Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, benzyl bromide and sodium ethylate in ethanol. EI-MS m/e (%):318 (M+, 50), 317 ([M—H]+, 100), 285 (20), 91 (84).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:16]1([C:21](N)=[O:22])[CH:20]=[CH:19][N:18]=[CH:17]1>>[N:18]1([CH2:19][CH2:20][NH:16][C:21]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:22])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:17]1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: NC(=O)n1ccnc1
Agent: Cl
Product: O=C(NCCNC(=O)OCc1ccccc1)NCCN1CCCCC1

Procedure:
Prepared from benzyl 2-aminoethylcarbamate hydrochloride and N-[2-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) by a similar procedure to Preparation 50. The title compound was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH2:13])[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=1.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([CH2:23][N:24]=[C:25]=[O:26])=[CH:21][CH:20]=1>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[C:5]([NH:13][C:25]([NH:24][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:30])[F:29])=[CH:28][CH:27]=2)=[O:26])[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)cc2cnccc12
Reactant: O=C=NCc1ccc(OC(F)(F)F)cc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)Nc1cc(C(F)(F)F)cc2cnccc12

Procedure:
Prepared from 7-(trifluoromethyl)isoquinolin-5-amine (Description 99) and [4-(trifluoromethoxy)benzyl]isocyanate (Description 59) according to Description 61. m/z (ES+) 414 (M+H)+.
Reaction SMILES: O=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+].O>C(O)C>[OH:16]/[N:15]=[C:2]1/[CH2:3][CH2:4][CH2:5][C:6]2[O:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]/1=2
Reactant: NO
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1coc2c1/C(=N\O)CCC2
Yield: 95.4 %

Procedure:
To a solution of 30.0 g of 4,5,6,7-tetrahydro-4-oxo-3-benzofurancarboxylic acid in 225 ml of ethanol is added 22.97 g of hydroxylamine hydrochloride, followed by 18.10 g of sodium acetate and 55 ml of water. The reaction mixture is heated at reflux for 2.5 hours and concentrated in vacuo to a residue which is diluted with 600 ml of ethyl acetate, washed with 2×200 ml of water, brine and dried over Na2SO4. The organic layer is concentrated in vacuo to a residue which is dried under vacuum to give 31.0 g of the desired product as a solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[C:10]([N:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][C@H:18]([OH:20])[CH3:19])=[N:11][C:12]([Br:15])=[CH:13][CH:14]=1.N1C=CC=CC=1>ClCCl>[CH2:21]([N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:10]1[C:9]([NH:8][C:1](=[O:3])[CH3:2])=[CH:14][CH:13]=[C:12]([Br:15])[N:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](O)CN(Cc1ccccc1)c1nc(Br)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Br)nc1N(Cc1ccccc1)C[C@@H](C)O
Temperature: 40 °C
Yield: 55.7 %

Procedure:
Acetic anhydride (0.623 mL, 6.60 mmol) was added to a solution of crude (R)-1-((3-amino-6-bromopyridin-2-yl)(benzyl)amino)propan-2-ol (2.22 g, 6.60 mmol) and pyridine (1.60 mL, 19.8 mmol) in dichloromethane (60 mL). The reaction mixture was then heated to 40° C. for 39 h. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in toluene (ca. 100 mL), which was then concentrated under reduced pressure in order to remove residual pyridine. The crude product was purified by column chromatography on silica gel (eluting with 2:1 dichloromethane-ethyl acetate followed by 3:2 dichloromethane-ethyl acetate) to afford (R)-N-(2-(benzyl(2-hydroxypropyl)amino)-6-bromopyridin-3-yl)acetamide (1.39 g, 56% yield). MS (ESI, pos. ion) m/z 378, 380 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:11]=[C:10]([CH:9]=[CH:8][C:6]=1[OH:7])[O:12][CH2:14][C:15]([O:17][CH3:18])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(O)c(C(C)(C)C)c1

Procedure:
33.2 g of tert.-butyl hydroquinone, 41.35 g of methyl bromoacetate and 37.3 g of potassium carbonate (anhydrous) are refluxed in 300 ml of acetone under nitrogen for 3 days. The solvent is removed under reduced pressure and 500 ml of ether are added. This ether solution is washed with water, dried with magnesium sulfate and evaporated. The residue is distilled in vacuo. The brown distillate obtained at 138°-140° under 10-3 mm Hg is purified by means of column chromatography. The methyl 2-(3-tert.-butyl-4-hydroxyphenoxy)-acetate thus obtained can be crystallised from hexane. Melting point: 87°-89°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:25]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CCN(CC)CC>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:28]4[CH2:29][CH2:30][N:25]([C:31]([NH2:33])=[O:32])[CH2:26][CH2:27]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: NC(=O)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (317 mg, 1 mmol), piperazine-1-carboxylic acid amide hydrochloride (273 mg, 1.65 mmol), absolute ethanol (12.7 ml), activated 3 Å molecular sieves (320 mg), Et3N (0.278 ml), titanium (IV) isopropoxide (1.46 ml, 5.20 mmol) and STAB (1.8 g, 8.5 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a off white solid (70 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.86 (d, 2H), 4.30 (br s, 2H), 4.02 (t, 2H), 3.80-3.71 (m, 2H), 3.58-3.48 (m, 2H), 3.23-3.15 (m, 4H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.40 (s, 2H), 2.19-1.73 (m, 14H).
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6](C(C(O)=O)C)[C:5]1=[O:17])=[N+]=[N-].NC1CCCCCNC1=O.C(O)(=O)C.O=[C:33]([CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>C(O)C.[Pd]>[CH2:37]([O:36][C:34]([CH:33]([NH:1][CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]1=[O:17])[CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:35])[CH3:38]
Reactant: CC(C(=O)O)N1CCCCCC(N=[N+]=[N-])C1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Pd]
Agent: NC1CCCCCNC1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCCCNC1=O

Procedure:
Reduce 3-azidoperhydroazocin-2-one (Example 3) to 3-aminoperhydroazocin-2-one using 10% Pd/C in ethanol. NMR (CDCl3, TMS): δ 1.67 (broad s, 8H), δ 2.25 (broad s, 2H), δ 3.35 (m, 2H), δ 3.8 (m, 1H), δ 7.0 (broad, 1H). Hydrogenate a solution of 1.42 g of this amine, 0.59 g acetic acid and 3.09 g ethyl 2-oxo-4-phenylbutyrate in 50 ml ethanol over 10% Pd/C catalyst. AFter filtration and concentration of the reaction, purify the product by chromatography over silica gel to isolate 3-[(1-ethoxycarbonyl-3-phenyl-1-propyl)amino]perhydroazocin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:9][CH2:10][CH2:11][O:12]2)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: Oc1ccc(C2OCCO2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(C2OCCO2)cc1Br
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
A mixture of 2-bromo-4-(1,3-dioxolan-2-yl)phenol (3a, 2.0 g, 8.2 mmol) and oven-dried potassium carbonate (2.7 g, 20.0) in dry acetone (20 mL) was stirred for 10 min. Dimethyl sulfate (0.9 mL, 10.0 mmol) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 18 h. Excess potassium carbonate was filtered off and washed with acetone (3×10 mL). Solvent was evaporated under reduced pressure and water (25 mL) was added. The mixture was extracted with chloroform (3×100 mL) and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was column chromatographed on silica gel eluting with 20% ethyl acetate in hexanes to afford compound 4b (1.9 g, 91% yield) as a colorless oil. Rf=0.51 (25% EtOAc-hexanes); 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=2.1 Hz, 1H), 7.33 (dd, J=8.4, 2.1 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 5.68 (s, 1H), 4.02 (m, 4H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 131.3, 126.8, 111.3, 102.6, 65.1, 56.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[C:23](O)=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN1CCCC1=O>[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[C:23]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:2]2)=[O:24])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cnoc1-c1ccccc1
Reactant: c1cncc(C2CCNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1cnoc1-c1ccccc1)N1CCC(c2cccnc2)C1
Reaction time: 72 h
Yield: 50.9 %

