Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([NH:14][C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[CH:19][N:18]=[C:17]([N:28]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH3:29])[N:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].CCN(CC)CC.[CH3:44][N:45]([CH3:49])[C:46](Cl)=[O:47]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C@@H:6]([NH:14][C:15]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[CH:19][N:18]=[C:17]([N:28]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH3:29])[N:16]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:46]([N:45]([CH3:49])[CH3:44])=[O:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(OC(=O)N(C)C)cc1

Procedure:
A solution of (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)-pyrimidin-4-ylamino)-3-(4-hydroxyphenyl)propanoic acid ethyl ester (1.0 eq), DMAP (1.0 eq), Et3N (1.2 eq) and dimethylcarbamyl chloride (1.2 eq) in CH2Cl2 was stirred at 22° C. for 8 hr. The mixture was diluted with EtOAc, and the resulting solution was washed successively with water, 0.5 M citric acid, sat. NaHCO3 and sat. NaCl. The CH2Cl2/EtOAc extracts were treated with MgSO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel using 6:4 hexanes/EtOAc to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(dimethylaminocarbonyl)oxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[SH:20]>CN(C)C=O>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8]
Reactant: Sc1cccs1
Reactant: O=Cc1sccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1sccc1Sc1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
A mixture of 3-chlorothiophene-2-carbaldehyde (1.0 g), potassium carbonate (2.8 g) and N,N-dimethylformamide (6.8 mL) was treated dropwise with thiophene-2-thiol (0.87 g), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was poured onto water (150 mL) and extracted with diethyl ether. The combined organic extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford the title compound as a red oil (1.5 g).
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([C:23](=O)[CH2:24][C:25]#[N:26])=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:15])=[O:7]>CCO>[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([C:23]2[NH:2][N:3]=[C:25]([NH2:26])[CH:24]=2)=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:15])=[O:7]
Reactant: COC(=O)c1sc(C(=O)CC#N)cc1OC(C)c1ccccc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: COC(=O)c1sc(-c2cc(N)n[nH]2)cc1OC(C)c1ccccc1Cl
Temperature: 80 °C
Yield: 28.1 %

Procedure:
Hydrazine hydrate (17.4 mg, 0.35 mmol, 1.1 Eq.) was added to a stirred solution of 3-[1-(2-Chlorophenyl)-ethoxy]-5-cyanoacetyl-thiophene-2-carboxylic acid methyl ester (115 mg, 0.32 mmol, 1.0 Eq.) in EtOH (4 mL) and the reaction heated at 80° C. overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (70/9/1 DCM/MeOH/Aq. NH3) to give the sub-title compound as a white solid (35 mg, 0.09 mmol, 29%);
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([C@@H:56]2[N:60]3[CH2:61][CH2:62][NH:63][CH2:64][C@@H:59]3[CH2:58][CH2:57]2)=[C:52]([CH3:65])[C:51]=1[CH3:66]>CC(N(C)C)=O.C1(C)C=CC=CC=1>[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([C@@H:56]2[N:60]3[CH2:61][CH2:62][N:63]([C:7]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)=[O:9])[CH2:64][C@@H:59]3[CH2:58][CH2:57]2)=[C:52]([CH3:65])[C:51]=1[CH3:66]
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Reactant: COc1ccc([C@H]2CC[C@H]3CNCCN32)c(C)c1C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2CC[C@H]3CN(C(=O)c4ccc(C(F)(F)F)nc4)CCN32)c(C)c1C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
6-Trifluoromethyl nicotinic acid (18.1 mg, 0.12 mmol), BOP (66.3 mg, 0.15 mmol), and Et3N (34.8 μL, 0.25 mmol) are added to a solution of (6R,8aS)-6-(4-methoxy-2,3-dimethylphenyl)-octahydro-pyrrolo[1,2-a]pyrazine (52.2 mg, 0.2 mmol) in anhydrous DMA (0.1 mL). The reaction mixture is stirred at 50° C. for 16 h, diluted with toluene, evaporated to dryness and the residue purified by filtration through an SCX cartridge, eluting with EtOAc-MeOH-NEt3 (10-1-1) to produce an oil (LC/MS: 434).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=O)(C)(C)C.[I-].[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:30])=[CH:25][N:26]=[N:27]2)=[CH:22][CH:21]=1>C1COCC1>[Cl:30][C:24]1[C:23]2[C:28](=[CH:29][C:20]([CH2:19][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3=[O:14])=[CH:21][CH:22]=2)[N:27]=[N:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: Clc1cnnc2cc(CBr)ccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CNCCN1Cc1ccc2c(Cl)cnnc2c1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
4-(t-Butyloxycarbonyl)-piperazin-2-one (0.6 g, 3.0 mmol), EXAMPLE 40, is dissolved in THF (80 mL), cooled in an ice bath and treated with tretrabutylammonium iodide (0.23 g, 0.62 mmol) and 60% sodium hydride (0.12 g, 3.0 mmol). The reaction mixture is stirred at ° C. for 40 minutes then treated dropwise with a solution of 7-bromomethyl-4-chlorocinnoline (10.7 g, 2.7 mmol), Example 15, in THF (20 mL). The resulting solution is warmed to ambient temperature over 2 hours. The solution is evaporated to dryness and the residue is taken up in ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, dried (sodium sulfate) and concentrated. The residue is chromatographed (ethyl acetate) to yield the title compound (0.6 g, 1.6 mmol). A portion of this material (0.21 g, 1.26 mmol) is dissolved in THF (˜4 mL) and treated with a saturated solution of HCl in ethyl acetate (50 mL) at room temperature for 2 hours. The solution is filtered and concentrated to a residue (0.14 g, 0.4 mmol). MS m/z: M+=275; 1H NMR (CD3OD, 300 MHz) δ9.15 (d, 1H), 8.5 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 5.0 (s, 2H), 4.1 (s, 2H), 3.7-3.8 (m, 2H), 3.6-3.7 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CC1(C)N([O])C(C)(C)CCC1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:1]
Reactant: CCOC(=O)CCCCCO
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: CCOC(=O)CCCCC=O
Reaction time: 2 h

