Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]#[C:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=O)[CH3:2].[NH2:26][NH2:27].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]1[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[N:27]([C:14]2[CH:15]=[CH:16][C:11]([CH3:9])=[CH:12][CH:13]=2)[N:26]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(CC#CC(=O)c1ccc(Br)cc1)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cc(-c2ccc(Br)cc2)n(-c2ccc(C)cc2)n1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115 %

Procedure:
To a solution of 6-(4-bromo-phenyl)-6-oxo-2-m-tolyl-hex-4-ynoic acid ethyl ester (7.5 g, 19 mmol) in THF (40 mL) was added hydrazine (4.5 g, 28 mmol, 1.5 equiv) and Cs2CO3 (9.0 g, 28 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (30 mL), and a satd aq solution of cesium carbonate (50 mL) was added. The resulting aqueous layer was back-extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with satd aq NaHCO3 (50 mL) then brine (50 mL), and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by chromatography (silica gel, 25% ethyl acetate/hexanes) to afford the desired compound (5.5 g, 58%). TLC (silica gel, 3:7 EtOAc/hexanes): Rf=0.35. MS (ESI): mass calculated for C28H27BrN2O2, 502.13; m/z found, 503/505 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.39 (d, J=10.7 Hz, 2H), 7.25-7.01 (m, 10H), 6.17 (s, 1H), 4.19-4.03 (m, 3H), 3.52 (dd, J=14.7, 9.6 Hz, 1H), 3.09 (dd, J=14.7, 6.0, 1H), 2.35 (s, 6H), 1.19 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16]C=O)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([Br:49])(Br)(Br)[Br:46]>ClC(Cl)C.ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH:16]=[C:45]([Br:49])[Br:46])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ncccc1CN1CCC(CC=O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncccc1CN1CCC(C=C(Br)Br)CC1
Reaction time: 1 h
Yield: 61.5 %

Procedure:
3.0 g of 1-[(2-methoxy-3-piridyl)methyl]-4-piperidine acetaldehyde, 5.4 ml of triethylamine, 20.1 g of triphenylphosphine and 12.9 g of carbon tetrabromide were dissolved in 77 ml of dichloroethane at 0° C., and the mixture was stirred for one hour. Dichloromethane was added to the reaction solution, the mixture was washed with an aqueous saturated sodium bicarbonate, and then it was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (hexane:ethyl acetate=20:1), to give 2.9 g of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]=O.[C:3]([C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)([CH3:6])([CH3:5])[CH3:4].[C:14]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:17][CH3:18])([CH3:16])[CH3:15]>[OH-].[Na+].O1CCOCC1>[C:3]([C@H:7]1[CH2:8][CH2:9][C@H:10]([NH:13][C:23]2[C:24]([CH3:1])=[C:19]([C:14]([CH2:17][CH3:18])([CH3:15])[CH3:16])[CH:20]=[CH:21][C:22]=2[OH:25])[CH2:11][CH2:12]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCC(C)(C)c1ccc(O)cc1
Reactant: C=O
Reactant: CC(C)(C)[C@H]1CC[C@H](N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(C)(C)c1ccc(O)c(N[C@H]2CC[C@H](C(C)(C)C)CC2)c1C
Temperature: 70 °C
Reaction time: 6 h

