Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=C2N=NN(O)C2=CC=1.O.C(Cl)Cl.[F:64][C:65]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:66]O>>[F:64][C:65]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:66][O:34][C:33](=[O:35])[C@H:32]([OH:36])[CH2:31][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[F:37])=[CH:9][CH:10]=1)[NH:16][C:17]([C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH:20]=1)=[O:18]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)OCC(F)(F)C(F)(F)F)c1cc(-c2ccccc2F)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (30.0 mg, 57 μmol), EDC HCl (65.4 mg, 341 μmol), and HOBt hydrate (52.2 mg, 341 μmol) in DCM (0.5 mL, 8 mmol) was stirred at room temperature for 10 minutes. 2,2,3,3,3-Pentafluoro-1-propanol (45.3 μL, 455 μmol) was added and the resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2 mL), filtered, and purified by reverse phase prep HPLC to yield the title compound (4.8 mg, purity 90.2%) as a TFA salt. MS m/z [M+H]+ calc'd for C29H21ClF7N3O5, 660.11. found 660.3.
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(C)=C)(=[O:30])[CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:28](=[O:30])[CH3:29])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=C(C)OC(C)=O
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CC[C@H]2[C@H]3CCc4cc(OC(C)=O)cc(OC(C)=O)c4[C@H]3CC[C@]12C
Temperature: 125 °C

Procedure:
A mixture of 5 g. of rac.-1,3-diacetoxy-8α-estra-1,3,5(10)-trien-17-one, 100 ml. of isopropenyl acetate, and 14.4 g. of p-toluenesulfonic acid is heated for 21 hours under a slight N2 stream to 105° C. After the mixture has been heated to 125° C., 50 ml. of isopropenyl acetate are gradually distilled off. After cooling, 10 ml. of pyridine is added, the mixture is diluted with methylene chloride, washed with saturated sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent is evaporated under vacuum. After chromatography on 260 g. of SiO2, 3 g. of oily rac.-1,3,17-triacetoxy-8α-estra-1,3,5(10),16-tetraene is obtained, which is further processed as the crude product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[NH:10])OC)[CH:2]=1.Cl.C([O:14][C:15](=O)[C@H:16]([CH3:18])[NH2:17])C.C(N(CC)CC)C>O1CCCC1>[CH3:18][CH:16]1[C:15](=[O:14])[NH:10][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:17]1
Reactant: COC(=N)c1cccnc1
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1N=C(c2cccnc2)NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A stirred mixture of methyl pyridine-3-carboximidate (10.6 g), alanine ethyl ester monohydrochloride (10 g), triethylamine (8.4 ml) and tetrahydrofuran (250 ml) was heated under reflux under nitrogen for 5 hours then allowed to cool to ambient temperature. The resulting solid was collected by filtration and washed with tetrahydrofuran. The filtrate and washings were combined and the solvent removed in vacuo. The residue was triturated with a 1:1 mixture of ether and ethyl acetate, and the resulting solid was collected by filtration and washed with ether. The two crops of solid were combined, suspended in water (130 ml), and the mixture was stirred at ambient temperature for 1 hour. The resulting solid was collected by filtration and dried in vacuo to give 4-methyl-2-(3-pyridyl)-2-imidazolin-5-one as a yellow solid (4.9 g), m.p. 238-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[S:23]([CH3:26])(=[O:25])=[O:24])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:4][CH:3]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:48][N:49]1[CH2:54][CH2:53][CH:52]([CH2:55][N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:51][CH2:50]1>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[S:23]([CH3:26])(=[O:25])=[O:24])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([N:59]2[CH2:58][CH2:57][N:56]([CH2:55][CH:52]3[CH2:53][CH2:54][N:49]([CH3:48])[CH2:50][CH2:51]3)[CH2:61][CH2:60]2)=[O:17])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(CN2CCN(C(=O)CCc3oc(-n4ccnc4S(C)(=O)=O)nc3-c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A mixture of 3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propionic acid (50 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (41 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (46 mg), 4-[(1-methyl-4-piperidinyl)methyl]piperazine (60 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, introduced into preparative HPLC and purified. Ethyl acetate was added to the obtained oil and the mixture was washed with saturated aqueous sodium hydrogen carbonate. A 4N hydrochloric acid ethyl acetate solution was added to the ethyl acetate layer and the mixture was concentrated to give 1-(3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propanoyl)-4-[(1-methyl-4-piperidinyl)methyl]piperazine 3 hydrochloric acid (65.0 mg, yield 66%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1F)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH2:25])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:23]([NH:25][C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[C:2]([F:14])([F:13])[F:1])[CH3:24])[CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Yield: 0 %

Procedure:
2,2,2-Trifluoro-1-(2,4-difluorophenyl)ethanone (0.66 g, 3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (0.59 g, 3.13 mmol) and N,N-diisopropylethylamine (0.81 g, 6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (0.11 mg, 9% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14].[H][H]>CO>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1cccc([N+](=O)[O-])c1C
Solvent: CO
Product: COC(=O)CCc1cccc(N)c1C

