Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[C:15]([O:35][CH3:36])=[C:16]([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13])=O)C1C=CC=CC=1.Cl.O.[H][H].N>[Pt].C(O)C>[NH2:11][CH:12]([C:14]1[C:15]([O:35][CH3:36])=[C:16]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13]
Reactant: [H][H]
Reactant: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(C)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pt]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 101 %

Procedure:
Platinum on carbon (10 wt. % loading (dry basis), matrix activated carbon, 200 mg) was added to a solution of tert-butyl 4-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5-chloro-2-methoxy-6-methylphenyl]-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.388 mmol) in ethanol (30 mL)/0.25 M HCl in water (3.9 mL, 0.97 mmol) and then the reaction was stirred at room temperature under 30 psi of hydrogen atmosphere for 3 d. The mixture was adjusted to basic pH with ammonia and then the solvent was removed. The residue was diluted with methylene chloride, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to give the crude desired product (0.15 g) which was used in the next step without further purification. LCMS calculated for C20H32ClN2O3 (M+H)+: m/z=383.2. found: 383.3.
Reaction SMILES: N1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])C=CN=C1.[CH2:34]([OH:37])[CH2:35][OH:36]>>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[C:8]([C:6]([O:36][CH2:35][CH2:34][OH:37])=[O:7])=[C:13]([CH3:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)[C:11](=[O:25])[NH:10]2)=[CH:33][CH:32]=1)#[N:31]
Reactant: OCCO
Reactant: CC1=C(C(=O)n2ccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Product: CC1=C(C(=O)OCCO)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
45.1 mg (0.1 mmol) of the compound of Example 25 are added to 0.5 ml ethylene glycol. The reaction mixture is stirred at approx. 100° C. for 1 hour. After cooling the reaction mixture is purified by preparative HPLC (column: Agilent Zorbax Extend C18 20 mm×50 mm, 5 μm; solvent A: acetonitrile, solvent B: water+0.1% conc. ammonia; gradient: 0 min 10% A, 2 min 10% A, 6 min 90% A, 7 min 90% A, 7.1 min 10% A, 8 min 10% A; wavelength: 220 nm; injection volume: approx. 500 μl; number of injections: 1). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCCC1.[CH3:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22].C([O-])(=O)C.[Na+]>O>[Cl:1][C:2]1[N:11]=[C:10]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Cc1ccccc1CN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1CNc1nc(Cl)nc2ccccc12
Yield: 33.8 %

Procedure:
2,4-Dichloroquinazoline (3.0g 0.015 mol) was stirred in a mixture of water (60 ml), tetrahydrofuran (100 ml), o-methylbenzylamine (1.83 g, 0.015 mol) and sodium acetate (1.38 g, 0.017 mol) for a total of 16 hours. The reaction mixture was evaporated under reduced pressure and crystallised from ethanol to give 2-chloro-4-(2-methylbenzylamino)quinazoline (1.44 g, 30%), m.p. 215°-217°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[O:26][C:27]([CH2:30][CH3:31])=[N:28][N:29]=2)([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:30]([C:27]1[O:26][C:25]([C:11]2([N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:29][N:28]=1)[CH3:31]
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCNCC1
Reaction time: 24 h
Yield: 99.5 %

Procedure:
A mixture of 1-benzyl-4-(ethyl-1,3,4-oxadiazolyl)-4-(N-phenylpropionamido)piperidine (8.20 g, 19.6 mmol) and 10% palladium on charcol (2.0 g) in methanol (100 ml) was reacted with hydrogen (50 psi) in a Parr shaker. After 24 hours, the resulting mixture was filtered and the filtrate was concentrated in vacuo. A foamy residue (6.42 g, 19.5 mmol) was obtained. It was used for reactions without further purification. ##STR30##
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[CH2:11](O)[CH2:12][CH2:13][OH:14]>CS(O)(=O)=O.C1(C)C=CC=CC=1>[CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([O:7][CH2:11][CH2:12][CH2:13][OH:14])=[O:6])[CH2:2][CH3:3]
Reactant: OCCCO
Reactant: CCCC(CCC)C(=O)O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCC(CCC)C(=O)OCCCO
Yield: 86.6 %