Procedure:
41 3 ml (0.55 mole) of 37% strength aqueous formaldehyde solution, 85.3 g (0.55 mole) of trans-4-tertbutylcyclohexylamine, 95 g (0.579 mole) of 4-tert-pentylphenol and 1 g of sodium hydroxide are added in succession to 300 ml of dioxane at from 20° to 35° C. The mixture is then stirred for 6 hours at 70° C. and cooled to +5° C., and the precipitate is filtered off under suction, washed with 100 ml of water and then with 50 ml of dioxane and dried. 104 g (57% of theory) of trans-2-(4'-tert-butylcyclohexylamino)-methyl-4-tert-pentylphenol are obtained as white crystals of melting point 148°-150° C. (active ingredient No. 1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:40][CH3:41])[CH:32]=1)=[O:30]>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH2:40][CH3:41])[CH:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: CCn1cc(C(=O)CCCCCBr)c2ccccc21
Agent: Cl
Product: CCn1cc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c2ccccc21
Yield: 33.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.56 g) as starting compound and 6-bromo-1-(1-ethyl-1 H-indol-3-yl)-1-hexanone (1.50 g) were reacted and treated in the same manner as in Example 199 to give 0.41 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(1-ethyl-1 H-indol-3-yl)-6-oxohexyl)piperidin-4-yl)methyl)-benzamide hydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([N:13](OC)[CH3:14])[N:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:17]2[CH:22]=[C:21]([N+:23]([O-])=O)[C:20]([F:26])=[CH:19][C:18]=2[CH3:27])[C:4]1=[O:28])[CH3:2].[H][H]>CO.[Pd]>[NH2:23][C:21]1[C:20]([F:26])=[CH:19][C:18]([CH3:27])=[C:17]([N:5]2[CH2:6][C:7]3[CH:12]=[N:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:28])[CH:22]=1
Reactant: CCN1C(=O)N(c2cc([N+](=O)[O-])c(F)cc2C)Cc2cnc(N(C)OC)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)N(c2cc(N)c(F)cc2C)Cc2cnc(NC)cc21
Yield: 77.8 %

Procedure:
1-Ethyl-3-(4-fluoro-2-methyl-5-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.2 g, 8.2 mmol) and Pd/C (0.3 g) were combined in MeOH (60 ml) and subjected to hydrogen (45 psi) at 50° C. overnight. The reaction mixture was filtered, concentrated in vacuo and purified by column chromatography to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (2.1 g, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.71 (s, 1 H), 6.88 (d, J=12.0 Hz, 1 H), 6.64 (d, J=8.4 Hz, 1 H), 6.38 (m, 1 H), 5.99 (s, 1 H), 5.01 (s, 2 H), 4.51 (d, J=13.6 Hz, 1 H), 4.29 (d, J=13.6 Hz, 1 H), 3.76 (m, 2 H), 2.75 (d, J=4.8 Hz, 3 H), 1.91 (s, 3 H), 1.14 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 330.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:52]=[CH:51][C:11]([C:12]([NH:14][C:15]2[S:16][C:17]3[C:23]([C:24]4[N:25]=[C:26]([NH:29]C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[S:27][CH:28]=4)=[CH:22][CH:21]=[C:20]([O:49][CH3:50])[C:18]=3[N:19]=2)=[O:13])=[CH:10][CH:9]=1)[CH3:6].Cl>CO>[NH2:29][C:26]1[S:27][CH:28]=[C:24]([C:23]2[C:17]3[S:16][C:15]([NH:14][C:12](=[O:13])[C:11]4[CH:10]=[CH:9][C:8]([CH2:7][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:6])=[CH:52][CH:51]=4)=[N:19][C:18]=3[C:20]([O:49][CH3:50])=[CH:21][CH:22]=2)[N:25]=1
Reactant: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(-c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3s2)cc1
Agent: Cl
Solvent: CO
Product: COCCN(C)Cc1ccc(C(=O)Nc2nc3c(OC)ccc(-c4csc(N)n4)c3s2)cc1

