Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].Br[CH2:11][C:12](=[O:34])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:33])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1>CC(O)C.C1(C)C=CC=CC=1>[CH2:7]([S:8][CH2:11][C:12](=[O:34])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C@H:27]([C:28](=[O:32])[CH2:29]2)[C@:25]2([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:33])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCc1ccccc1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSCc4ccccc4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
Toluene-α-thiol (1.0 ml.) was added to a warm solution of sodium (0.6 g.) in a mixture of propan-2-ol (25 ml.) and toluene (30 ml.). 21-Bromo-3α-hydroxy-5α-pregnane-11,20 -dione (0.7 g.) was then added and the mixture was gently refluxed for 2 hr. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was purified by preparative t.l.c. (CHCl3) to give title compound (0.4 g.) as a white foam, [α]D + 89° (c 1.1).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@:14]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C@@H:16]([CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:19])[OH:17])[OH:15])=[O:12].[NH3:38]>C(O)C>[NH2:38][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]([C:13]([F:37])([F:36])[C@@:14]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])([C@@H:16]([CH:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:19])[OH:17])[OH:15])=[O:12]
Reactant: N
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)ncnc21
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 0.5 g (0,936 mmol) of 1-(6-chloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose dissolved in 75 ml of absolute ethanol was saturated with anhydrous ammonia at about 0° C. The reaction flask was sealed, and the mixture was allowed to warm to room temperature. The mixture was stirred for about 72 hours at room temperature and the volatiles were evaporated under reduced pressure to provide 420 mg of 1-(6-amino-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose. Mass spec=458 [515-(t-butyl)]
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]([F:17])([F:16])[F:15])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[C:24]([F:32])[CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([CH3:19])([CH3:18])[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[C:8]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)=[O:30])=[C:24]([F:32])[CH:23]=1
Reactant: CCOC(=O)C(C)(C)Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1ccc(NC(=O)Cc2ccc(Br)cc2F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Ethyl-3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.691 mmol) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (161 mg, 0.691 mmol), HATU (315 mg, 0.830 mmol) and TEA (0.482 mL, 3.46 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 2 h, and then the solution was distributed between DCM and H2O. The combined organic extract was dried over MgSO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM, Rf=0.5) to yield a light yellow oil of ethyl 3-(4-(2-(4-bromo-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (320 mg, 0.571 mmol, 83.0% yield): 1H NMR (400 MHz, MeOH-d4) δ 7.94 (d, J=1.54 Hz, 1H), 7.68 (d, J=8.38 Hz, 1H), 7.27-7.36 (m, 2H), 7.22 (d, J=8.38 Hz, 1H), 6.90-6.97 (m, 1H), 4.09-4.18 (m, 2H), 3.74 (s, 2H), 3.07 (s, 2H), 1.20-1.25 (m, 3H), 1.15 (s, 6H); ES-LCMS m/z 504 (M+H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:22][C:23]1[C:37]([CH3:38])=[CH:36][C:26]2[NH:27][C:28]([C:30]3[C:34]([NH2:35])=[CH:33][NH:32][N:31]=3)=[N:29][C:25]=2[CH:24]=1.[N:39]1([CH2:44][C:45](O)=[O:46])[CH:43]=[N:42][N:41]=[N:40]1>CN(C)C=O>[CH3:38][C:37]1[C:23]([CH3:22])=[CH:24][C:25]2[NH:29][C:28]([C:30]3[C:34]([NH:35][C:45](=[O:46])[CH2:44][N:39]4[CH:43]=[N:42][N:41]=[N:40]4)=[CH:33][NH:32][N:31]=3)=[N:27][C:26]=2[CH:36]=1
Reactant: O=C(O)Cn1cnnn1
Reactant: Cc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3n[nH]cc3NC(=O)Cn3cnnn3)[nH]c2cc1C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
A stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg) and diisopropylethylamine (269 μl) in dimethylformamide (10 ml) were treated with 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [100 mg, Example 233(c)] and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). The reaction mixture was stirred for 72 hours then treated further with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg), diisopropylethylamine (269 μl) and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). Stirring was continued for a further 48 hours then the reaction mixture was partitioned between ethyl acetate and water. The organic phase was evaporated and the residue was treated with 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1:4, 8 ml). After 1 hour this mixture was extracted with ethyl acetate. The extract was washed with brine, then dried over magnesium sulfate and then evaporated to dryness. The residue was subjected to preparative HPLC to give N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide (13.7 mg) as an off-white solid. MS: 338.14 (M+H)+. HPLC (METHOD B1): RT=7.26 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(F)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg), 4-fluorophenyl boronic acid (0.451 moles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23](=[O:24])[CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=4)[CH2:19]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COC(=O)c1ccc(C2CCC(=O)CC2)cc1
Product: COC(=O)c1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(4-oxo-cyclohexyl)-benzoic acid methyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3].[CH3:20][C@@H:21]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C@H:22]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:23](ON1C(=O)CCC1=O)=[O:24]>CN(C)C=O>[NH:33]([C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C@H:22]([C:23]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5])[CH3:3])=[O:24])[C@@H:21]([CH3:20])[O:44][C:45]([CH3:47])([CH3:48])[CH3:46]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)N)C(=O)NCC(=O)OC
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC

Procedure:
1.36 g of H-Ala-Ile-Gly-OMe (compare Example 1) and 2.5 g of Z-Thr(tBu)-OSU in 3 ml of dimethylformamide are stirred for 20 hours at room temperature. The tetrapeptide derivative is precipitated by ether, filtered off and washed with ether. After recrystallisation from ethanol the melting point is 229°-230° C. [α]D20 = -43° (c = 1 in methanol). Rf = 0.55 in the system chloroform-methanol (95:5) on silica gel.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4](=[O:25])[CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>C(Cl)Cl.O>[C:13]1([P:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][C:4]([O:3][CH3:2])=[O:25])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 93.2 %

Procedure:
A mixture of (2-methoxy-2-oxoethyl)triphenylphosphonium bromide (10.0 g, 24.08 mmol) in 100 mL DCM, 50 mL water and NaOH (10 N) (4.82 ml, 48.2 mmol) was vigorously shaken in a separatory funnel. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic layers were dried (MgSO4) and concentrated to give methyl 2-(triphenylphosphoranylidene)acetate (7.5 g, 93% yield) as a white solid. A solution of 3-chloro-2-methylbenzaldehyde (0.7 g, 4.53 mmol) and 2-(triphenylphosphoranylidene)acetate (1.817 g, 5.43 mmol) in MeOH (22.6 ml) was stirred at room temperature for 2 h. The mixture was concentrated and purified by flash chromatography (0-30% ethyl acetate:hexanes) to afford the title compound (0.23 g, 24% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=15.9 Hz, 1H), 7.47-7.40 (m, 2H), 7.17-7.15 (m, 1H), 6.33 (d, J=15.9 Hz, 1H), 3.83 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(=O)CC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.4 %

Procedure:
To 1-(4-hydroxy-phenyl)-propan-1-one (4.6 g, 30 mmol) and K2CO3 (5 g, 36 mmol) in DMF (10 mL) was added allylbromide (7.26 g, 60 mmol) dropwise with violent stirring. The reaction mixture was stirred at room temperature for 12 h and filtered to remove salt. The filtrate was concentrated to yield the titled compound (5.5 g, 97%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, 2H, J=9.0 Hz), 7.05 (d, 2H, J=9.0 Hz), 6.05 (m, 1H), 5.44, 5.38, 5.30, 5.26 (4d, 2H, J=3.0 Hz), 4.66 (d, 2H, J=6.0 Hz), 2.98 (q, 2H, J=7.5 Hz), 1.07 (t, 3H, J=7.5 Hz). MS (ESI) m/e 191 (M+H)+; 189 (M−H)−.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][N:13]([CH3:19])[C:12]=3[N:11]=[C:10]2S)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:23]>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][N:13]([CH3:19])[C:12]=3[N:11]=[C:10]2[Cl:23])=[CH:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(S)nc21
Agent: Cl
Product: Cn1cnc2c(=O)n(-c3ccc(Br)cc3)c(Cl)nc21
Temperature: 135 °C

Procedure:
1-(4-Bromophenyl)-2-mercapto-9-methyl-1,9-dihydro-6H-purin-6-one hydrochloride (2.05 g, 5.49 mmol) is added to POCl3 (87 mL) and the resulting solution is refluxed at 135° C. for 38 h. Most volatiles are removed under vacuum and the residual solvents are co-evaporated with toluene (50 mL×3). The resulting dark solid is dissolved in CH2Cl2 (300 mL), washed with saturated NaHCO3 solution (100 mL×5), brine (50 mL×2), and dried over MgSO4. After removing solvent in vacuo, silica gel column chromatography (EtOAc:hexanes=50:50) gives the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) 7.51 (1H, s), 7.67 (2H, d), 7.14 (2H, d), 3.83 (3H, s); m/z (ES+) 340.90 (M+).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[Cl:29]>CC(N(C)C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:30][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1cc(Oc2ccc(Cl)c(Cl)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 98.9 %

