Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=NCCCN(C)C)C.[O:12]=[C:13]1[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]1[CH2:30][C:31]([OH:33])=O.Cl.Cl.[F:36][C:37]([F:53])([F:52])[C:38]1[CH:39]=[C:40]([CH:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH3:45])[CH:41]=[CH:42][CH:43]=1>ClCCl>[O:33]=[C:31]([N:49]1[CH2:48][CH2:47][N:46]([CH:44]([C:40]2[CH:41]=[CH:42][CH:43]=[C:38]([C:37]([F:52])([F:53])[F:36])[CH:39]=2)[CH3:45])[CH2:51][CH2:50]1)[CH2:30][N:14]1[CH2:15][CH2:16][C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]1=[O:12]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC(c1cccc(C(F)(F)F)c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)CN2CCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Reaction time: 8 h

Procedure:
A solution of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.074 mL, 0.416 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.058 g, 0.198 mmol) and the product from Example 44B (0.066 g, 0.198 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.40-7.56 (m, 4H), 7.20-7.37 (m, 10H), 4.10-4.22 (m, 2H), 3.52-3.63 (m, 2H), 3.50 (t, J=6.6 Hz, 2H), 3.34-3.43 (m, 3H), 2.80 (t, J=6.5 Hz, 2H), 2.43-2.51 (m, 1H), 2.16-2.36 (m, 3H), 1.33 (d, J=6.7 Hz, 3H); MS (ESI+) m/z 536 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:16]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>O1CCCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:16]=1)=[C:24]=[S:25]
Reactant: Nc1ccc2sc(-c3cccnc3)nc2c1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1ccc2sc(-c3cccnc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(3-pyridinyl)benzothiazole, 8.0 g, 0.035 M, is dissolved in 400 cc of tetrahydrofuran and 9.8 cc, 0.070 M, of triethylamine. Thiophosgene, 2.7 cc, 0.035 M is added, and the resulting mixture stirred overnight at ambient temperature. The solids which form are filtered and washed with tetrahydrofuran. The filtrate is concentrated to dryness and chromatographed on Alumina IV; elution with benzene yields 1.0 g of white solid which is recrystallized from acetonitrile to yield the title compound, 0.52 g, m.p. 160°-162° (12% of theory).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=3[C:35]([F:38])([F:37])[F:36])[N:19]=[CH:18]4)[C:11](=[O:13])[N:12]=2)[CH2:3]1.[F:39][CH:40]([F:50])[CH2:41]OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:36][C:35]([F:38])([F:37])[C:26]1[CH:27]=[C:28]([C:31]([F:34])([F:32])[F:33])[CH:29]=[CH:30][C:25]=1[CH2:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:4]4[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:41][CH:40]([F:50])[F:39])[CH2:3]4)=[N:12][C:11]3=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: N[C@H]1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N=C(N2CCC[C@H](NCC(F)F)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Temperature: 70 °C

Procedure:
To a solution of DMF (1 mL) was added 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one (0.03 g, 0.05 mmol), Trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (0.02 g, 0.09 mmol) and potassium carbonate (0.014 g, 0.1 mmol). The resulting mixture was heated at 70° C. overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with MeOH/CH2Cl2 (7/93) to afford the title product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 2.5 h
Yield: 85.2 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (9.2 g), p-hydroxyacetophenone (7.95 g), potassium carbonate (6.73 g) and N,N-dimethylformamide (DMF) (100 ml) was stirred for 2.5 hours at temperatures ranging from 70° to 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (MgSO4), then the solvent was distilled off to give 4'-(5-methyl-2-phenyl-4-oxazolylmethoxy)acetophenone (11.6 g, 85%). Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.126°-127° C.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[C:17]2[O:16][CH2:15][CH:14]([C:18]([NH2:20])=O)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.CCOCC>[F:7][C:8]1[C:17]2[O:16][CH2:15][CH:14]([C:18]#[N:20])[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)C1COc2c(F)cccc2O1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: N#CC1COc2c(F)cccc2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111 %