Procedure:
48.7 g (220.1 mmol) of methyl (2E)-3-(2-methyl-3-nitrophenyl)acrylate were dissolved in 2.2 liters of methanol, and the solution was hydrogenated in a continuous-flow hydrogenation reactor (“H-Cube midi” from Thales Nano, Budapest) at a flow rate of 6-10 ml/min and at a reaction temperature of 35-40° C. and at maximum hydrogen pressure. After the reaction had ended, the product-containing solution was concentrated under reduced pressure. This gave 40.0 g of the target product as a solid (92.1% of theory).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].S1(CCCC1)(=O)=O>COCCOC>[N+:19]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:20])=[O:18]
Reactant: O=[N+]=O
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: O=S1(=O)CCCC1
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Temperature: -50 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-(trifluoromethoxy)phenol (4 g, 0.0225 mol) in ethylene glycol dimethyl ether (90 mL) was added a 0.5 M solution of nitronium tetrafluoroborate in sulfolane (46 mL, 0.0229 mol) at −50° C. The mixture was stirred at −50° C. under an atmosphere of nitrogen for 6 hours. The mixture was filtered through silica gel pad, and the pad was washed with 25% ethyl acetate/n-heptane. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica using 0%-50% ethyl acetate/n-heptane as a mobile phase to give 2-nitro-4-(trifluoromethoxy)phenol (2.5 g, 0.011 mol). TLC (ethyl acetate/n-heptane=25:75) Rf 0.50 MS: MH−: 222.
Reaction SMILES: N1(CCOC2C=CC(NC3C4N(C=CN=4)C(C4C=NNC=4)=CN=3)=CC=2)CCOCC1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=2)[CH2:34][CH2:33]1>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=2)[CH2:34][CH2:33]1
Reactant: CN1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Agent: c1cn2c(-c3cn[nH]c3)cnc(Nc3ccc(OCCN4CCOCC4)cc3)c2n1
Solvent: CCO
Product: CN1CCC(COc2ccc(N)cc2)CC1

Procedure:
In the same way as described for Compound 150, step 1, using 1-methyl-4-(4-nitro-phenoxymethyl)-piperidine (0.65 g, 2.6 mmol) in ethanol (40 mL) and palladium hydroxide (0.182 g, 0.26 mmol). Filtration over Celite 521 and evaporation gave a red oil that was purified by silica gel column chromatography eluting with DCM and a 80:20 mixture DCM:MeOH. The title compound was obtained as a white solid (0.402 g, 70%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.30-1.51 (2H, m), 1.65-1.88 (3H, m), 1.89-2.09 (2H, t), 2.29 (3H, s), 2.90 (2H, d,), 3.45 (2H, br s), 3.73 (2H, d), 6.67 (2H, d), 6.75 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH3:28])=[N:13][C:14]=1[CH2:15][CH3:16].Cl[C:32]1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.ICC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:29][CH3:30])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:32])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Solvent: CCI
Product: CCO[C@H]1Cc2ccccc2[C@@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting (1S,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and iodoethane and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.81, 1.17-1.21, 1.30-1.34, 1.51-1.59, 1.98, 3.90-3.96, 4.02-4.08, 6.71-6.73, 7.04-7.07, 7.19; MS (ESI+) for C25H27Cl2N3O m/z 457 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:36]([F:39])([F:38])[F:37])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[NH:27][CH2:26]4)=[O:24])=[C:19]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C)C=O.[F:45][C:46]([F:51])([F:50])[CH2:47][CH2:48]I.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:36]([F:37])([F:38])[F:39])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][C:28](=[O:30])[N:27]([CH2:48][CH2:47][C:46]([F:51])([F:50])[F:45])[CH2:26]4)=[O:24])=[C:19]([CH2:31][C:32]([F:33])([F:35])[F:34])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)CCI
Reactant: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)CN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2CC(F)(F)F)CN1CCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 25-mL round-bottom flask, was placed 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)phenyl)carbonyl]imidazolidin-4-one (150 mg, 0.26 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), 1,1,1-trifluoro-3-iodopropane (114 mg, 0.51 mmol, 2.01 equiv), Cs2CO3 (166 mg, 0.51 mmol, 1.98 equiv). The resulting solution was stirred overnight at 50° C. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLCplate with ethyl acetate/petroleum ether (1:1). This resulted in 22.3 mg (12%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)phenyl)carbonyl]-3-(3,3,3-trifluoropropyl)imidazolidin-4-one as a light yellow solid. (ES, m/z): [M+CH3CN]− 726.0; 1H NMR (300 MHz, CDCl3): δ7.86-7.98 (m, 5H), 7.63 (d, J=8.1 Hz, 1H), 5.14 (s, 1H), 4.78 (s, 1H), 4.15-4.42 (m, 3H), 3.57-3.92 (m, 5H), 2.40-2.66 (m, 2H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1)[CH3:7]>C(#N)C>[CH3:7][N:6]([CH2:8][C:9]1[O:13][C:12]([CH2:14][S:15][CH2:16][CH2:17][NH:18][C:3]([NH:2][CH3:1])=[O:4])=[CH:11][CH:10]=1)[CH3:5]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CN=C=O
Solvent: CC#N
Product: CNC(=O)NCCSCc1ccc(CN(C)C)o1