Procedure:
To a 15 mL round-bottomed flask equipped with magnetic stirring was added 3-(pyrrolidin-3-yl)pyridine (250 mg, 1700 μmol, source: ASDI Inc.) and 4 mL of N-methylpyrrolidinone (NMP). 5-Phenylisoxazole-4-carboxylic acid (300 mg, 1600 μmol, source: CiVentiChem) was added followed by 1-hydroxybenzotriazole (250 mg, 1800 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (380 mg, 2000 μmol). Added 2 mL more NMP, and the reaction mixture was stirred at ambient temp. After 3 days, added 30 mL of water and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with sat'd NaHCO3 and brine. The organic layers were then dried over MgSO4, filtered and concentrated in vacuo. The sample was absorbed onto silica gel and purified on a 40 g Isco Redi-sep® silica gel column that had been pre-equilibrated with CH2Cl2+2% MeOH. The product was eluted sample with CH2Cl2+2% (2M NH3 in MeOH). A viscous yellow oil was isolated as desired product (mass=260 mg). Mass Spec. m/z+ion=320.1.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[S:18])[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[OH-].[Na+].[CH3:23]I>CO>[CH3:23][S:18][C:7]1[CH2:8][C:9](=[O:17])[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]2[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=2[N:6]=1
Reactant: O=C1CC(=S)Nc2ccc(Cl)cc2N1c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2ccc(Cl)cc2N(c2ccccc2)C(=O)C1
Reaction time: 1 h

Procedure:
To 3.03 g of 7-chloro-5-phenyl-1H-1,5-benzodiazepin-4-one-2-thione in a solution of 0.40 g sodium hydroxide and 15 ml of methanol is added, with stirring a solution of 1.39 g of methyl iodide in 5 ml of methanol. Stirring is continued for 1 hour, the reaction is evaporated, diluted with 30 ml methylene chloride and filtered through a short Florisil column. After washing the column with ethyl acetate, the combined filtrates are evaporated to give the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([O:34][CH3:35])=[O:33])(=[O:16])=[O:15])[CH3:2]>C(O)C.C(O)=O>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[CH:31]=[CH:30][C:21]2[C:22]3[CH:23]=[CH:24][O:25][C:26]=3[CH2:27][CH2:28][O:29][C:20]=2[C:19]=1[C:32]([O:34][CH3:35])=[O:33])(=[O:16])=[O:15])[CH3:37]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCCc1occc1-2
Solvent: O=CO
Solvent: CCO
Product: CCN(CC)CCCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCCc1occc1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Methyl 8-[2((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (Intermediate 5, 0.147 g) was suspended in ethanol. Formic acid (2 drops) was added and the flask was evacuated and purged with nitrogen gas. Palladium hydroxide (20% wt, 0.015 g) was added and nitrogen was replaced by hydrogen and the mixture was stirred at room temperature under an atmosphere of hydrogen for 1 hour. The mixture was filtered through a pad of Celite and washed with ethanol. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 2.5-10% to give methyl 8-[2-(3-diethylaminopropyl)-4-fluorobenzenesulfonylamino]-4,5-dihydro-3,6-dioxabenzo[e]azulene-7-carboxylate (0.134 g) as a yellow glassy solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:9]Cl)=[CH:5][CH:6]=[CH:7][CH:8]=1.C(=O)(OC)[O:12]C.O>CN(C)C=O>[CH2:2]1[O:12][CH2:9][C:4]2[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)OC
Reactant: ClCc1ccccc1CCl
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)COC2
Reaction time: 22 h
Yield: 37 %

