Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[N:44]([CH2:47][CH2:48][O:49][CH3:50])=[C:45]=[O:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([C:45]([NH:44][CH2:47][CH2:48][O:49][CH3:50])=[O:46])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: COCCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCNC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NC(C)C)nc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (39.0 mg, 0.075 mmol) in DCM (754 μL) at 0° C. was added triethylamine (31.5 μL, 0.226 mmol) and 1-isocyanato-2-methoxyethane (11.8 μL, 0.113 mmol). The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 45% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (24.5 mg, 52.6%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.32 (d, J=6.6 Hz, 6H), 1.97 (m, 2H), 2.14 (m, 2H), 2.77 (t, J=5.8 Hz, 2H), 3.12 (m, 2H), 3.37 (m, 5H), 3.46 (m, 4H), 3.71 (t, J=5.8 Hz, 2H), 4.13 (m, 1H), 4.50 (m, 3H), 6.88 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 505.6.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][CH2:18][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: OCCCCl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CCCO

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 3-chloro-1-propanol: 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.56 (s, 1H), 4.30 (t, J=6.9 Hz, 2H), 3.62 (br, 2H), 2.51 (s, 3H), 1.99 (m, 2H), 1.61 (s, 1H); MS (ES) m/z 283 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH2:29])=[N:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]C)[N:8]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:7]=1[CH3:28])=[O:5].[Cl:30]CCl.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[ClH:30].[NH2:29][C:2]([NH2:1])=[N:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[N:8]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:7]=1[CH3:28])=[O:5]
Reactant: ClCCl
Reactant: COc1ccccc1-c1cc(C(=O)N=C(N)N)c(C)n1CCc1ccc(F)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C(=O)N=C(N)N)cc(-c2ccccc2O)n1CCc1ccc(F)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 400 mg portion of N-(diaminomethylene)-1-[2-(4-fluorophenyl)ethyl]-5-(2-methoxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide was dissolved in 10 ml of dichloromethane, and 3.04 ml of a 1 M boron tribromide dichloromethane solution was added dropwise thereto at −70° C. under an atmosphere of argon, followed by stirring at room temperature for 15 hours. Then, 100 ml of a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by three times extractions with 20% methanol/chloroform. After drying the organic layer with anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex (registered trademark), methanol:chloroform=10:90-20:80). Then, the resulting product was dissolved in 3 ml of ethyl acetate and, under ice-cooling, 0.132 ml of 4 M hydrogen chloride/ethyl acetate was added, followed by stirring overnight at room temperature. The resulting solid was collected by filtration to obtain 90 mg of N-(diaminomethylene)-1-[2-(4-fluorophenyl)ethyl]-5-(2-hydroxyphenyl)-2-methyl-1H-pyrrole-3-carboxamide hydrochloride as a white solid.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[N+:5]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])([O-:7])=[O:6].[N:15]#[C:16][NH2:17]>C(O)C>[N+:1]([O-:4])([OH:3])=[O:2].[N+:5]([C:8]1[CH:9]=[C:10]([NH:11][C:16]([NH2:17])=[NH:15])[CH:12]=[CH:13][CH:14]=1)([O-:7])=[O:6]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1cccc([N+](=O)[O-])c1

Procedure:
42 ml (0.6 mol) of nitric acid (65%) are added dropwise to a yellow suspension of 82.88 g (0.6 mol) of 3-nitroaniline in 200 ml of ethanol. After the exothermic reaction has subsided, 75.7 g (0.9 mol) of cyanamide (50% in water) are added and the reaction mixture is boiled at reflux for 21 hours. After cooling to 0°, the mixture is filtered and washed six times with ethanol/diethyl ether (1:1). Drying under HV at 40° yields 3-nitrophenyl-guanidine nitrate; m.p. 205°-207°.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[F:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-:23].[K+].[K+]>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:13])=[O:23]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: Oc1cccc(F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Oc1cccc(F)c1