Procedure:
2-propylpentanoic acid (10.0 g, 69.3 mmol) was mixed with propane-1-3-diol (42.1 g, 555.0 mmol) and methyl-sulfonic acid (5 drops) in toluene (200 ml) and the mixture was heated under reflux using a Dean Stark trap for 12 h. After that, toluene was removed under reduced pressure and the crude mixture was dissolved in dichloromethane (200 ml) and extracted with water (pH 5, 3×200 ml). The combined organic layers were dried over sodium sulfate and the volatiles were removed under reduced pressure giving a clear oil (14.0 g, 60.0 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:42][C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:42][C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33])=[O:24]
Reactant: ClCc1ccncc1
Reactant: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)c(Cl)c3)ccnc2cc1OCc1ccncc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)-oxy]phenyl}-N′-(2,4-difluorophenyl)urea (55 mg), potassium carbonate (62 mg), and 4-(chloromethyl)pyridine hydrochloride (22 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 80° C. for one hr. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 35 mg (yield 55%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:14][C:13](=O)[C:12]3[CH:16]=[CH:17][S:18][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[C:12]2[CH:16]=[CH:17][S:18][C:11]=2[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3sccc3c(=O)[nH]2)cc1
Product: COc1ccc(-c2cc3sccc3c(Cl)n2)cc1
Temperature: 120 °C
Yield: 73 %

Procedure:
6(4-methoxyphenyl)-5H-thieno[3,2-c]pyridin-4-one (9.1) g) was added to phosphorus oxychloride (90 g), and the mixture was heated at 120° C. for 3 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporate, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a white powder (6.6 g, yield; 73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15](=O)[NH:14][C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>C(N(CC)C1C=CC=CC=1)C>[Cl:26][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][S:10][C:11]=2[N:12]=[C:13]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1nc2scc(-c3ccc(F)cc3)c2c(=O)[nH]1
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)Cc1nc(Cl)c2c(-c3ccc(F)cc3)csc2n1
Reaction time: 8 h

Procedure:
Ethyl 2-[5-(4-fluorophenyl)-4-oxo-4-H-thieno[2,3-d]pyrimidin-2-yl]acetate (10 g, 0.0301 mol) in N,N-diethylaniline (50 mL) and phosphorous oxychloride (150 mL) was heated to 115° C. for 4.5 hrs. The mixture was concentrated in vacuo and the residue poured into ice-water and allowed to stand overnight. The aqueous solution was neutralized with sodium bicarbonate, filtered, then extracted with DCM. The reaction was repeated on a further 10 g of ethyl 2-[5-(4-fluorophenyl)-4-oxo-4-H-thieno[2,3-d]pyrimidin-2-yl]acetate and the DCM extract combined with that of the first batch. The solvent was removed in vacuo and the residue purified by silica column chromatography eluting first with petroleum ether/DCM 50:50 v/v, then petroleum ether/DCM 25:75 v/v, followed by DCM (100%). Further fractions were eluted from the column with 25% diethyl ether in DCM. Fractions were analysed by TLC, combined and concentrated to give ethyl 2-[4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]acetate as a brown solid (14 g). LCMS RT=4.83 min, M+1=351.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=[CH:3]1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19]O)=[NH:18])=[N:15][CH:16]=1.O>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:19]=[C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)[O:8][N:18]=2)=[N:15][CH:16]=1
Reactant: N=C(NO)c1ccc(Cl)cn1
Reactant: Cn1cncc1C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cn1cncc1-c1nc(-c2ccc(Cl)cn2)no1
Temperature: 25 °C
Yield: 4.6 %

Procedure:
A mixture of 3-methyl-3H-imidazole-4-carbonyl chloride (91 mg, 0.5 mmol), 5-chloro-N-hydroxy-pyridine-2-carboxamidine (85.8 mg, 0.5 mmol) in pyridine (5 ml) was refluxed for 4 h and then cooled to room temperature. To the solution was added water (20 ml) and the product precipitated from the solution. The solid was collected by filtration and washed with water, dried to give 6 mg (5%) of the title compound. 1H NMR (CDCl3): 8.78 (d, J=2.4 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.87 (dd, J=2.7 Hz, J=8.7 Hz, 1H), 7.70 (s, 1H), 4.14 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:17])[CH3:18])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from [4-chloro-5-(isopropyl-methyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C12) (4.07 g, 11.8 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pale brown solid (3.08 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:19]Cl>C(O)(=O)C>[Cl:1][C:2]1[C:3]([C:9]2[C:13]([Cl:19])=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2Cl)cc1C(F)(F)F
Reactant: ClCl
Solvent: CC(=O)O
Product: Cn1nc(-c2ncc(Cl)cc2Cl)c(Cl)c1C(F)(F)F
Yield: 90 %