Procedure:
To a mixture of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (1.00 g, 4.16 mmol) and DMA (21 mL) was added K2CO3 (1.15 g, 8.32 mmol) and 3,4-dichloro-phenol (1.36 g, 8.32 mmol). The mixture was heated to 85° C. for 18 h. The mixture was cooled to 23° C. and poured into ice water. The precipitate was collected, dissolved in EtOAc (150 mL) and washed with brine (2×30 mL). The organic layers were combined, dried, filtered, and concentrated under reduced pressure to yield the titled compound (1.51 g, 99%). 1H NMR (500 MHz, CDCl3): 8.52 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.26 (d, J=3.2 Hz, 1H), 7.00 (dd, J=8.7, 2.7 Hz, 1H), 6.37 (s, 2H), 6.06 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:20][C:21]#[N:22])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26](O)[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:20][C:21]#[N:22])[CH2:18][CH2:17][CH:16]([O:19][C:26]4[CH:25]=[C:24]([CH3:23])[O:28][N:27]=4)[CH2:15][CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CCC(O)CC1
Reactant: Cc1cc(O)no1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCC(CC#N)(n3cc(-c4ccnc(Cl)n4)cn3)CC2)no1
Temperature: 70 °C

Procedure:
To a solution of 1-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-4-hydroxycyclohexylacetonitrile (0.6 g, 0.00189 mol) in tetrahydrofuran (9 mL) was added 5-methylisoxazol-3-ol (0.22 g, 0.0023 mol), triphenylphosphine (0.594 g, 0.00226 mol), followed by diisopropyl azodicarboxylate (0.446 mL, 0.00226 mol). The mixture was heated at 70° C. overnight. After evaporating to dryness, the residue was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product. LCMS (M+H) 399.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10](OCC)=[O:11])=[N:5]1.Cl.[OH-].[NH4+:19]>>[F:1][C:2]([F:16])([F:15])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10](=[O:11])[NH2:19])=[N:5]1
Reactant: CCOC(=O)C1=NN(CC(F)(F)F)C(=O)C1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: NC(=O)C1=NN(CC(F)(F)F)C(=O)C1
Reaction time: 120 h

Procedure:
0.71 Mole (169 g) of 1-(2',2',2'-trifluoroethyl)-3-carbethoxy-2-pyrazolin-5-one were stirred for 8 hours in concentrated ammonium hydroxide and left standing afterwards for 5 days in a sealed recipient at room temperature. After filtration the filtrate obtained was poured out on ice and acidified with hydrochloric acid. As soon as the product had crystallized out completely, it was filtered and washed with water.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][N:25]=[C:26](F)[CH:27]=3)[N:22]=[CH:21][C:20]=2[C:30]#[N:31])[CH:14]=[CH:15][C:16]=1[F:17]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][N:25]=[C:26]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:27]=3)[N:22]=[CH:21][C:20]=2[C:30]#[N:31])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Solvent: c1ccncc1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 26.7 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (0.44 mL, 2.73 mmol) and 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.50 g, 1.58 mmol) in pyridine 5.3 mL was heated to 80° C. for 7 days. The solvent was evaporated and the crude product was purified by flash column chromatography (7% MeOH in CHCl3) to give a yellow solid (0.18 g, 44%). 1H NMR (400 MHz, CDCl3) δ 2.5 (m, 4 H) 2.6 (d, J=11.9 Hz, 2 H) 3.2 (m, 2 H) 3.7 (m, 4 H) 5.5 (t, J=5.1 Hz, 1 H) 6.2 (s, 1 H) 6.9 (s, 1 H) 7.1 (m, 1 H) 7.2 (t, J=8.6 Hz, 1 H) 7.3 (m, 1 H) 8.5 (s, 1 H) 9.1 (d, J=0.5 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:29])=[C:24](B(O)O)[CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=3[CH3:29])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccc(F)cc1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3C)cccc2c1N
Yield: 86.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 5-fluoro-2-methyl-phenylboronic acid (154 mg, 1.000 mmol) were reacted to afford the title compound (142 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.53 (br, 1H), 7.91 (m, 1H), 7.77-7.63 (m, 2H), 7.26 (m, 1H), 7.07-6.97 (m, 2H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 2.01 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=339 (M+H). HPLC 1.77 min.
Reaction SMILES: CS[C:3](=[N:12][CH2:13][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([Cl:11])[CH:5]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[CH2:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH2:31][C:26]([C:21]3[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=3)([C:27]([F:28])([F:30])[F:29])[CH2:13][N:12]=2)=[CH:5][C:6]=1[Cl:11]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CN=C(c2ccc(Br)c(Cl)c2)C1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a solution of 4-bromo-3-chloro-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (9.60 g, 27.4 mmol) in dry THF (100 mL) was added 2-(3,5-dichlorophenyl)-1,1,1-trifluoro-2-propene (8.94 g, 33.4 mmol) at −7° C. A solution of tetrabutyl ammoniumfluoride (5.32 mL, 1 M in THF, 5.33 mmol) was added at this temperature and the mixture was allowed to warm to room temperature over night. All volatiles were removed in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (9.50 g, 74%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 3:1) to yield 80 mg (31%) colorless powder.