Procedure:
13.7 ml of pyridine (169 mmol, 2 eq.) are added to a suspension of 16.7 g of amide from Stage 1 (84.5 mmol) in 180 ml of dioxane at 0° C., followed, 10 minutes later, by dropwise addition of 13.1 ml of trifluoroacetic anhydride (19.5 g; 93 mmol, 1.1 eq.). The reaction mixture is kept cold for 1 hour and is then stirred at room temperature for 16 hours. The solution is taken up in Et2O/1N HCl. The organic phase is washed with 1N NaOH, dried over MgSO4, filtered and then evaporated to dryness. 16.8 g of a pale yellow oil are obtained (quantitative yield).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12].O.[NH2:15][NH2:16]>C(O)C>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([NH:15][NH2:16])=[O:2]
Reactant: COC(=O)c1ccc(OC)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)NN)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of 5.04 g (27.2 mmol) of 2-fluoro-4-methoxybenzoic acid methyl ester in ethanol (50 mL) are added 36.9 mL (408.6 mmol) of hydrazine hydrate. The reaction is stirred at room temperature for 15 h. The mixture is concentrated under reduced pressure and the solid is washed with DCM/heptane (2:1) to give 4.26 g (23.0 mmol) of 2-fluoro-4-methoxybenzoic acid hydrazide. Yield: 85%, ES-MS: m/z [M+H] 185.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH3:12][NH2:13]>C(O)C>[C:12]([NH:5][C:4]([NH:3][CH3:2])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: CN
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 4 h

Procedure:
A solution of 4-methyl-5-[(2 -aminoethyl)thiomethyl]-imidazole (1.93 g.) and dimethyl-N-cyanoimidodithiocarbonate (1.65 g.) in ethanol (33 ml.) was set aside overnight at room temperature. Ethanolic methylamine (33%, 22 ml.) was added and the solution was then set aside for 4 hours. Concentration and recrystallisation from isopropyl alcohol-ether yielded N-cyano-N'-methyl-N-"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.0 g.), m.p. 139°-140°. (Found: C, 47.5; H, 6.5, N, 33.3; S, 12.7. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [Na+].[Cl-].CC(C)=CC[C:7]1[C:12]([OH:13])=[CH:11][C:10]([OH:14])=[CH:9][C:8]=1[C:15]1[O:23][C:22]2[CH:21]=[C:20]([OH:24])[CH:19]=[CH:18][C:17]=2[CH:16]=1>CO>[CH3:9][C:8]([CH3:15])=[CH:7][CH2:12][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][C:20]=1[OH:24])[O:23][C:15]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[C:12]([OH:13])[CH:7]=1)=[CH:16]2
Reactant: CC(C)=CCc1c(O)cc(O)cc1-c1cc2ccc(O)cc2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCc1cc2cc(-c3cc(O)cc(O)c3)oc2cc1O

Procedure:
Needles; mp 183-184° C.; UV (MeOH) λmax (log ε) 330.5 (4.43), 319.5 (4.49), 218 (4.49) nm; IR (NaCl) γmax 3356, 2924, 1617, 1456 cm−1; 1H NMR (CD3OD, 500 MHz) δ 1.72 (3H, s, H-4″), 1.74 (3H, s, H-5″), 3.32 (2H, brd, H-1″), 5.35 (1H, m, H-2″), 6.23 (1H, t, J=2.2 Hz, H-4′), 6.74 (2H, d, J=2.2 Hz, H-2′), 6.84 (1H, s, H-3), 6.87 (1H, s, H-7), 7.18 (1H, s, H-4); 13C NMR (CD3OD, 125 MHz) δ 17.8 (C-4″), 26.0 (C-5″), 29.5 (C-1″), 97.8 (C-7), 102.2 (C-3), 103.3 (C-4′), 103.8 (C-2′), 121.4 (C-4), 122.7 (C-9), 124.4 (C-2″), 126.2 (C-5), 132.8 (C-3″), 134.0 (C-1′), 154.6 (C-6), 155.5 (C-2), 155.7 (C-8), 159.9 (C-3′); EIMS m/z 310 (M+, 76), 255 (100), 254 (56), 226 (10).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CN(C=O)C.CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:29]#[C:28][C:26]([OH:30])([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][N:20]=1)[CH3:27])[N:5]=2
Reactant: C#CC(C)(O)c1cnccn1
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(C)(O)c3cnccn3)nc21