Procedure:
g of 4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-{4-methoxy-7-[2-(trityl-amino)-thiazol-4-yl]-benzothiazol-2-yl}-benzamide (0.00014 Mol) were treated with cc HCl (0.03 ml) in MeOH (1 ml) for 1 h at reflux. After evaporation of the solvent the residue was taken up in water (10 ml), treated with sat. NaHCO3 (10 ml) and extracted 4× with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was subjected to column chromatography (silicagel, ethyl acetate, CH2Cl2/MeOH 19:1 and 9:1). The title compound was obtained as a white solid (53%); F.p.: 199-206° C.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21]([CH3:26])([OH:25])[CH2:20][CH2:19][CH2:18][C:17]=3[N:16]=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1>[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([OH:25])[CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=1
Reactant: CC1(O)CCCc2nc(N=C(c3ccccc3)c3ccccc3)ccc21
Agent: Cl
Solvent: C1CCOC1
Product: CC1(O)CCCc2nc(N)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of 2-(diphenylmethyleneamino)-5-methyl-5,6,7,8-tetrahydroquinolin-5-ol (180 mg, 0.526 mmol) in THF (20 ml) was added aqueous hydrochloric acid (2.0 M, 1.00 ml, 2.0 mmol). After 20 minutes, the reaction mixture was partially concentrated under reduced pressure to a volume of approximately 2 mL. The mixture was diluted with ethyl acetate (30 mL), saturated aqueous sodium bicarbonate solution (15 mL), saturated aqueous sodium carbonate (10 mL), and brine (15 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0.5-10% methanol/dichloromethane linear gradient) to yield 2-amino-5-methyl-5,6,7,8-tetrahydroquinolin-5-ol. MS ESI calc'd. for C10H15N2O [M+H]+ 179. found 179. 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J=8.5 Hz, 1H), 6.38 (d, J=8.5 Hz, 1H), 4.42 (s, 2H), 2.80-2.63 (m, 2H), 2.02-1.75 (m, 5H), 1.50 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH:5]([CH:7]([CH:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])[C:8](OCC)=O)=[O:6].[O-]CC.[Na+]>C(O)C>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([CH:13]([C:7]2[C:5](=[O:6])[NH:1][C:2](=[S:3])[NH:4][CH:8]=2)[CH3:14])[CH:16]=1
Reactant: CCOC(=O)C(C=O)C(C)c1cccnc1
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(c1cccnc1)c1c[nH]c(=S)[nH]c1=O
Reaction time: 8 h
Yield: 51 %

Procedure:
Thiourea (1.4 g) and ethyl 2-formyl-3-(3-pyridyl)butyrate (3.4 g) was added to a solution of sodium ethoxide (from 0.78 g sodium) in ethanol (45 ml). The mixture was heated under reflux for 7 hours and evaporated. The residue was taken up in water and extracted with chloroform at pH 13. The pH was adjusted to 7.0 and the mixture allowed to stand at 0° overnight. The solid was filtered off to give 5-[1-(3-pyridyl)ethyl]-2-thiouracil (1.83 g) m.p. 225°-228° (from 2-propanol).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][N:13]([C:15](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[O:17])[CH3:14].[CH:25]1[C:30]([CH:31]2[O:41][C:40]3[CH:39]=[C:38]([OH:42])[CH:37]=[C:36]([OH:43])[C:35]=3[C:33](=O)[CH:32]2[OH:44])=[CH:29][C:28]([OH:45])=[C:27]([OH:46])[CH:26]=1>Cl.CO>[O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][N:13]([C:15](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:16]=[O:17])[CH3:14].[CH:25]1[C:30]([CH:31]2[O:41][C:40]3[CH:39]=[C:38]([OH:42])[CH:37]=[C:36]([OH:43])[C:35]=3[CH2:33][CH:32]2[OH:44])=[CH:29][C:28]([OH:45])=[C:27]([OH:46])[CH:26]=1
Reactant: O=C1c2c(O)cc(O)cc2OC(c2ccc(O)c(O)c2)C1O
Agent: CN(C)C(C=O)=Cc1ccccc1
Agent: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: CO
Product: Oc1cc(O)c2c(c1)OC(c1ccc(O)c(O)c1)C(O)C2

Procedure:
Working solution of 1% vanillin was prepared by dissolving 0.1 g of vanillin in 10 mL of 5 N HCl, whereas 5% dimethylaminocinnamaldehyde (DMACA) was prepared in methanol containing 5% H2SO4. Lyophilized extract for 100 mg of dry kernels was dissolved in 0.5 mL of vanillin or DMACA working solutions. Taxifolin and catechin each at a concentration of 100 ppm were used as reference compounds for color reactions. Because vanillin is catechin-specific and produces bright red color, no color is developed when it reacts with taxifolin. DMACA reacting with catechin produces dark greenish blue color, whereas reacting with taxifolin produces purple color.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C[N+]1([O-])CC[O:17]CC1.[OH2:21]>CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:21][C@H:3]1[C@@H:4]([OH:17])[CH2:5][N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2]1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77 %

