-chloronicotinaldehyde (14.2 g), 2-aminoethanethiol (7.7 g) and benzene (80 ml) was heated with stirring for 5 hours while removing water as an azeotrope. After the reaction, benzene was distilled off under reduced pressure, and further volatile materials were removed at 1 mmHg and 70° C. to give 2-(2-chloro-5-pyridyl)thiazolidine (18 g) as a residue. Ten grams of 2-(2-chloro-5-pyridyl)thiazolidine was dissolved in 100 ml of ethanol, and sodium borohydride was added. With stirring, the mixture was gradually heated and thereafter refluxed for 1 hour. Ethanol was distilled off under reduced pressure, and chloroform was added to the residue. Insoluble materials were separated by filtration and the chloroform layer was washed with water and dehydrated. Chloroform was distilled off under reduced pressure to give the desired N-(2-chloro-5-pyridylmethyl)2-aminoethanethiol (8.3 g).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:10][C:11]=2[CH:12]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:37][NH:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42]>>[CH:1]1([C:7]2[O:8][C:9]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)=[CH:10][C:11]=2[CH:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([N:38]([CH3:37])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:23])=[CH:25][CH:26]=2)[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CC(C)CC(Oc1ccc(C(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Product: CC(C)CC(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Yield: 91.7 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-(1-{2-cyclohexyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}-3-methylbutoxy)benzoic acid (150 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (161 mg, 91%) as an amorphous compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[C:16]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[CH2:29][OH:30])=[O:23])=[CH:15][C:14]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl>CO.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[C:17]([NH2:19])[C:16]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH:25]2[CH2:29][OH:30])=[O:23])=[CH:15][C:14]=1[O:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])cc1OCCC(=O)OCc1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(C(=O)N2CCCC2CO)c(N)cc1OCCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
The nitro compound C5 (59 g, 0.128 mol) was dissolved in methanol (650 mL). Tin chloride (130 g, 0.577 mol, 4.5 eq) was added and the mixture was heated under reflux for 6 hours until completion of the reaction (TLC, 5% methanol in ethyl acetate). The methanol was removed under vacuum and the residue was dissolved in ethyl acetate (1 L) in a 5 L flask and 2 L of saturated sodium hydrogen carbonate aqueous solution was carefully added. The mixture was mechanically stirred for 2 hours and the resulting emulsion was then left to settle overnight. The pH was 8. It was filtered through celite. The residue was washed twice with ethyl acetate and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried with magnesium sulfate, and concentrated in vacuo to leave the crude product as a black tar (50 g). TLC analysis showed presence of small quantities of impurities but the product was use in the next step with no further purification. 1H NMR (CDCl3) δ 7.36 (m, 5H), 6.74 (s, 1H), 6.28 (s, 1H), 5.19 (s, 2H), 4.28 (t, J=6.2 Hz, 2H), 3.73 (s, 3H), 3.77-3.50 (m, 2H), 2.91 (t, J=6.2 Hz, 2H), 2.15 (m, 1H), 1.88-1.60 (m, 2H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:20][C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:20][C:21]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)=[O:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (210 mg, 1.13 mmol) and pyridine (137 mg, 1.73 mmol) in anhydrous CH2Cl2 (2 mL) was cooled to 0° C. under an atmosphere of N2, treated with a solution of triphosgene (402 mg, 1.35 mmol) in anhydrous CH2Cl2 (2 mL) and stirred at 0° C. for 1 h. The cooling bath was then removed and the reaction stirred at room temperature for a further 1 h. After this time, the mixture was diluted with 1 M hydrochloric acid (25 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and the drying agent removed by filtration. The filtrate was concentrated to dryness under reduced pressure to provide tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate as a white solid (280 mg, 100%): 1H NMR (500 MHz, CDCl3) δ 10.76 (br s, 1H), 7.33 (dd, J=17.0, 9.0 Hz, 1H), 7.11 (dd, J=9.0, 4.0 Hz, 1H), 4.88-4.52 (m, 2H), 4.69 (br s, 2H), 4.62 (s, 2H), 3.49 (apparent t, J=4.5 Hz, 4H), 3.32 (apparent t, J=4.5 Hz, 4H), 3.25 (apparent t, J=12.5 Hz, 1H), 3.14-2.88 (m, 2H), 1.94 (d, J=12.5 Hz, 2H), 1.72-1.66 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:5].[C:17]([O-])([O-])([O:19][CH3:20])[CH3:18].C(O)(=O)C>C1C=CC=CC=1>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:4](=[O:5])[C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[N:1]=[C:17]([O:19][CH3:20])[CH3:18]
Reactant: COC(C)([O-])[O-]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(C)=Nc1ccccc1C(=O)c1ccccc1Cl