Procedure:
A suspension of 1 g (3.56 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 25 ml of a DMF/Et3N mixture (V/V; 2.5/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.792 g of (±)-2-pyrazin-2-ylbut-3-yn-2-ol (5.34 mmol), 0.068 g of CuI (0.36 mmol) and 0.125 g of bis(triphenylphosphine) palladium(II)dichloride (0.18 mmol) are successively added.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:2]1.C([Li])CCC.CCCCCC.O1CCCC1.O1CCCC1.O1CCCC1.[Cl-:44].[Cl-].[Cl-].[Cr+3:47]>O1CCCC1>[Cl-:44].[Cl-:44].[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:1]=[C:2]1[Cr+2:47]
Reactant: C1=C(CCc2ccccn2)c2ccccc2C1
Reactant: [Cr+3]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Cr+2]C1=Cc2ccccc2C1CCc1ccccn1
Temperature: -100 °C
Reaction time: 0.83 h

Procedure:
A solution of 22.1 g (0.1 mol) of 2-[2-(1H-inden-3-yl)ethyl]pyridine in 470 ml of tetrahydrofuran was cooled to −100° C. 62.5 ml of a 15% strength n-butyllithium solution in hexane (0.1 mol) were slowly added dropwise. After the addition was complete, the reaction mixture was stirred for a further 50 minutes at −100° C. The mixture was subsequently allowed to warm to room temperature. After stirring for another 2 hours, the solution was cooled to −60° C. and 38 g (0.1 mol) of chromium trichloride tris(tetrahydrofuran) were added while stirring. The mixture was allowed to warm slowly to room temperature and was subsequently stirred for another 10 hours at room temperature. The reaction mixture was then refluxed for 20 minutes and subsequently cooled to room temperature. The solid which had precipitated was filtered off and washed with hot tetrahydrofuran. The solid was subsequently washed with diethyl ether and dried under reduced pressure. This gave 28.1 g of (1-(2-pyridylethyl)indenyl)chromium dichloride (82%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][C:32]3[C:33]([CH3:38])=[N:34][O:35][C:36]=3[CH3:37])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1noc(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 4-(bromomethyl)-3,5-dimethylisoxazole using potassium carbonate as a base in DMF at 80° C. Mass: 519.01 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=3)([C:12]([F:15])([F:14])[F:13])[O:9][N:8]=2)[O:4][C:3]=1[CH:25]=O.[CH:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH2:11][C:10]([C:16]3[CH:17]=[C:18]([Cl:24])[C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=3)([C:12]([F:14])([F:13])[F:15])[O:9][N:8]=2)[O:4][C:3]=1[CH2:25][NH:32][C:30]([CH:27]1[CH2:29][CH2:28]1)=[O:31]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1C=O
Reactant: NC(=O)C1CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)oc1CNC(=O)C1CC1
Temperature: 110 °C
Yield: 78.3 %