Procedure:
A solution of the crude tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate mixture (57.5 g; 0.22 mol) in acetone (500 mL) was added dropwise to a mixture of N-methyl morpholine-N-oxide (28.45 g; 0.243 mol), osmium tetroxide (1.0 g; 0.004 mol) and water (500 mL) while keeping the temperature below 25° C. The reaction mixture was then stirred for 5 hours at ambient temperature. Acetone was evaporated off and the organic phase extracted with ethyl acetate. The combined organic phases were washed in turn with water and brine and dried over magnesium sulphate. The solvent was evaporated under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with ethyl acetate/petroleum ether (1/1) and ending with pure ethyl acetate. A second flash chromatography using increasingly polar solvent mixtures, starting with methanol/dichloromethane (2/98) and ending with methanol/dichloromethane (5/95) was done. Evaporation of the solvent gave tert-butyl (3R,4S)-3,4-dihydroxypyrrolidine-1-carboxylate (34.6 g; 77%) as a brown oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[O:12]=[C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH:14]=[CH:15]/[C:16](O)=[O:17].C(Cl)(Cl)Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH:6]([O:8][C:16](=[O:17])/[CH:15]=[CH:14]/[C:13](=[O:12])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1
Reactant: O=C(O)/C=C/C(=O)c1ccccc1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1CCC(C(C)C)C(OC(=O)/C=C/C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.43 g (0.028 mole) of (+)-menthol and 0.34 g (0.003 mole) of 4-dimethylaminopyridine are added to a solution of 5.0 g (0.028 mole) of (E)-4-oxo-4-phenyl-2-butenoic acid in 60 ml of anhydrous dichloromethane. After cooling the solution to 0° C., a solution of 5.86 g (0.028 mole) of N,N-dicyclohexylcarbodiimide in 20 ml of anhydrous dichloromethane is added. The mixture is stirred at 0° C. for 30 minutes, then at room temperature for one hour. The reaction mixture is worked up as described in Example 1 to give the crude product as a dark-brown oil in a yield of 8.1 g (91%) which is purified by using column chromatography as described in Example 1. The named compound is obtained in a yield of 6.7 g, Rf =0.78 (dichloromethane); [α]D25 =+65° (c=2.0, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24](OC)([O:26]C)[CH3:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Cl>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][C:24](=[O:26])[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)OC
Agent: Cl
Solvent: CC#N
Product: CC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2,2-dimethoxypropoxy)methyl)piperidine-1-carboxylate, obtained as described above, 2 N HCl (100 mL) and CH3CN (100 mL) was vigorously stirred at rt for 22 h. After the reaction mixture was evaporated under reduced pressure, the crude 1-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)propan-2-one was directly used in the next step without further purification. MS ESI +ve m/z 284 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.C([O:24][CH:25]=[C:26]([C:32](OCC)=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])C.O>CN(C)C=O>[O:24]=[C:25]1[N:3]2[CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:21])[CH2:14][CH2:15][CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:10][C:11]=3[C:2]2=[N:1][CH:32]=[C:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Nc1ncnc2ccc(NC(=O)CCC3CCCC3)cc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c3cc(NC(=O)CCC4CCCC4)ccc3ncn2c1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of 4-amino-6-(3-cyclopentylpropionamido)quinazoline (4.4 g) and diethyl ethoxymethylenepropanedioate (5.5 g) in N,N-dimethylformamide (20 ml) was stirred at 100° C. for 3 hours. To the reaction mixture was added water. The resulting crystals were collected by filtration, washed with water, and suspended in dichloromethane under heating. After the suspension was cooled to ambient temperature, the resulting crystals were collected by filtration and washed with dichloromethane. There was obtained ethyl 4-oxo-10-(3-cyclopentylpropionamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (2.4 g). The filtrate was concentrated to 1/4 of its original volume and cooled to 0° C. to yield an additional 0.37 g of the same product. The cryde substance (2.77 g) obtained above was chromatographed on silica gel with 2% methanoldichloromethane. The product was recrystallized from a mixture of methanol and dichloromethane to give crystalline pure product (2.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9].C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:24])=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9]
Reactant: Nc1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc(Br)cc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2-Amino-phenyl)-(4-chloro-phenyl)-methanone (9.41 g, 0.04 mmol) dissolved in 150 mL DCM was added NBS (7.25 g, 0.04mol) at 0° C. The mixture is stirred at RT for overnight. The mixture is extracted with DCM, washed with NaHCO3, dried over NaSO4 and concentrated. This provides the desired compound. This is used without further purification.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH3:17])[C:10]1=[O:18].Br>ClCCl.C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH3:17])[C:10]2=[O:18])[CH:4]=[CH:5][CH:6]=1
Reactant: CCCN1CCCC(C2=C(Br)C(=O)CCC2)C1=O
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCN1CCCC(c2cccc(O)c2)C1=O
Yield: 87.2 %