Procedure:
2.0 g of 3-(3,5-dichloro-2-pyridyl)-5-trifluoromethyl-1-methyl-[1H]-pyrazole (Example H12) are initially introduced into glacial acetic acid at 40° C., and chlorine gas is passed slowly over the solution, while stirring. The reaction can be monitored analytically by means of thin layer chromatography (silica gel 60 F254, eluting agent: n-hexane/ethyl acetate 4/1, UV). When no further starting material can be detected, the glacial acetic acid is removed in vacuo and the residue is partitioned between dilute aqueous sodium hydroxide solution and ethyl acetate. After extraction by shaking, the organic phase which has been separated off is washed with brine, dried over sodium sulfate, filtered and concentrated. The yellow oil is purified by means of flash chromatography (silica gel, eluting agent: n-hexane/ethyl acetate 5/1). 1.6 g of the desired compound are obtained as a yellow oil (70% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]=[C:13]=[O:14]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:13]([NH:12][CH3:11])=[O:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: ClCCl
Product: CNC(=O)N[C@H](C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a stirred solution of (R)-(+)-1-(4-bromophenyl)ethylamine (0.5 g, 2.49 mmol) in anhydrous CH2Cl2 was added methyl isocyanate (0.15 mL, 2.49 mmol). The resulting solution was stirred at 25° C. overnight. CH2Cl2 was evaporate and residue partitioned between EtOAC and 1N HCl. The organic layer was washed with H2O, brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (80% EtOAc in hexanes) to provide the desired product (0.60 g, 94%) as a white solid. 1H NMR (CDCl3) δ: 1.42 (d, J=7.0 Hz, 3H), 2.72 (d, J=4.9 Hz, 3H), 4.25 (brs, 1H), 4.73 (brs, 1H), 4.74-4.81 (m, 1H), 7.20 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H). ESIMS (MNa+): 258.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1.[OH-].[K+]>CCO>[CH2:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:29])=[O:2])=[CH:12][CH:13]=2)=[CH:25][CH:24]=1)[CH3:28]
Reactant: CCNc1ccc(CCCc2ccc(Nc3ccccc3C(=O)OC)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCNc1ccc(CCCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Yield: 90 %

Procedure:
The title compound was prepared from 2-{4-[3-(4-ethylaminophenyl)-propyl]phenylamino}benzoic acid methyl ester (from Example 161), EtOH (10 mL), and 3 M-KOH solution (1.0 mL) using the procedure described in Example 162. This procedure yielded a yellow solid, 253 mg of the desired product (90% for 0.1 hydrate).
Reaction SMILES: Br.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]1=[O:17].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(Cl)Cl.O>[CH2:10]([O:9][N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][S:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[CH:34]=[CH:35][C:19]([Cl:18])=[CH:20][CH:21]=3)=[CH:25][CH:26]=2)(=[O:31])=[O:32])[C:4]1=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: N[C@@H]1CCCN(OCc2ccccc2)C1=O
Agent: Br
Solvent: O
Solvent: ClCCl
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCCN1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a suspension of (R)-3-amino-1-benzyloxy-piperidin-2-one hydrogen bromide salt (0.086 g, 0.29 mmol) (synthesized according to Miller's procedure J. Org. Chem. 2002, 67, 4759) and 4-(4-chloro-phenoxy)-benzenesulfonyl chloride (0.095 g, 0.31 mmol) in dry CH2Cl2 (3 mL) was treated with TEA (0.12 mL, 0.86 mmol) under N2. The reaction mixture was stirred at room temperature for 6 h and diluted with CH2Cl2 and water. After the usual work-up, the crude material was purified by chromatography (silica gel, 35% EtOAc/hexanes) to give the desired product, (R)—N-(1-Benzyloxy-2-oxo-piperidin-3-yl)-4-(4-chloro-phenoxy)-benzene-sulfonamide. MS (EI) 487 (M+H)+.
Reaction SMILES: [Na].[SH:2][C:3]1[S:4][CH2:5][CH2:6][N:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([NH:18][C:19](=[O:21])[CH:20]=1)=[O:17].Cl>O1CCCC1>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH:20]([S:2][C:3]2[S:4][CH2:5][CH2:6][N:7]=2)[C:19](=[O:21])[NH:18][C:16]1=[O:17]
Reactant: O=C1C=C(c2ccccc2Cl)C(=O)N1
Reactant: SC1=NCCS1
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccccc2Cl)C1SC1=NCCS1
Yield: 29.6 %

Procedure:
A solution of mercaptothiazoline sodium (4.50 g) in tetrahydrofuran (30 ml) is added to a refluxed solution of 2-(2-chlorophenyl)maleimide (3.00 g) in tetrahydrofuran (40 ml) and the mixture is refluxed for 10 minutes. After cooling, the reaction mixture is diluted using diluted hydrochloric acid and the solvent is distilled off. The residue is extracted with ethyl acetate and the extract is washed with water and dried over magnesium sulfate. The ethyl acetate is distilled off and the residue is subjected to silica gel chromatography, elution being carried out with dichloromethanemethanol (50:1). The eluate is recrystallized from ethanol to give 2-(2-chlorophenyl)-3-(2-thiazolin-2-ylthio)succinimide (1.40 g), m.p. 195°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1B(O)O>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[C:13]([CH3:15])([CH2:14][C:25]3[CH:24]=[CH:23][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[CH2:12][O:11][C:6]=2[CH:5]=1)=[O:16]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC2(C)Cc1ccc2ccccc2c1
Yield: 22 %