Procedure:
The procedure described in Example 1 was followed in reacting 0.05 g mole of α,α'-dichloro-o-xylene with 0.06 g mole of dimethyl carbonate in 50 ml of N,N-dimethylformamide. After 22 hours, the reaction mixture was poured into 100 ml of water and the organic portion was extracted from the mixture with three 5050 ml portions of hexane. The combined extracts were dried over MgSO4 and the hexane was distilled off. The residue was distilled under reduced pressure to obtain 2.29 g (37 percent yield) of phthalan (1,3-dihydroisobenzofuran), b.p. 95° C./30 mm.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH2:7]Cl)=[O:4].[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14]>CN1CCCC1=O>[CH3:1][CH:2]([CH3:9])[C:3]([O:5][CH2:6][CH2:7][O:15][C:13](/[CH:12]=[CH:11]/[C:10]([OH:17])=[O:16])=[O:14])=[O:4]
Reactant: CC(C)C(=O)OCCCl
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)C(=O)OCCOC(=O)/C=C/C(=O)O
Yield: 12.1 %

Procedure:
Following general procedure A, chloroethyl 2-methylpropanoate (0.24 g, 1.58 mmol) was reacted overnight with the pre-formed bis-dicyclohexylamine salt (DCHA) of fumaric acid (FA) (0.50 g, 1.26 mmol) in N-methylpyrrolidinone (NMP) at ca 100° C. The crude material was purified by mass-guided preparative HPLC to afford (0.035 g, 12% yield) of the title compound (49) as a white, waxy, semi-solid. 1H NMR (CD3CN, 400 MHz): δ 6.89-6.83 (q, J=5.6 Hz, 1H), 6.82-6.81 (d, J=16.0 Hz, 1H), 6.73-6.69 (d, J=16.0 Hz, 1H), 2.58-2.49 (heptet, J=6.8 Hz, 1H), 1.49-1.47 (d, J=5.6 Hz, 3H), 1.12 (d, J=7.2 Hz, 3H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI): m/z=239.01 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.CN(C)CCCN=C=NCC.[CH3:40][C:41]1[N:42]=[C:43]([C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[S:44][C:45]=1[C:46](O)=[O:47]>C(OCC)(=O)C.C(OCC)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]1[CH:17]=[C:7]([C@H:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:46]([C:45]3[S:44][C:43]([C:49]4[CH:50]=[CH:51][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:53][CH:54]=4)=[N:42][C:41]=3[CH3:40])=[O:47])[CH2:2]2)[CH:8]=[CH:9][C:10]=1[CH3:18])[CH3:16]
Reactant: CCOC(=O)c1cc([C@H]2CCCNC2)ccc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1cc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.6 %

Procedure:
(R)-ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid (Example 9; 2.13 g, 5.36 mmol) was dissolved in 100 mL ethyl acetate and washed with 100 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 20 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (2.05 g, 10.72 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (1.69 g, 5.90 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 72 h. The reaction was diluted with 200 mL diethyl ether and washed with water (100 mL), saturated aqueous NaHCO3 (2×100 mL), 0.5 N HCl (2×100 mL), water (100 mL), and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield (R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzoic acid ethyl ester (2.62 g, 95%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:11][O:12]C(Cl)Cl.FC1C=C(F)C=C(OC)C=1C=O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[C:7]=1[CH:11]=[O:12]
Reactant: COC(Cl)Cl
Reactant: COc1cc(F)cc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COc1cc(F)cc(F)c1C=O
Solvent: ClCCl
Product: COc1cc(F)c(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(Intermediates 26A and 26B were prepared in a similar manner to the preparation described in WO 2004046133). To a stirred solution of 3,5-difluoroanisole (1.0 g, 7.0 mmol) in dichloromethane (6 mL) at 0° C. was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) and dichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion of addition, the reaction mixture was stirred for 1 h and then poured into ice-water (50 mL). The resulting mixture was extracted with dichloromethane (3×50 mL). The combined organics were washed with H2O (50 mL), brine (50 mL), dried over Na2SO4 and filtered. The volatiles were removed under reduced pressure to provide a residue. The residue was subjected to chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to give 2,6-difluoro-4-methoxybenzaldehyde, Intermediate 26A [less polar material, 230 mg, 19%, 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3 H), 6.47 (d, J=10.55 Hz, 2 H), 10.17 (s, 1 H)] and 2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polar material, 740 mg, 62%, 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3 H) 6.43-6.51 (m, 2 H) 10.30 (s, 1 H)], both as white solids.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7](=[O:22])[C:8]([CH2:18][CH2:19][CH:20]=O)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:22])[C:8]([CH2:18][CH2:19][CH2:20][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)=[C:9]([N:11]([C:15](=[O:17])[CH3:16])[C:12](=[O:14])[CH3:13])[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1
Reaction time: 17 h
Yield: 24 %