Procedure:
The product of Example 8 (10.5 g, 33.4 mM) in dichloromethane (70 ml) was treated with 48% hydrogen bromide in acetic acid (ca 0.5 ml). After 16 h the solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and water. The organic phase was dried and evaporated and the residue was chromatographed on alumina (neutral, grade 3) using 4% methanol in chloroform as eluant. The appropriate fractions were avaporated and recrystallised from ether to yield the title compound (6.8 g) m.p. 61°-3° (Found: C, 71.9; H, 7.8; 5.6% C14H19NO2 requires C, 72.1; H, 8.2; 6.0%).
Reaction SMILES: OC[C:3]([CH2:8][OH:9])([CH2:6]O)CO.[C:10]([O:15][CH2:16][C:17]([CH2:27][OH:28])([CH2:25][OH:26])[CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])(=[O:14])[CH2:11][CH2:12][CH3:13].[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>N1C=CC=CC=1>[C:29]([O:26][CH2:25][C:17]([CH2:27][O:28][C:8](=[O:9])[CH2:3][CH3:6])([CH2:18][O:19][C:20](=[O:24])[CH2:21][CH2:22][CH3:23])[CH2:16][O:15][C:10](=[O:14])[CH2:11][CH2:12][CH3:13])(=[O:32])[CH2:30][CH3:31]
Reactant: CCCC(=O)OCC(CO)(CO)COC(=O)CCC
Reactant: OCC(CO)(CO)CO
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)OCC(COC(=O)CC)(COC(=O)CC)COC(=O)CCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In this example, pentaerythritol dibutyratedipropionate was prepared from pentaerythritol dibutyrate as follows. To a solution of pentaerythritol dibutyrate (0.5 g; 1.81 mmol) in dry pyridine (10 mL, under argon) at 0° C. was added propionyl chloride (0.6 mL) dropwise over one hour. The ice bath was removed after one hour, and the reaction stirred 24 hours at room temperature. Water (5 mL) was added and the bulk of pyridine was removed on the rotary evaporator at 2 Torr. The residue was dissolved in 1N HCL (5 mL) and the desired product extracted with CHCl3 (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated under vacuum. Purification of the crude product by flash column chromatography using silica gel afforded pentaerythritol dibutyrate dipropionate (0.6 g).
Reaction SMILES: [CH2:1]([C:3]1(O)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:14]([O:21][C:22](=[O:33])[NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:33])[NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[C:29]2[C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCC1(O)CCc2cc(F)ccc21
Reactant: O=C(Nc1cccc2cc[nH]c12)OCc1ccccc1
Product: CCC1(c2c[nH]c3c(NC(=O)OCc4ccccc4)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 1-ethyl-5-fluoro-indan-1-ol and (1H-indol-7-yl)-carbamic acid benzyl ester, the tide compound is prepared as in example 1. 7.78 g (100%). LC-MS m/z 249.1 (M++1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a stirred solution of (1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methanol (4.02 g, 20.0 mmol), methyl 4-hydroxybenzoate (3.04 g, 20.0 mmol) and Ph3P (6.28 g, 24.0 mmol) in THF (50 ml) was added DIAD (4.85 g, 24.0 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (5:1, v/v) as eluent to give methyl 4-(1-tert-butoxycarbonyl(2S)-pyrrolidinyl)methoxybenzoate (5.4 g, 81%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.47 (s, 9H), 1.88-2.04 (m, 4H), 3.41 (m, 2H), 3.91 (s, 3H), 3.90-3.92 (m, 1H), 4.11-4.16 (m, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.94 (d, J=8.3 Hz, 2H).