Procedure:
A solution of 20 parts of 2-amino-2'-chlorobenzophenone, 15 parts of methyl orthoacetate, 12 volume parts of acetic acid in 250 parts of benzene is refluxed for 5 hours. The mixture is washed with saturated aqueous sodium bicarbonate solution and water, and then dried over sodium sulfate. Evaporation of the solvent gives 2'-chloro-2-(1-methoxyethylideneamino) benzophenone as an oily substance in almost quantitative yield.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C(N(CC)CC)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1)([O-:31])=[O:30]>O1CCCC1>[ClH:21].[ClH:1].[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][NH:4][C:39]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:37][CH:36]=3)=[O:40])[CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCN1CCN(Cc2ccc(Cl)cc2)CC1)Nc1ccc([N+](=O)[O-])cc1
Yield: 110.5 %

Procedure:
The procedure described in Example 3 was followed, using 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole), tetrahydrofuran (50 ml), triethylamine (4.2 ml; 30 mmole) and 4-nitrophenyl isocyanate (1.64 g; 10 mmole). Recrystallization from methanol/water provided the title compound (2.79 g; 55% yield) as yellow-white crystals, m.p. 230°-231° C. (dec.).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].[NH2:19][C:20]([NH2:22])=[S:21]>CN(C=O)C>[NH2:22][C:20]1[S:21][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[N:19]=1
Reactant: O=C(CBr)CCCN1C(=O)c2ccccc2C1=O
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: Nc1nc(CCCN2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
1-bromo-5-phthalimido-2-pentanone (0.500 g, 1.61 mmol) was dissolved in DMF (3.5 mL) at 0° C. and thiourea (0.135 g, 1.77 mmol) was added drop-wise as a solution in DMF (0.50 mL). The solution was allowed to warm to room temperature and stirring was continued for 2 h at which time the DMF was removed under reduced pressure and the resulting slurry was made alkaline with 10% K2CO3 (100 ML). The aqueous solution was then extracted with EtOAc (3×40 mL) and the organic layer was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated to obtain 51 (448 mg, 97%) as a fine white powder in its freebase form: 1H NMR (300 MHz, DMSO-d6) δ 7.85 (m, 4H), 6.78 (s, 2H), 6.13 (s, 1H), 3.56 (t, 2H, J=6.9 Hz), 2.42 (t, 2H, J=7.5 Hz), 1.88 (quint., 2H, J=7.5 Hz); 13C NMR (75 MHz, DMSO-d6) δ 168.01, 167.87, 151.20, 134.25, 131.61, 122.89, 100.17, 37.27, 28.70, 27.09; HRMS (ESI) calcd for C14H14N3O2S (MH+) 288.0801, found 288.0799.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1.[OH-].[Na+]>O1CCCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc(-c2ccccc2F)cc1
Reaction time: 23 h
Yield: 95.6 %

Procedure:
To a stirred solution of 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (7.17 g, 0.0250 mol) in tetrahydrofuran (60 mL) at room temperature was added a solution of sodium hydroxide (1.04 g, 0.026 mol) in methanol (60 mL), and the mixture was stirred for 23 hours. To the reaction was added 1.0 M aqueous sodium hydroxide (10 mL), and the mixture was stirred for an additional 24 hours. The mixture was rotary evaporated, and the residue was partitioned between water and chloroform. The aqueous layer was washed with chloroform (3×) and acidified with concentrated hydrochloric acid to pH=3. The resulting solids were filtered, washed with dilute aqueous hydrochloric acid (pH=3), and dried under house vacuum (air bleed) to give 6.51 g of 4-(2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid as a pale yellow solid; mp 148-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl>C(O)C>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:11]=1
Reactant: Nc1ccccn1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A mixture of 4.7 g (0.05 mole) of 2-aminopyridine and 6.4 g (0.05 mole) of 1,3-dichloropropan-2-one in 50 ml of ethanol was stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was triturated with acetonitrile. The solid that formed was recrystallized from acetonitrile-methanol to yield ca. 1 g of 2-chloromethylimidazo[1,2-a]pyridine as the hydrated hydrochloride salt. [Calcd. for C8H7N2Cl.HCl.H2O: C, 43.42; H, 4.52; N, 12.67; Cl, 32.12. Found: C, 42.94; H, 4.62; N, 12.68; Cl, 32.12.] A mixture of 790 mg (3.89 mmole) of the chloromethyl compound and 585 mg (3.90 mmole) of 2-mercaptobenzimidazole in 200 ml of isopropyl alcohol was stirred for two days. The mixture was concentrated in vacuo and the residue was dissolved in boiling isopropyl alcohol. The precipitate that formed upon cooling was collected and partitioned between saturated aqueous sodium bicarbonate and chloroform. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to a solid. Recrystallization from isopropyl alcohol yielded (in two crops) 500 mg of the title compound as an analytically pure solid, m.p. 220°-222°. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.