Procedure:
Methylisocyanate (0.33 g) was added to a suspension of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine, phthalhydrazine complex (2 g) in acetonitrile (50 ml). After 2 hr the solution was filtered and the filtrate evaporated to give an oil which was purified by column chromatography (silica/methanol) to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-methylurea. Analysis Found: C, 52.38; H, 7.61; N, 15.25. C12H21N3O2S.1/4H2O requires: C, 52.24; H, 7.76; N, 15.32%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxopropionate (34.7 g, 115.5 mmol) in acetonitrile (300 ml) were added 4-trifluoromethylbenzyl bromide (27.6 g, 115.5 mmol) and potassium carbonate (31.9 g, 231 mmol), and the mixture was stirred at room temperature for 4 hrs. The reaction solution was diluted with water (1 L) and extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Hexane was added to the residue and the precipitated crystals were washed with hexane to give ethyl 3-(4-fluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (31 g, 76%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.1 %

Procedure:
Into a 1 L, 2-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 g, 38.31 mmol, 1.00 equiv), tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (15.4 g, 76.52 mmol, 2.00 equiv), PPh3 (20.1 g, 76.63 mmol, 2.00 equiv), and N,N-dimethylformamide (400 mL). DIAD (15.5 g, 76.65 mmol, 2.00 equiv) was added dropwise over 30 min. The resulting solution was stirred for 12 h at 25° C. and then diluted with 1 L of water. The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum and the residue was placed on a silica gel column and eluted with chloroform/methanol (100/1) to give 1.2 g (6%) of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a off-white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1csc(NC2CCCCC2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1csc(NC2CCCCC2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 10 g of 2-cyclohexylaminothiazol-4-ylmethanol, 22.4 g of sulfur trioxide pyridine complex, 14.3 g of triethylamine and 100 ml of dimethyl sulfoxide, giving the title compound as a pale brown oil.
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Ti+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(N(CC)CC)C>CCOCC>[Cl-:1].[Cl-:1].[CH:4]1([Ti+2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: [Ti+3]C1C=CC=C1
Reactant: Oc1ccccn1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C1=CC([Ti+2]Oc2ccccn2)C=C1
Reaction time: 8 h

Procedure:
To a solution of 0.002 moles of cyclopentadienyl titanium trichloride in 50 mL of ether a solution of 2-hydroxy pyridine (0.002 moles) and triethylamine (0.002 moles) in 50 mL of ether was added at 0° C. and stirred overnight. The product was recovered from the ether filtrate. The product has the formula:
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[N:17]=[C:4]1[N:8]2[CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16][C@H:7]2[CH2:6][S:5]1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cnccn1
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cnccn3)N1C2
Yield: 60 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (16.3 g) and 2-aminopyrazine (8.5 g) as the starting materials, (S)-3-(pyrazin-2-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.6 g) is obtained in the form of white crystals, m.p.=140° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>C(O)(=O)C.C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
2-Chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (101 mg, 0.343 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (77 mg, 0.343 mmol) in acetic acid (2 mL) and THF (2 mL). The reaction mixture was heated at 80° C. overnight. Partial conversion to the desired product was observed. The reaction was further heated at 120° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (35.5 mg, 0.059 mmol, 17.19% yield). LC-MS (M+H)+=481.3. 1H NMR (500 MHz, CDCl3) δ ppm 11.08 (1H, s), 8.33 (1H, s), 7.48 (2H, d, J=2.1 Hz), 7.30 (2H, d, J=8.2 Hz), 7.20 (1H, d, J=1.5 Hz), 7.13 (2H, d, J=8.5 Hz), 5.83-5.93 (1H, m), 4.38-4.48 (1H, m), 3.97 (1H, s), 3.86 (3H, s), 3.22 (3H, d, J=4.9 Hz), 2.85-2.95 (1H, m), 2.77 (2H, dd, J=8.7, 5.3 Hz), 2.20-2.32 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH3:19])[N:3]=1
Reactant: N#Cc1nc(N)nc(Nc2cccc(F)c2F)n1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1nc(N)nc(C#N)n1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To 2-amino-4 cyano-6-(2,3-difluorophenylamino)-[1,3,5]triazine (Intermediate 54, 332 mg, 1.34 mmol) were added potassium carbonate (203 mg, 1.46 mmol), methyl iodide (83 μL, 1.34 mmol) and anhydrous DMF (3 mL). The mixture was stirred at room temperature for 1 h and then diluted with 1M aq. citric acid (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL) and the combined extracts washed with water (4×10 mL), saturated brine (10 mL) and dried further over anhydrous sodium sulfate. Evaporation of the solvent gave a gum which was loaded onto a silica column and eluted with heptane-30% ethyl acetate to give the desired compound (320 mg, 91%). Method B HPLC-MS: MH+ requires m/z=262. Found: m/z=262, Rt=1.76 min (98%).