Procedure:
A mixture of 3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-carbaldehyde (100 mg), cyclopropanecarboxamide (61 mg), trifluoroacetic acid (54 μl) and triethylsilane (112 μl) in toluene (2 ml) is refluxed at 110° C. After 4 hours 30 minutes the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {3-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-2-ylmethyl}-amide (91 mg, compound 3.1 in Table 3) as a white solid. MS (HPLC/MS): 495 (MH+). Retention time: 2.08 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][C:18]4[C:19]([C:28]#[N:29])=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1>C(O)=O.O.[Pt](=O)=O>[NH2:29][CH2:28][C:19]1[C:18]([CH2:17][N:15]2[C:14](=[O:30])[N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:31]4[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=4)[C:10]3=[N:16]2)=[CH:23][CH:22]=[C:21]([C:24]([F:25])([F:27])[F:26])[N:20]=1
Reactant: N#Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: O=[Pt]=O
Solvent: O=CO
Solvent: O
Product: NCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
To a solution of 3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)picolinonitrile (51 mg, 0.1 mmol) in formic acid (0.8 mL) and water (0.2 mL) was added platinum (IV) oxide (20 mg). The resulting suspension was stirred at 70° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3, water, then saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The product was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 7.4 mg of the title compound as a yellow powder. HPLC/MS: retention time=2.26 min, [M+H]+=511.0.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:46]3[CH2:47][CH2:48][CH:43]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:44][CH2:45]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-pyrrolidin-1-yl-piperidine (Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C37H47N6O2Cl2 [(M+H)+] 677.3132, observed 677.3132.
Reaction SMILES: [F:1][C:2]([F:24])=[C:3]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22]C)=[CH:14][C:13]=1[CH2:12][CH2:11]3.[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[F:1][C:2]([F:24])=[C:3]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH2:5][CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A solution of 5 g of 17-difluoromethylene-3-methoxy-18-methyl-estra-1,3,5(10)-triene in 95 ml of toluene is refluxed with 95 ml of a 1.6 M diisobutylaluminum hydride solution in toluene for 3 hours at a bath temperature of 140° C. Then, it is cooled to room temperature, slowly added to 200 g of ice, mixed with 400 ml of 1 M sulfuric acid, stirred for 1 hour at room temperature, extracted three times with ethyl acetate, the organic phases are washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 4.5 g of 17-difluoromethylene-18-methyl-estra-1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 120-121° C., [α]D22 =+37.8° (c=0.5% in pyridine).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
A mixture of 4-chloro-2-methylpyridine (10 g, 79 mmol) and (4-fluorophenyl)boronic acid (13.2 g, 94 mmol) in DME (150 ml) and 2M Na2CO3 (94 ml) was degassed for 5 minutes with a stream of nitrogen before adding Pd(PPh3)4 (1.8 g, 2 mol %) and then refluxing overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), washed with 4 N NaOH (40 ml) and then with brine (50 ml). The organic layer was then dried over MgSO4, concentrated in vacuo and purified by chromatography on silica gel eluting with a gradient 30-50% ethyl acetate/hexane to afford 9.0 g of the title compound (61%): δH (360 Mz, CDCl3) 2.62 (3H, s), 7.16 (2H, t, J 8.5), 7.27 (1H, d, J 5.0), 7.33 (1H, s), 7.58-7.62 (2H, m), 8.53 (1H, d, J 5.0); m/z (ES+) 188 (MH30 ).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([O:8]C)=[O:7])[CH2:3][Zn]I.[NH:17](C(OCC1C=CC=CC=1)=O)[CH2:18][CH2:19][C:20](Cl)=[O:21]>>[O:21]=[C:20]([CH2:19][CH2:18][NH2:17])[CH2:3][C@@H:2]([C:6]([OH:8])=[O:7])[NH2:1]
Reactant: O=C(Cl)CCNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](C[Zn]I)NC(=O)OC(C)(C)C
Product: NCCC(=O)C[C@H](N)C(=O)O

Procedure:
Boc-L-Ala(ZnI)-OMe is reacted with Z-beta-Ala-Cl under conditions described in J. Org Chem 57, 1992, pp 3397-3404 to give a protected 4-keto-L-lysine which is then dissolved in DCM and treated with DAST to yield protected 4,4-difluoro-L-lysine. The epsilon carbobenzoxy protecting group is then removed under catalytic hydrogenolysis conditions. The resulting compound is reacted with methyl acetimidate hydrochloride to yield the epsilon amidine which was then reacted with 2 N HCl to give the title compound.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](F)=[O:8])([F:4])[F:3].[Cl:14]C(C1C=CC=CC=1C(Cl)=O)(Cl)Cl.BrC(C1C=CC=CC=1C(Br)=O)(Br)Br.[Br-]>>[F:1][C:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:14])=[O:8])([F:4])[F:3]
Reactant: O=C(F)c1ccccc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1C(Cl)(Cl)Cl
Agent: O=C(Br)c1ccccc1C(Br)(Br)Br
Agent: [Br-]
Product: O=C(Cl)c1ccccc1C(F)(F)F
Yield: 400 %

Procedure:
Under ideal stoichiometic conditions three moles of trifluoromethylbenzoyl fluoride are contacted with one mole of trichloromethylbenzoyl chloride or tribromomethylbenzoyl bromide in the presence of a halogen transfer catalyst to yield four moles of trifluoromethylbenzoyl chloride or bromide. It will be understood however, that greater or less than stoichiometric amounts of the reactants can be employed. Thus, in accordance with the process of this invention substituted or unsubstituted trichloromethylbenzoyl chloride or tribromomethylbenzoyl bromide may be reacted with corresponding substituted or unsubstituted trifluoromethylbenzoyl fluorides, in the presence of a halogen transfer catalyst to produce the corresponding substituted or unsubstituted trifluoromethylbenzoyl chloride or bromide.