Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH2:10]([N:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][NH2:16])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:3][C:2]1[N:1]=[C:8]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:7]=[C:5]([NH:16][CH2:15][CH2:14][CH2:13][N:12]([CH2:17][CH3:18])[CH2:10][CH3:11])[N:4]=1
Reactant: CCN(CC)CCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCN(CC)CCCNc1nc(Cl)nc(NCCCN(CC)CC)n1
Temperature: 3 °C
Reaction time: 8 h

Procedure:
Following the procedure described in Japanese Patent Publication 39272/74, 50.0 ml of water was cooled to 3° C. and slowly 18.4 g (0.1 mole) of cyanuric chloride was added while maintaining 3°-5° C. by means of an external ice-water bath. Slowly 26.0 g (0.2 mole) of 3-(diethylamino)propylamine was added while maintaining 3°-12° C. by means of an ice-water bath. The resulting solution was stirred at ambient temperature for approximately eight hours and allowed to stand overnight. Slowly a 10 percent aqueous potassium carbonate solution was added to the reaction solution until it was slightly alkaline. The solid which precipitated was collected by filtration. The water wet filter cake was resuspended in water and dissolved by the addition of hydrochloric acid. Slowly 10 percent aqueous potassium carbonate was added until the mixture was slightly alkaline. The resulting solid was collected by filtration, washed with water and dried in vacuo to obtain 2-chloro-4,6-bis[3-(diethylamino)-propyl]amino-1,3,5-triazine, a water-insoluble, white colored solid which melted at 119° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].Br[CH2:28][C:29]#[N:30]>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:28][C:29]#[N:30])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: N#CCBr
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCC#N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 and 2-bromoacetonitrile using an analogous procedure to that outlined in the preparation of Compound 205.11-1 NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.33 Hz, 3H) 3.22 (q, J=7.33 Hz, 3H) 5.14 (s, 2H) 7.31-7.37 (m, 2H) 7.82 (t, J=7.71 Hz, 1H) 7.91 (d, J=7.83 Hz, 1H) 8.09 (d, J=7.83 Hz, 1H) 8.11-8.15 (m, 2H) 8.22 (s, 1H) 14.04 (br. s., 1H) [M+H] calc'd for C22H19N3O3S, 406; found, 406.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][N:25]([CH2:27]CO)[CH3:26].C1(C)C=CC=CC=1.[H-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH2:18][CH2:24][N:25]([CH3:27])[CH3:26])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CN(C)CCOC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Temperature: 50 °C

Procedure:
A mixture of 4 g of the ester of Example 1, 2.45 ml of dimethylaminoethanol and 50 ml of anhydrous toluene was heated to reflux and then cooled to 50° C. and 95 mg of a 50% sodium hydride oil suspension was added thereto. The mixture was again heated to reflux and was then cooled to 40° C. and 0.2 ml of acetic acid were added thereto. The mixture was evaporated to dryness and the residue was dissolved in methylene chloride. The solution was filtered and the filtrate was washed with water, dried and filtered. The filtrate was evaporated to dryness to obtain 4.01 g of 2-dimethylaminoethyl 2-(7-chloro-4-quinolinylamino)-5-fluorobenzoate.
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([CH:21]=[N:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[Br:24][C:21]1[N:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:14][CH2:13][CH:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:11][CH2:10]3)=[C:3]([C:1]#[N:2])[C:4]2=[N:23][N:22]=1
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2cnnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(Br)nnc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of intermediate D8 (0.49 g, 1.615 mmol) in DCM (20 ml) was added N-bromosuccinimide (0.316 g, 1.777 mmol). The resulting mixture was stirred at r.t. for 1.5 h. The mixture was carefully washed with NaHCO3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to yield intermediate D97 (0.48 g, 78%).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.C(N(CC)CC)C.[NH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[OH:33]>CC#N>[OH:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[NH:27][C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cn1c(Cl)nc2ncn(Cc3ccccc3)c2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2ncn(Cc3ccccc3)c2c1=O

Procedure:
Heat at reflux for 2 days a mixture of 2-chloro-1-methyl-7-(phenylmethyl)purin-6-one (3.14 g=11.4 mmol), triethylamine (1.7 g=16.8 mmol), and (±)-trans-2-aminocyclopentanol (4.04 g=39.9 mmol) in CH3CN (150 ml). Collect the precipitate, wash with water, and dry to give the title compound, a solid, FAB MS: M+1=340.
Reaction SMILES: CC(C)(OC([NH:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([NH2:16])=[O:15])=[CH:10][C:9]=1[CH3:19])=O)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([NH2:16])=[O:15])=[CH:10][C:9]=1[CH3:19]
Reactant: Cc1cc(OCC(N)=O)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC(N)=O)ccc1N
Temperature: 0 °C
Reaction time: 5 h
Yield: 50.7 %