Procedure:
A mixture of 1.25 g (4.00 mmol) of 3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propionaldehyde, 0.743 g (4.50 mmol) of ethyl p-aminobenzoate, 1.0 ml of glacial acetic acid, and 3A molecular sieves in 25 ml of methanol was stirred at room temperature for 3 hours under nitrogen before 0.28 g (4.47 mmol) of sodium cyanoborohydride was added during a 2 minute period. After stirring for 17 hours, the mixture was filtered. The filtrate was spin evaporated in vacuo to a yellow foam. The product was separated from a mixture by flash chromatography on Silica Gel 60 (100 g; 230-400 mesh, EM Reagents) with ethyl acetate. Appropriate fractions were combined on the basis of TLC correlation, and solent was removed by spin evaporation in vacuo. Recrystallization from ethyl acetate yielded 0.44 g (24% of theory) of ethyl 4-[3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propylamino]benzoate as a white solid, mp 197°-198°; TLC (ethyl acetate), Rf =0.5; NMR (DMSO-d6) δ 1.28 (t, J=7.1 Hz, 3H, CH3), 1.65 (m, 2H, CCH2C), 2.14 (s, 3H, Ac), 2.2 (m, 2H, CH2Het), 2.23 (s, 6H, 2Ac), 3.05 (m, 2H, CH2N), 4.22 (q, J=7.1 Hz, 2H, CO2CH2), 6.5 (br, 1H, AcNH obscured by Ar), 6.57 (d, 2H, ArH), 7.69 (d, 2H, ArH). Elemental analysis. Calculated for C22H27N5O6, 0.5 H2O (MW 466.49): C, 56.64; H, 6.05; N, 15.01. Found: C, 56.88; H, 6.01; N, 14.88.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=S)[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1.O.[NH2:25][NH2:26]>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][NH:13][C:12](=[N:25][NH2:26])[C@@H:11]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=S
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](c2cccc(F)c2F)CNC1=NN
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-thioxopiperidin-3-yl]carbamate (100 mg, 0.29 mmol) in methanol (2.9 mL) was added hydrazine hydrate (55%, 780 μL, 8.76 mmol). The mixture was stirred 40 min, and then concentrated. Water was added, and the mixture was extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude title compound. MS 341.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:27](=[O:29])[CH3:28])[CH:20]=[CH:19]2
Reactant: CC(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(C)=O)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 41 %

Procedure:
6,7-Dimethoxy-4-[(1H-5-indolyl)oxy]quinoline (50 mg) was dissolved in N,N-dimethylformamide (1 ml), and 60% sodium hydride (7 mg) was added to the solution, followed by stirring under ice cooling for 30 min. Acetyl chloride (16.6 μl) was added to the reaction solution, and the mixture was stirred under ice cooling for additional one hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (23 mg, yield 41%).