Procedure:
To a flask containing ethyl 6-hydroxyhexanoate (4.07 mL, 25.0 mmol) in CH2Cl2 (25 mL) was added TEMPO (391 mg, 2.50 mmol) followed by iodobenzene diacetate (8.86 g, 27.5 mmol). The reaction was stirred 2 hours and then diluted with CH2Cl2 (100 mL). Saturated aqueous solution of Na2S2O3 (100 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organics were washed with saturated aqueous NaHCO3 (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (20-40% Et2O/pentanes) to provide the title compound, which was identical to the reported literature compound. (See: Taber, D. F.; Teng, D. (2002) J. Org. Chem., 67: 1607.)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:18])=[O:17])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:11]([O:35][CH3:36])[N:10]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C([Cl:44])C1C=CC=CC=1>CO.[Pd]>[ClH:44].[NH2:2][CH2:1][C:3]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:18])=[O:17])[C:12]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[C:11]([O:35][CH3:36])[N:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C#N)c2)nc1OC
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(CN)c2)nc1OC
Product: Cl

Procedure:
A solution of 100 mg of 5-methyl-pyridine-2-sulfonic acid [2-(2-cyano-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide, product of example 19, dissolved in MeOH (5 ml), was treated with 47.5 mg of benzyl chloride, 10 mg of palladium on charcoal (10%) and then hydrogenated at RT for hours until TLC analysis indicated completion of transformation. The catalyst was filtered off, and the solution concentrated in vacuo. The crystalline solid that precipitated was collected by filtration, washed with ether and dried in a high vacuum to give 5-methyl-pyridine-2-sulfonic acid [2-(2-aminomethyl-pyridin-4-yl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide hydrochloride as light yellow crystals. ISP mass spectrum, m/e 509.3 (M+1 calculated for C24H24N6O5S: 509).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:18]([O-])(=[O:20])=[O:19])=[CH:13]3)=[C:4]([O:22][CH3:23])[CH:3]=1.[Na+].S(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:18]([Cl:27])(=[O:20])=[O:19])=[CH:13]3)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)[O-])ccc12
Reactant: O=S(Cl)Cl
Agent: [Na+]
Product: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Cl)ccc12
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A round bottom flask was charged with sodium 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonate (0.137 g, 0.369 mmol) and a septum was attached and the flask flushed with N2. DMF (1.232 mL) was added followed by thionyl chloride (0.081 mL, 1.108 mmol) by syringe at rt, an exotherm was observed. The solution was maintained at rt for 1 h, and then poured into a separatory funnel containing ice. The resulting mixture was extracted with DCM (2×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (1×10 mL) and dried over Na2SO4 and concentrated to give 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonyl chloride (0.121 g, 0.329 mmol), which was used immediately without further purification.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C@H:5]([OH:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1.S(O)(O)(=O)=O.[NH2:24][CH2:25][CH3:26].C1(C)C=CC=CC=1>O.CO>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]2[O:18][CH2:26][CH2:25][NH:24][CH2:4]2)=[CH:8][C:9]=1[C:14]([F:17])([F:16])[F:15]
Reactant: O[C@@H](CCl)Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CCN
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C[C@@H]2CNCCO2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Powdered sodium hydroxide (3.36 g, 84 mmol) was dissolved in water (5.6 mL) and cooled to room temperature. Intermediate (d) (R)-1-chloro-3-(4-fluoro-3-trifluoromethylphenyl)-2-propanol (assumed 13 mmol) was added as a solution in methanol (13.3 mL in total) and the mixture stirred for 5 minutes at room temperature. 2-aminoethane hydrogen sulfate (7.90 g, 56 mmol) was added in one portion and the resultant mixture warmed to 40° C. (bath temperature) for 2 hrs. Toluene (35 mL) and sodium hydroxide (powdered 3.36 g, 84 mmol) were added and the reaction heated at 65° C. (bath temperature) for 18 hrs, with vigorous stirring. The reaction was allowed to cool to room temperature and poured into water (80 mL), layers separated and the aqueous layer extracted with ethyl acetate (40 mL×2). Combined organic layers were washed with brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica; triethylamine/ethanol ethanol/ethyl acetate, 1/20/79 ratio) yielded the desired intermediate (c), (R)-2-(4-fluoro-3-trifluoromethylbenzyl)morpholine, as yellow oil (2.34 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[N:19]([CH3:18])[CH:23]=[CH:22][N:21]=3)=[CH:29][CH:28]=2)(=[O:31])=[O:32])[C:4]1=[O:17])#[N:13]
Reactant: Cn1ccnc1-c1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: Cn1ccnc1-c1ccc(S(=O)(=O)N[C@H]2CCN(Cc3cccc(C#N)c3)C2=O)cc1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B using (1-methyl-1H-imidazol-2-yl)benzene-4-sulfonyl chloride in place of 6-methoxynaphthalene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white foam.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([F:19])[C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])C.[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([F:19])[C:11]=1[F:18])[N:8]([CH3:20])[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]2=[O:16]
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)cc2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reaction time: 10 h
Yield: 77.3 %