Procedure:
A solution of 4-Iodo-3-(2-methyl-allyloxy)-benzoic acid methyl ester (455 mg, 1.37 mmol) in DMF (15 mL) were added Potassium carbonate (379 mg, 2.74 mmol), Tetrabutylammonium chloride (380 mg, 1.37 mmol), Palladium acetate (25.6 mg, 0.136 mmol) in DMF (5 mL) and 2-Naphthylboronic acid, (282 mg, 1.64 mmol) was submitted to microwave irradiation at 150° C. for 16 minutes. The resulting mixture was filtered over silica, washed with water, dried over MgSO4 and concentrated. Column chromatography (silica gel, heptane/CH2Cl2: 4/6) afforded 100 mg (22%) of the title compound as a slightly brown oil which crystallized.
Reaction SMILES: C([C:5]1[C:13]([CH2:14][N:15]([C:17](=[O:24])[CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16])=[C:12]([NH2:25])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:25][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][N:15]([C:17](=[O:24])[CH:18]([OH:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:16]
Reactant: CC(C)CC(O)C(=O)N(C)Cc1c(N)ccc(C(=O)O)c1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(O)C(=O)N(C)Cc1cc(C(=O)O)ccc1N
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-hydroxy-4,N-dimethylpentanoylamino)methyl]benzoic acid (3.50 g, 10.0 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were evaporated, washed with hexanes and dried under high vacuum overnight affording the title compound as an orange oil (4.42 g, 10.8 mmol). This product was used without further purification: MS (ES) m/de 295 (M+H-TFA)+.
Reaction SMILES: [CH2:1]([N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+:25].[Na+]>O.C(=O)([O-])[O-].[Zr+].[NH4+]>[CH2:2]([N:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6])[CH2:1][N:12]([CH2:17][C:18]([O-:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].[Na+:25].[Na+:25]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Zr+]
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Ammonium zirconium carbonate (AZC) having the formula (NH4)2 [Zr(OH)2 (CO3)2 ] was dissolved in water in an amount sufficient to produce a 0.2 molar solution. With the solution at between about 50°-80° C., disodium salt of EDTA was added to the solution in an amount sufficient to produce a one to one molar ratio between disodium salt of EDTA and the AZC. Disodium salt of EDTA was prepared by reacting reagent grade EDTA obtained from Baker Chemical Co. with sodium carbonate. The resulting chelated solution was strongly alkaline. The chelated solution was then heated to a temperature of about 100° C. and maintained at that temperature for approximately 2 days to produce a solid residue in the form of white flakes or powder. Upon testing, the white flakes were found to be readily soluble in water. The flakes were then calcined at 600° C. for 6 hours to produce metal oxide particles having Na2CO3 as an impurity mixed therewith. The Na2CO3 was then removed by washing with distilled water to obtain ZrO containing an impurity of about 0.3 mole % Na2O. The resultant metal oxide powder was comprised of metal oxide particles having a mean diameter of approximately 250 angstroms and a uniform size distribution. The particles were generally spherical and substantially unagglomerated as shown by the SEM in FIG. 1.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C@H:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][NH:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[C:20]([Cl:28])[CH:19]=2)[N:15]=[CH:14][N:13]=1)(C)(C)C>C(Cl)Cl>[ClH:28].[Cl:28][C:20]1[CH:19]=[C:18]([C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][CH2:10][C@@H:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[NH2:8])[CH:17]=2)[CH:23]=[CH:22][C:21]=1[C:24]([F:26])([F:25])[F:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)ncn1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: N[C@@H](CNc1cc(-c2ccc(C(F)(F)F)c(Cl)c2)ncn1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 156.8 %

Procedure:
A HCl solution (2 M in Et20, 1.01 mL) was added to tert-butyl[(1R)-2-({6-[3-chloro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)-1-phenylethyl]carbamate (200 mg, 0.41 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at rt overnight. The precipitate was filtered and washed with Et2O to yield the title compound (138 mg, 79%). MS (ESI): mass calcd. for C19H16ClF3N4, 392.10; m/z found, 393.1 [M+H]+. 1H NMR (CD3OD): 8.85 (s, 1H), 8.13 (s, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.56-7.44 (m, 5H), 7.15 (s, 1H), 4.74-4.70 (m, 1H), 4.26 (dd, J=14.1, 7.1 Hz, 1H), 4.14 (dd, J=14.4, 7.1 Hz, 1H).