Procedure:
To a 200 m1L round bottomed flask with a stirring bar and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetamide (4.91 g, 17.52 mmol) and trifluoroacetic acid (50 mL). This solution was stirred at 0° C. for 5 h. The trifluoroacetic acid was removed in vacuo and the residue was partitioned between EtOAc and aqueous NaHCO3 solution. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 1.60 g of 4-amino-3-methylphenoxy-acetamide as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].[NH2:25][OH:26].[OH-].[K+].CO>C1COCC1>[OH:26][NH:25][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: COC(=O)CCCCCS(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCCCCS(=O)c1ccc(-c2ccc(Cl)cc2)cc1)NO
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of the 6-(4′-chloro-biphenyl-4sulfinyl)-hexanoic acid methyl ester (400 mg, 1.1 mmol) in distilled THF (10 mL) containing 50% aqueous hydroxylamine (0.65 mL, 9.9 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1.9 mL, 1M, 1.9 mmol) in a dropwise manner. After stirring at 0° C. for 1 h, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (2×20 mL) and the combined extracts were washed with brine (40 mL), dried over anhydrous MgSO4, filtered and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (315 mg, 79%) as a white powder, mp 108-110° C.
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(OCC)(=O)C>C(#N)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[CH2:18][CH2:19]2)[CH2:36][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCC(CCN3CCOCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
The 4-tosyloxyethyl-N-(4-nitrophenyl)piperidine (2.02 g, 5.0 mmol) obtained in Example 6(2) was dissolved in acetonitrile (20 ml), and potassium carbonate (1.38 g, 10 mmol) and morpholine (0.65 ml, 7.5 mmol) were added thereto, followed by stirring at 80° C. for 15 hours. After the reaction mixture was allowed to cool to room temperature, ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:50 to 1:20), thereby obtaining 4-morpholinoethyl-N-(4-nitrophenyl)piperidine (1.23 g, 77%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.CN(C=O)C.[CH2:31]1[O:39][CH:32]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][N:13]([CH2:31][CH:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[OH:39])[CH:14]=2)[CH:7]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=2)[CH:5]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
NaH (0.0075 g, 0.19 mmol, 60% dispersion) was added to N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (0.02 g, 0.06 mmol) suspended in DMF (1 mL, 0.06 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes. Styrene oxide (0.01 g, 0.08 mmol) was then added. The vial was capped and allowed to stir at 45° C. for 12 hours. H2O (0.2 mL) was added and the reaction was concentrated under reduced pressure. The residue was taken up in DMSO (1.0 mL) and was passed through a syringe filter. The eluent was purified by reverse phase HPLC (0 to 95% ACN/water with 0.1% formic acid modifier) to afford racemic 2-(4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)-1-phenylethanol. MS ESI calcd. for C23H21F3N5O [M+H]+ 440. found 440. 1H NMR (600 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.77 (d, J=4.8, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.34-7.27 (m, 5H), 7.25-7.19 (m, 2H), 7.01 (s, 1H), 5.69 (d, J=4.6, 1H), 4.94 (d, J=5.2, 1H), 4.20 (d, J=6.4, 2H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[NH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:33]([N:19]1[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=2[C:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:18]1)(=[O:35])[CH3:34]
Reactant: Clc1ccc(N2CCN(CCCc3c[nH]c4c3CCCC4)CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)c2c1CCCC2

Procedure:
3-(3-(4-(4-Chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole (0.5 g) obtained in Example 161 and triethylamine (0.6 ml) were dissolved in dichloromethane (10 ml) and acetyl chloride (0.3 g) was added under ice-cooling with stirring. The reaction mixture was stirred for 2 hours at room temperature and an aqueous potassium carbonate solution is added, and the chloroform layer was separated. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give 1-acetyl-3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:20]3([S:36][CH2:35][CH2:34][S:33]3)[C:19]1=2>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[C:27]2[C:26](=[CH:6][C:7]3[C:8]([CH:5]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:20]3([S:33][CH2:34][CH2:35][S:36]3)[C:19]1=2
Reactant: COC(=O)C1CC2=C(C(=O)C=CC2=O)C2(C1)SCCS2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)C1CC2=C(C(=O)c3cc4ccccc4cc3C2=O)C2(C1)SCCS2
Yield: 60.3 %

Procedure:
A mixture of 70 mg (0.32 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 66 mg (0.21 mmol) of methyl rac-1',2',3',4',5',8'-hexahydro-5',8'-dioxospiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate [prepared as described in Example 2(A)] in 5 ml of xylene was stirred and heated under reflux under an atmosphere of nitrogen for 23 hours. The mixture was evaporated to dryness and the residue was stirred with 5 ml of diethyl ether and then filtered to give 52 mg (60%) of methyl rac-1',2',3',4',5',12'-hexahydro-5',12'-dioxospiro[1,3-dithiolane-2,4'-naphthacene]-2'-carboxylate in the form of a bright yellow solid of melting point 216° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][N:17]3[C:22]=2[C:21]([NH:23][C:24]2[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)[N:28]=[CH:27]4)=[N:20][CH:19]=[N:18]3)[CH2:9][CH2:8]1)=[O:6].Cl>CO.C1COCC1>[F:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][N:29]1[C:30]2[C:26](=[CH:25][C:24]([NH:23][C:21]3[C:22]4=[C:14]([CH2:13][N:10]5[CH2:9][CH2:8][CH:7]([C:5]([OH:6])=[O:4])[CH2:12][CH2:11]5)[CH:15]=[CH:16][N:17]4[N:18]=[CH:19][N:20]=3)=[CH:32][CH:31]=2)[CH:27]=[N:28]1
Reactant: COC(=O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aqueous NaOH (2.1 mL, 1.0 N) was added to a solution of 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid methyl ester (352 mg, 0.686 mmole) in a mixture of MeOH (0.2 ml) and THF (0.2 ml) at 0° C. After stirring at 0° C. for 1 hour, the reaction mixture was allowed to warm to RT and left stirring overnight. Aqueous HCl (2.1 ml, 1.0 N) was added dropwise and the reaction was extracted with DCM. The organic extracts were dried (Na2SO4) and the solvents were removed to leave 1-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}-piperidine-4-carboxylic acid, as a solid (329 mg, purity 84% by LCMS) which was used as such. A solution of the crude acid (100 mg, 0.168 mmole) in THF (2 ml) was added dropwise to a solution of 1,1′-carbonyldiimidazole (33 mg, 0.2 mmole) in THF (0.3 ml) and this was heated at reflux for 30 min. After cooling to RT, cyclopropylsulfonamide (82 mg, 0.67 mmole, 4 equiv.) was added followed by a solution of DBU (50 uL, 0.336 mmole, 2 equiv.) in THF (0.2 ml). The reaction was stirred for 18 hr, diluted with EtOAc (120 ml), washed with pH 4.0 buffer (9 mL), brine (5 mL) and dried (Na2SO4). Removal the solvent followed by radial chromatography (2 mm silica gel plate gradient elution with DCM containing 1 to 5% MeOH) afforded the title compound as a solid (58 mg, 57%). 1H NMR (CDCl3) δ 0.98-1.00 (m, 2H), 1.22-1.27 (m, 2H), 1.84-1.92 (m, 4H), 2.03-2.16 (m, 2H), 2.24-2.3 (m, 1H), 2.83-2.92 (m, 1H), 3.08-3.11 (m, 2H), 3.74 (s, 2H), 5.54 (s, 2H), 6.46 (d, 1H, J=2.5 Hz), 6.81-6.97 (m, 3H), 7.20-7.27 (m, 1H), 7.36-7.51 (m, 3H), 7.84 (s, 1H), 8.06 (s, 2H), 11.82 (bs, 1H). MS: 603.7 (M+H+); HPLC Ret Time: 1.21 min (Gradient Time=2 min, Flow Rate=5 ml/min, Xterra 3.0×50 mm S7 C18 column).
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].[CH3:7][NH2:8].[ClH:9]>C(O)C>[ClH:9].[CH3:7][NH:8][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: C=CS(C)(=O)=O
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNCCS(C)(=O)=O
Reaction time: 8 h

Procedure:
Methylvinyl sulphone (2.1 g, 19.78 mmol) and methylamine (33% solution in IMS, 40 ml, excess) were mixed and heated at reflux under a nitrogen atmosphere for 6 hours. After standing overnight at room temperature, the mixture was concentrated in vacuo to give a yellow oil, which was treated with ethereal HCl to give a sticky solid. Trituration with absolute ethanol gave the title compound as a white solid which was collected by filtration and dried at 60° C. in vacuo (1.01 g, 5.82 mmol, 29%); δH [2H6]DMSO 9.27 (2H,br s), 3.59 (2H,dd), 3.31 (2H,dd), 2.57 (3H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([NH:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:14]([OH:17])(=O)[CH3:15]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]([CH2:12][CH3:13])[C:14](=[O:17])[CH:15]=[C:7]2[OH:8]
Reactant: CCNc1ccc(Cl)cc1C(=O)O
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCn1c(=O)cc(O)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
5-Chloro-N-ethyl anthranilic acid (13.1g; 0.006 mole) in acetic acid (35 ml) and acetic anhydride (35 ml) was refluxed for 24 hours. The cooled mixture was poured into ice-water and basified to pH 14. The precipitated red oil was separated and the supernatant acidified to pH 5 to give the title compound as a white crystalline solid. m.p. (EtOH) 305°-8° C (Found: C, 58.80; H, 4.64; N, 6.49; Cl, 15.95; C11H10CINO2 requires, C, 59.07; H, 4.51; N, 6.26; Cl, 15.85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]([CH2:8][O:9][CH3:17])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Br)cnc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ncc(Br)cc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-3-isopropoxy-pyridin-2-yl)-methanol (stage 190.1.2, 0.61 mmol) in DMF (3 ml) was added 55% NaH in oil (0.688 mmol) was added. The RM was stirred for 30 min at rt then was added iodomethane (0.684 mmol). The RM was stirred for 2.5 h at rt then was quenched with MeOH and purified by preparative HPLC. The fractions containing product were combined, basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a yellow oil. (HPLC: tR 2.83 min (Method A); M+H=260, 262 MS-ES).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][C@@H:17]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([O:44]C(C)(C)C)=[O:43])[CH:37]=2)=[O:34])[C:16]1=[O:49])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:18][C@@H:17]([NH:32][C:33](=[O:34])[NH:35][C:36]2[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=2)[C:42]([OH:44])=[O:43])[C:16]1=[O:49])=[O:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)N[C@@H]2CN(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)CN1C(=O)[C@H](NC(=O)Nc2cccc(C(=O)O)c2)CN(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Trifluoroacetic acid (40 ml) was added to a solution of (R)-(−)-1-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea (8 g) in methylene chloride (40 ml), the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, a mixed solvent (32 ml) of diisopropyl ether and ethanol (15:1) was added to the residue for crystallization, collected by filtration, to thereby obtain 6.35 g of the title compound (Yield 88%).
Reaction SMILES: [OH:1][C@@H:2](C)[C:3](N1CCNCC1)=O.[OH:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15]>>[C:2]([O:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15])(=[O:1])[CH3:3]
Reactant: C[C@H](O)C(=O)O
Reactant: C[C@H](O)C(=O)N1CCNCC1
Product: CC(=O)O[C@@H](C)C(=O)O

Procedure:
Scheme 3 shows the synthesis of intermediate, oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V from (S)-2-hydroxypropanoic acid (L-lactic acid) 1. Acetylation of 1 gave (S)-2-acetoxypropanoic acid 2, followed by treatment with a chlorinating reagent, such as oxalyl chloride, to give acid chloride, (S)-1-chloro-1-oxopropan-2-yl acetate 3 (Example 6). Reaction of 3 with the dihydrochloride salt of 1-benzylpiperazine in dichloromethane in the presence of triethylamine gave (S)-1-(4-benzylpiperazin-1-yl)-1-oxopropan-2-yl acetate 4 (Example 7). Hydrolysis of the acetate of 4 with lithium hydroxide gave (S)-1-(4-benzylpiperazin-1-yl)-2-hydroxypropan-1-one 5 (Example 8), followed by hydrogenation to remove the N-benzyl group to give (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one 6 (Example 9). The oxalate salt was formed from 6 with oxalic acid in ethanol and tetrahydrofuran to give V (Example 9).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1)[C:3]([OH:5])=[O:4].[CH3:14][Mg]Cl>C(OCC)C>[F:13][C:8]1[CH:7]=[C:6]([C:2]([OH:1])([CH3:14])[C:3]([OH:5])=[O:4])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: C[Mg]Cl
Reactant: O=C(O)C(=O)c1cc(F)cc(F)c1
Solvent: CCOCC
Product: CC(O)(C(=O)O)c1cc(F)cc(F)c1
Reaction time: 1.5 h

Procedure:
The compound was prepared according to the general procedure of Stiller et al., J. Med. Chem., 15:1029 (1972). A solution of alpha-keto-3,5-difluorophenylacetic acid (prepared according to Middleton et al., J. Org Chem., 45:2883 (1980)) in diethyl ether was cooled to 0° C. Methylmagnesium chloride (4.7 eq., 3.0 M solution in THF) was added dropwise via syringe pump at a rate of 10 ml/min so that the internal temperature did not exceed 5.5° C. The cooling bath was removed and stirring continued at ambient for 1.5 hours. After approximately 30 minutes, the clumps of solid dissolved. The mixture was poured onto ice and acidified with 1N HCl. The aqueous layer was extracted thrice with ethyl acetate. The combined organics were washed with 5% NaHSO3, water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to a yellowish solid. The solid was recrystallized from dichloromethane, giving a white crystalline solid having a melting point of 102.5-103.2 C. C9H8F2O3 (MW 202.17); mass spectroscopy found (M−H) 201.2. Anal calcd for C9H8F2O3: C, 53.47, H, 3.99. Found: C, 53.76; H, 3.82.