Procedure:
A mixture of 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (0.3 g), anhydrous potassium carbonate (0.8 g), methyl iodide (1.6 g), and N,N-dimethyl-formamide (DMF) (10 ml) was heated with stirring at 90°-100° C. for 10 hours. The mixture was evaporated to dryness. The residue was treated with water, extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was added to a mixture of 18% hydrochloric acid (5 ml) and ethanol (2.5 ml) and the mixture was refluxed for 2.5 hours. After water (5 ml) and ethanol (5 ml) added and cooled, the resulting precipitate was filtered off and recrystallized from a mixture of DMF and ethanol to give 6,7,8-trifluoro-1,4-dihydro-1-methyl-4-oxoquinoline-3-carboxylic acid (0.22 g), mp 255°-258° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.C([C@@:35]1([C:44]([OH:46])=[O:45])[CH2:39][CH2:38][CH2:37][N:36]1[C:40](=[O:43])[CH2:41]Br)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:41][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:44]([OH:46])=[O:45])=[O:43])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:15])[CH3:14]
Reactant: O=C(CBr)N1CCC[C@@]1(Cc1ccccc1)C(=O)O
Reactant: CCOP([O-])CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.24 g, 0.0011 mole) in chloroform (10 ml) was added triethylamine (0.34 ml, 0.002 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (0.29 ml, 0.0023 mole) was added to the above solution dropwise, followed by benzyl bromoacetyl-L-proline (0.25 g, 0.0011 mole). The ice bath was removed and the mixture stirred at room temperature for 4 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil was vacuum dried to get 0.23 g (57%) of title compound, TLC: silica gel, CH2Cl2 :MeOH:HOAc shows one main spot at Rf =0.23.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:20]([F:23])([F:22])[F:21])=[C:15]([CH:19]=1)[C:16]([OH:18])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:20]([F:23])([F:22])[F:21])=[C:15]([CH:19]=1)[C:16]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:18]
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 5-fluoro-2-trifluoromethyl-benzoic acid (53.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 50% EtOAc in hexane as eluent) to afford 58 mg (43.8% yield) of biphenyl-4-carboxylicacid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 98.5%, 1H NMR: (DMSO) δ 8.7 (s, 1H), 8.0-7.9 (d, 3H), 7.84-7.7 (q, 4H), 7.6-7.4 (m, 5H), 4.2 (d, 2H), 3.8-3.4 (m, 6H), 3.24-3.06 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:7][CH2:6][CH2:5]2.C=O.[C:19](O)(=O)C.C([BH3-])#N.[Na+]>CO.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:16][CH2:15][N:14]([CH3:19])[CH2:13]1)[CH2:7][CH2:6][CH2:5]2
Reactant: CC(=O)O