Procedure:
The title compound was prepared using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde and 3-fluorophenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(C1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([CH3:29])([CH3:28])C)N=1)(C)(C)C.FC(F)(F)[S:32](OS(C(F)(F)F)(=O)=O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:32][CH2:29][C:26]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CSCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg (2.32 mmol) of 1-t-butoxycarbonyl-4-(hydroxymethyl)piperidine (Example 201) and 1 mL (4.5 mmol) of 2,6-di-t-butylpyridine in 10 mL of CH2Cl2 was added 0.4 mL (2.32 mmol) of triflouromethanesulfonic anhydride at −78° C. After stirring for 0.5 h, 0.5 mL (4.5 mmol) of benzylmercaptane were added. The mixture was warmed to 0° C. and allowed to stir for another 15 min. 10 mL of sat'd NaHCO3 solution were added and the mixture was extracted with CH2Cl2. The combined organic fractions were washed with sat'd NaHCO3 solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 4:1) to give the title compound.
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH3:7].C.[CH3:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([NH:20][C:21]([NH:23][S:24]([C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([O:31]C)=O)(=[O:26])=[O:25])=[O:22])[N:11]=1>CCCCCC.C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:5][N:6]([CH3:7])[C:29]([C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[S:24]([NH:23][C:21]([NH:20][C:12]1[N:11]=[C:10]([CH3:9])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:22])(=[O:25])=[O:26])=[O:31]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2ccccc2n1
Reactant: CNC
Agent: C
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)N(C)C)nc2ccccc12
Reaction time: 2 h

Procedure:
To 21.2 ml of 25% trimethylaluminum in hexane (2.36 M) in 100 ml dry methylene chloride is added 2.2 g dimethylamine. The mixture is stirred at ambient temperature until evolution of methane gas ceases and then 20.0 g of methyl 2-[[(4-methylquinazolin-2-yl)aminocarbonyl]aminosulfonyl]benzoate and 200 ml of dry toluene is added. The resulting mixture is heated to distill off the methylene chloride and hexane, after which heating is continued at the reflux temperature of toluene. After 2 hours, the toluene is removed in vacuo, and 200 ml of methylene chloride and 100 ml of 10% hydrochloric acid are added. The phases are separated, and the methylene chloride phase is washed once with water, dried over magnesium sulfate, and filtered, and the methylene chloride distilled to yield the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2].C=O.[C:24](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[N+:1]([C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH3:24])[CH2:18][CH2:19]2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OCC1CCN(C)CC1
Yield: 86.3 %

Procedure:
2-nitro-4-(1-piperidin-4-ylmethoxy)5-methoxybenzonitrile (771 mg, 2.65 mmol) in CH2Cl2 (8 ml) and MeOH (4 ml) was reacted for 0.5 hour with formaldehyde (13.3 M, 300 μl, 4 mmol), acetic acid (191 mg, 3.18 mmol) and NaBH(OAc)3 (674 mg, 3.18 mmol) slowly added over 15 minutes. The solution was evaporated, the oily residue was taken up in a mixture of Na2CO3 and ethylacetate, extracted with ethylacetate. The organic phase was dried over MgSO4, evaporated to give title compound as a yellow solid (698 mg, 86%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=2)[C:21]#[N:22])=[N:13][CH:12]=1)[CH3:2].[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31].C([BH3-])#N.[Na+]>C(O)C>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[S:15][C:11]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][N:28]4[CH2:35][CH2:34][CH2:33][C@H:29]4[C:30]([OH:32])=[O:31])[CH:7]=[CH:6][CH:5]=3)=[CH:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCc1c(CN2CCC[C@H]2C(=O)O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
A solution of 5-[5-(2-ethyl-3-formylphenyl)-1,3-thiazol-2-yl]-2-[(1-methylethyl)oxy]benzonitrile (D73) (80 mg, 0.212 mmol) and L-proline (48.9 mg, 0.425 mmol) in Ethanol (10 mL) was stirred at room temperature for 15 min, then sodium cyanoborohydride (40.1 mg, 0.637 mmol) was added. The mixture was stirred at room temperature for 2 h. After concentration, the residue was partitioned between ethyl acetate and aqueous diluted HCl, washed with saturated brine. The organic phase was evaporated in vacuo. The residue was purified by mass Directed AutoPrep to afford 1-{[3-(2-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]methyl}-L-proline (E81) (26 mg) as a TFA salt.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[C:7]([O:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])([CH3:10])([CH3:9])[CH3:8].O>CO.ClCCl>[C:7]([O:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C@@H:18]([OH:20])[CH3:19])[CH3:3])([CH3:8])([CH3:10])[CH3:9]
Reactant: [BH3-]C#N
Reactant: C[C@H](O)CNCCCC(=O)OC(C)(C)C
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: C[C@H](O)CN(C)CCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add 0.62 ml (670 mg, 7.81 mmol) of 35% aqueous formaldehyde solution and 101 mg (1.61 mmol) sodium cyanoborohydride to a solution of 350 mg (1.61 mmol) 4-{[(2S)-2-hydroxypropyl]amino}butyric acid tert.-butyl ester in 10 ml methanol. Stir the reaction mixture for 16 h at room temperature. After adding 30 ml water and 40 ml dichloromethane, dry the organic phase over sodium sulphate, and filter. Concentrate the filtrate by vacuum evaporation, and dry. 323 mg (81% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1](=[O:3])=O.[CH2:4]([NH2:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH2:4]([N:12]=[C:1]=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCN
Reactant: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCN=C=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (30 mL) solution containing octylamine (n-OctylNH2) (0.04 mol, 5.2 g), N-cyclohexyl-N',N',N",N"-tetraethylguanidine (0.04 mol, 10.2 g) and triethylamine (0.08 mol, 8.0 g) at -10° C. (ice and salt bath) for 1 h at a pressure of 0 psig. The reaction mixture was transferred via cannula all at once under carbon dioxide to the precooled solution of phosphorus oxychloride (0.04 mol, 6.2 g) in 30 mL dichloromethane. After stirring for ca. 30 min at -10° C. the reaction mixture turned yellow-brown and a ppt. formed. The crude reaction was filtered and the filtrate concentrated in vacuo. The residue was extracted with 2×100 mL diethyl ether. The ether layers (light yellow) were concentrated and the residue was distilled under vacuum (ca. 0.1-0.3 torr) collecting product, octyl isocyanate, at 42°-44° C. (3.9 g, 63%) of 99% purity as by GC. IR (neat) 2274 cm-1. 1H NMR (in CDCl3) δ 3.23-3.29 (t, 2H), 1.54-1.63 (m, 2H), 1.23-1.40 (br, 10H), 0.84-0.90 (t, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:21]([C:18]2[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a stirring, 0° C. solution of piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 6.29 mmol, 1.05 equiv) and TEA (1.67 mL, 11.98 mmol, 2.0 equiv) in DCM (10 mL) was added 4-bromo-benzenesulfonyl chloride (1.53 g, 5.99 mmol, 1 equiv). The reaction was allowed to warm to ambient temperature and stir for 3 h. The reaction solvents were evaporated and the resulting solids were dried, washed with water and filtered, yielding a white powder (2.24 g, 92% yield). MS (ESI+): m/z=306.9, LC retention time: 3.17 min. Rf=0.56 (30% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.C(Cl)Cl.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[C:3]([CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:4]([CH2:8][NH:9][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:5]=[N:6][CH:7]=1
Reactant: NCc1cncc(Cl)c1COC1CCCCO1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)C(=O)NCc1cncc(Cl)c1COC1CCCCO1
Reaction time: 8 h

Procedure:
To a solution of C-[5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridin-3-yl]-methylamine (0.37 g, 1.4 mmol) in DCM (20 mL) DIPEA (0.41 mL, 2.2 mmol) and isobutyryl chloride (0.18 mL, 1.6 mmol) were added. Stirring was continued overnight at RT. The solvent was evaporated and the residue was used in the following step without further purification. MS (m/z): 326.9 [M+H+].
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:25])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].C[O-].[Na+]>COCCO>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[C:14]([OH:15])=[C:5]([C:3]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:4])[C:6](=[O:25])[O:7]3)=[CH:23][CH:22]=1
Reactant: COC(=O)c1c(O)c2c(OCc3ccc(F)cc3)cccc2oc1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2c(OCc3ccc(F)cc3)cccc2oc1=O)C(=O)O
Yield: 60.8 %

Procedure:
To a mixture of 5-(4-fluoro-benzyloxy)-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (86 mg, 0.25 mmol) and L-alanine (334 mg, 3.75 mmol) in 2-methoxyethanol was added sodium methoxide (176 mg, 3.25 mmol). Resulting mixture was refluxed overnight and concentrated. Residue was dissolved in water (100 mL) and acidified using 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried. Crude product was triturated with MeOH. Solid was collected and dried in vacuo to provide the title compound (61 mg). MS ESI(+) m/e: 402.13 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:13])[CH3:12].O>ClCCCl>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: ClCCCl
Solvent: O
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 50 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
2-Oxindole (3 g) was suspended in 1,2-dichloroethane and 3.2 mL of acetyl chloride slowly added. The resulting suspension was stirred at 50° C. for 5 hours, cooled, and poured into water. The resulting precipitate was collected by vacuum filtration, washed copiously with water and dried under vacuum to give 2.9 g (73% yield) of 5-acetyl-2-oxindole as a brown solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@H:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:10][C@H:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36]
Reactant: CC(=O)OCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(N[C@H]1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O)c1cc2ccccc2[nH]1
Yield: 89.5 %

Procedure:
A mixture of (3S)-1-(2-acetoxyethyl)-3-(2-indolylcarbonylamino) -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (1.80 g) and potassium carbonate (0.30 g) in 85% aqueous ethanol (30 ml) was heated at 65° to 70° C. for 1 hour under stirring. After cooling, ethanol was removed under reduced pressure, and to the residue was added water. The aqueous mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Removal of the solvent afforded a light yellow amorphous powder, which was chromatographed on silica gel with an eluent of a mixture of chloroform and ethyl acetate (3:1). The fractions containing the desired product were combined and evaporated to give (3S)-1-(2-hydroxyethyl)-3-(2-indolylcarbonylamino) -1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (1.47 g) as a colorless amorphous powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:13](=[CH2:16])[C:14]#[N:15]>O>[NH2:15][C:14]1[CH:13]=[CH:16][N:4]([CH2:3][CH2:2][OH:1])[N:5]=1
Reactant: NNCCO
Reactant: C=C(Cl)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccn(CCO)n1
Reaction time: 17 h

Procedure:
2-Hydroxyethylhydrazine (7.6 g.) was added slowly to a solution of potassium carbonate (13.8 g.) in water (40 ml.). The mixture was cooled to 0°, then 2-chloroacrylonitrile (8.75 g.) was added slowly with vigorous stirring. Stirring was continued for a further 17 hours and the mixture was then continuously extracted with EtOAc for 20 hours. On evaporation of the solvent, 3-amino-1-(2-hydroxyethyl)pyrazole was obtained (7.7 g.; 60%), b.p. 170/0.5 mm.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[Cl-].[NH4+]>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:10](=[O:11])[CH2:9][Cl:8])=[CH:26][CH:25]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(OCc2nc3ccccc3s2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 1 h
Yield: 65.5 %

Procedure:
0.24 ml of triethylamine and 0.17 ml of chloroacetyl chloride were added to a solution of 300 mg of 4-(benzothiazol-2-ylmethoxy)aniline [prepared as described in step (b) above] in 6 ml of methylene chloride cooled in an ice-water bath, and the resulting mixture was stirred for 1 hour. After this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with methylene chloride. The resulting extract was washed with water, dried over anhydrous sodium sulfate and the solvent was then removed by evaporation under reduced pressure. The resulting residue was recrystallized from a mixed solvent of methylene chloride and hexane to obtain 259.4 mg (yield 65.5%) of the title compound as a solid having a melting point of 196° to 197° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](O)=[O:29])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([NH2:37])([CH3:36])([CH3:35])[CH3:34].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH:22]2[C:28](=[O:29])[NH:37][C:33]([CH3:36])([CH3:35])[CH3:34])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CCC(=O)CC2C(=O)O)OC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=O)C1CC(=O)CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.1 %

Procedure:
A solution of 4-Benzyl-5-(2-carboxy-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.66 g, 3.74 mmol) in dry dichloromethane (20 ml) was stirred at 0° C. during sequential treatment with tert-butyl amine (1.4 ml, 12.7 mmol), 1-hydroxybenzotriazole hydrate (570 mg, 5 mmol) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (970 mg, 5 mmol). The resulting mixture was allowed to warm to room temperature and was stirred for 20 hours and then concentrated in vacuo. The crude mixture was dissolved in ethyl acetate and the resulting solution washed with saturated aqueous sodium hydrogen carbonate solution, 1 M hydrochloric acid and brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexane: 1/3 to 4/6) provided 4-benzyl-5-(2-tert-butylcarbamoyl-4-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.2 g, 61%). Mass spectrum 502 [M+H]+.