Reactant: Brc1ccc2c(c1)CCCN2C1CCNC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N2CCCc3cc(Br)ccc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-bromo-1-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline (200 mg, 0.71 mmol) in 7 mL anhydrous methanol was treated with formaldehyde (37% aqueous solution, 79 μL, 1.07 mmol) followed by acetic acid (100 μL, 1.78 mmol). The solution was treated with sodium cyanoborohydride (67 mg, 1.07 mmol). The suspension was stirred at room temperature for 3 hours. The mixture was concentrated to dryness and partitioned between 20 mL 1N NaOH and 100 mL of CH2Cl2. After extraction, the organic layer was dried over Na2SO4, filtered and concentrated to give an oily residue which was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2. A yellow oil was obtained (153 mg, 72.9%). 1H-NMR (CDCl3) δ 7.10 (dd, J=2.4, 8.7 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.57 (d, J=9.0 Hz, 1H), 4.47-4.38 (m, 1H), 3.26 (t, J=5.7 Hz, 2H), 2.81-2.68 (m, 4H), 2.60-2.55 (m, 1H), 2.40-2.24 (m, 1H), 2.35 (s, 3H), 2.24-2.13 (m, 1H), 1.92-1.79 (m, 3H). MS(ESI): 295.1 and 297.1 (M+1).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([CH2:25][CH3:26])[S:22][C:12]=3[N:13]=2)[CH:17]=1
Reactant: NCc1ccccc1
Reactant: CCc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-3-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([CH:37]([CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:38]([OH:40])=O)[CH:32]=[CH:33][C:34]=1[S:35][CH3:36].C(N(CC)C(C)C)(C)C.[NH2:56][C:57]1[S:58][CH:59]=[CH:60][N:61]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:37]([CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)[C:38]([NH:56][C:57]2[S:58][CH:59]=[CH:60][N:61]=2)=[O:40])[CH:32]=[CH:33][C:34]=1[S:35][CH3:36]
Reactant: Nc1nccs1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 71.8 %

Procedure:
A solution of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.62 g, 1.41 mmol) and 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid (0.29 g, 0.95 mmol) in methylene chloride (10 mL) was treated with N,N-diisopropylethylamine (500 μL, 2.87 mmol) and 2-aminothiazole (140 mg, 1.27 mmol). The mixture was stirred under nitrogen at 25° C. for 14 h. The reaction mixture was then washed with a 6N aqueous hydrochloric acid solution (1×15 mL) and washed with a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (0.26 g, 71%) as a white solid: EI-HRMS m/e calcd for C18H21ClN2OS2 (M+) 380.0783, found 380.0792.
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[CH2:17][O:16][CH2:15][C@@H:14]3[CH:18]=[CH:19][CH2:20][C:21](=[O:22])[N:13]23)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]>[H][H].[Pt]=O>[F:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[CH2:17][O:16][CH2:15][C@@H:14]3[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[N:13]23)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: [H][H]
Reactant: O=C1CC=C[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2COC[C@@H](c3cc(F)c(F)c(F)c3)N12
Yield: 100.1 %

Procedure:
Platinum oxide (20.1 mg) was added to a methanol solution (6 mL) of (4R,9aS)-4-(3,4,5-trifluorophenyl)-3,4,7,9a-tetrahydro-1H-pyrido[2,1-c][1,4]oxazin-6-one (250 mg). The resulting reaction solution was stirred at room temperature for 2 hr in hydrogen atmosphere and then filtered through Celite. The filtrate was concentrated under reduced pressure to give 252 mg of the title compound. The physical property values of this compound were as follows: