Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])C=1.[CH:27](N(C(C)C)CC)(C)C.CC(N)C>C(#N)C>[CH:6]([NH:5][C:8](/[N:10]=[C:11]1\[S:12][C:13]([CH3:26])=[CH:14][N:15]\1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=1)=[O:9])([CH3:27])[CH3:7]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CC(C)N
Solvent: CC#N
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)NC(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (45 mg, 0.1 mmol, Example 18B) dissolved in acetonitrile (0.6 mL) was added followed by the addition of diisopropylethylamine (22 μL, 0.13 mmol) dissolved in acetonitrile (0.6 mL). Then to the solution was added propan-2-amine (6 mg, 0.11 mmol) dissolved in acetonitrile (0.5 mL). The vial was capped and shaken overnight at room temperature. The reaction was concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[N:28]=[C:27]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([C:27]4[NH:26][N:25]=[C:24]([C:23]([F:37])([F:36])[F:22])[N:28]=4)=[CH:30][CH:31]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2nc(C(F)(F)F)n[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
95 mg (purity 83%, 0.26 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 75 mg (0.31 mmol) of 4-[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]aniline (Example 1.1C) were reacted according to General Method 1. Yield: 30 mg (purity 92%, 21% of theory)
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH:18]([C:27](O)=[O:28])[CH2:17]1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:27]([CH:18]1[CH2:17][C:16](=[O:15])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19]1)=[O:28])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)C1CC(=O)N(c2ccccc2)C1
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1CC(=O)N(c2ccccc2)C1

Procedure:
The product from Example 92B and 5-oxo-1-phenylpyrrolidine-3-carboxylic acid (Princeton Bio) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.91 (t, J=7.3 Hz, 3H), 1.26-1.38 (m, 2H), 1.58-1.66 (m, 2H), 1.61 (s, 9H), 2.64-2.69 (m, 2H), 2.85-2.89 (m, 2H), 3.49-3.58 (m, 1H), 4.12 (s, 1H), 4.14 (d, J=1.7 Hz, 1H), 7.08-7.14 (m, 1H), 7.31-7.38 (m, 2H), 7.62-7.68 (m, 2H), 8.48 (s, 1H). (ESI+) m/z 400 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[ClH:34].[NH2:35][C:36]1[CH:37]=[C:38]([C:42]2[C:50]3[S:49][C:48]([C:51]([NH:53][C@@H:54]4[CH:59]5[CH2:60][CH2:61][N:56]([CH2:57][CH2:58]5)[CH2:55]4)=[O:52])=[CH:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:40][CH:41]=1.[CH3:62][O:63][CH2:64][C:65](O)=[O:66]>CN(C=O)C>[ClH:34].[N:56]12[CH2:57][CH2:58][CH:59]([CH2:60][CH2:61]1)[C@@H:54]([NH:53][C:51]([C:48]1[S:49][C:50]3[C:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:65](=[O:66])[CH2:64][O:63][CH3:62])[CH:37]=4)=[CH:43][CH:44]=[CH:45][C:46]=3[CH:47]=1)=[O:52])[CH2:55]2
Reactant: COCC(=O)O
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
96.4 mg (0.25 mmol) of HATU and 71.5 μl (0.41 mmol) of N,N-diisopropylethylamine are added to a solution of 50 mg (0.12 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride (Example 81) and 18.5 μl (0.24 mmol) of methoxyacetic acid in 0.5 ml of DMF at 0° C. The mixture is stirred at room temperature for 3 h. Purification by preparative HPLC is followed by concentration of the product fractions and, after addition of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, concentration again. Drying under high vacuum results in 7 mg (11% of theory) of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][C:23]1([CH3:36])[NH:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1>>[CH3:22][C:23]1([CH3:36])[N:28]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[C:9]([C:12]4[NH:20][C:19]5[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=5[CH:13]=4)[CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Product: CC(C)(C)OC(=O)N1CCN(c2cnc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C(C)(C)C1
Temperature: 120 °C
Yield: 16 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 100 mg, 0.354 mmol) and tert-butyl 3,3-dimethylpiperazine-1-carboxylate (152 mg, 0.709 mmol), heating at 120° C. for 1 d. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10-100% ACN/water with 0.1% TFA) provided tert-butyl 3,3-dimethyl-4-(8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)piperazine-1-carboxylate (16% yield). MS (ESI, pos. ion) m/z: 477.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:27]=1[C:28](Cl)=[O:29].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
A mixture of 0.625 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.629 g (3 mmol) of 2,5-dichlorobenzoyl chloride, 0.303 g (3 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 10 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is washed with water, 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed to give crystals. Recrystallization from hexane-CH2Cl2 gives 0.16 g of white crystals, m.p. 203°-231° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535.0 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonic acid amide (1.7 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A19. A solution of 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (231.2 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (442.0 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B19. Solution B19 was added to Solution A19 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid (4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amide (94.7 mg, 30%) as a white solid: MS (ESI) M+1=386.2.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[CH2:5]([O:12][C:13]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])[O-].[K+].[K+].C(#N)C>[CH2:5]([O:12][C:13]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:39][CH2:40][N:41]([CH:1]([CH3:3])[CH3:2])[CH2:42][CH2:43]2)=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:16])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1OCc1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(C)C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.033 mg) and isopropyl iodide (0.024 mL) were sequentially added to an acetonitrile (1.9 mL) suspension of methyl 2-(2-(benzyloxy)-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate (0.13 g), followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and potassium carbonate (6.7 mg) and isopropyl iodide (4.8 μL) were sequentially added thereto, followed by heating to reflux for 2 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-95% chloroform/methanol] to obtain 0.12 g of methyl 2-(2-(benzyloxy)-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoate as an orange oily sub stance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH:19]=C)=[N:9]2)[CH:5]=[N:6][CH:7]=1.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:10]([CH:19]=[O:22])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C=Cc1nn(-c2cncc(F)c2)cc1NC(=O)C(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cn(-c2cncc(F)c2)nc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
To a solution of N-(1-(5-fluoropyridin-3-yl)-3-vinyl-1H-pyrazol-4-yl)isobutyramide (0.706 g, 2.57 mmol) in tetrahydrofuran (12.87 ml) and water (12.87 ml) was added osmium tetroxide (0.164 ml, 0.026 mmol). After 10 minutes at room temperature, sodium periodate (1.101 g, 5.15 mmol) was added in portions over 3 minutes and the resulting solution was stirred at room temperature. After 18 hours, the solution was poured into 10 mL water and was extracted with 3×10 mL dichloromethane. The combined organic layers were dried, concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give N-(1-(5-fluoropyridin-3-yl)-3-formyl-1H-pyrazol-4-yl)isobutyramide (626 mg, 2.266 mmol, 88% yield) as a yellow solid: mp 140.0-142.0° C.; 1H NMR (300 MHz, CDCl3) δ 10.12 (s, 1H), 9.14 (s, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.82 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.92 (dt, J=9.2, 2.4 Hz, 1H), 2.65 (dt, J=13.8, 6.9 Hz, 1H), 1.31 (d, J=6.9 Hz, 6H); ESIMS m/z 277 ([M+H]+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:13]=[CH:12][O:11][CH:10]=2)O1.Br[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:40])[CH2:24][O:25][CH2:26][C:27]([NH:29][C:30]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:31]=2[C:32]([OH:34])=[O:33])=[O:28])[CH:19]=[CH:20][CH:21]=1>>[Cl:39][C:36]1[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[CH2:26][O:25][CH2:24][C:23]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:9]3[CH:13]=[CH:12][O:11][CH:10]=3)[CH:17]=2)=[O:40])=[C:31]([CH:35]=1)[C:32]([OH:34])=[O:33]
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 5-(i), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan was reacted with the 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 19-(i) to give 5-chloro-2-([(2-([3-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 75%).
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH2:11]([S:14][C:15]1([C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=O)[CH2:17][CH2:16]1)[CH2:12][CH3:13].[OH-].[K+]>C(O)(C)(C)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:21]=[CH:20][C:18]1([C:15]2([S:14][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17]2)[CH2:10][O:9]1
Reactant: COS(=O)(=O)OC
Reactant: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reaction time: 14 h
Yield: 89.2 %

Procedure:
30 ml (0.41 mol) of dimethyl sulphide and 43.5 g (0.35 mol) of dimethyl sulphate are added to 60 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 40 g (0.13 mol) of 2,4-dichlorophenylethenyl 1-propylmercaptocyclopropyl ketone in 120 ml of tert.-butanol is first added to the reaction mixture with stirring and 39.1 g of potassium hydroxide powder are then introduced, while keeping the temperature of the reaction mixture at 20° to 30° C. The mixture is stirred at 30 C. for 3 hours more, then the dimethyl sulphide is removed under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water and concentrated by removing the solvent under reduced pressure after drying over sodium sulphate. In this manner, 38.2 g (91% of theory) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane are obtained in the form of an oily product, which is reacted further without additional purification. ##STR73##
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[CH3:19]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[C:13]([CH3:19])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1cc(N)ccc1F
Product: Cc1cc(Nc2nc3ccccc3[nH]2)ccc1F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-fluoro-3-methylaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (solid, mp 246-248° C.). MS(ES+) m/z 242 ([M+1]+, 100).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([NH2:7])[CH3:6].Cl[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH:16]=2)[CH:12]=[CH:11][N:10]=1>>[F:28][C:24]1[CH:23]=[C:22]([NH:21][C:17]2[CH:16]=[C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([NH:7][CH:5]([CH3:6])[CH2:4][CH2:3][O:2][CH3:1])[N:14]=3)[CH:20]=[CH:19][N:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: Fc1cccc(Nc2cc(-c3ccnc(Cl)n3)ccn2)c1
Reactant: COCCC(C)N
Product: COCCC(C)Nc1nccc(-c2ccnc(Nc3cccc(F)c3)c2)n1

Procedure:
The title compound was prepared from 3-methoxy-1-methylpropylamine (i.e., the product of Step B) and 4-(2-chloro-4-pyrimidinyl)-N-(3-fluorophenyl)-2-pyridinamine (i.e., the product of Example 17, Step C) in the same fashion as described in Example 17, Step D to give the title compound as a yellow solid, m.p. 104-106° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=O)[N:10]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:9]=[CH:8]2.[NH2:27][C@H:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:27][C@H:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])=[O:16])[N:10]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[N:9]=[CH:8]2
Reactant: N[C@H]1CCNC1=O
Reactant: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.8 %

Procedure:
5-(2,4-Difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylic acid (200 mg, 0.552 mmol) was dissolved in N,N-dimethylformamide (2 mL). To his was added (S)-3-aminopyrrolidin-2-one (4a) (111 mg, 1.10 mmol), 4-(dimethylamino)pyridine (6.7 mg, 0.055 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg, 0.607 mmol) successively, and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 100% acetone to yield pure (S)-5-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ij) (83 mg, 34%). Mass spec: 445 (M+1). 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.26 (brd, 1H), 7.93 (s, 1H), 7.18 (m, 1H), 7.04 (s, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 6.04 (br, 1H), 4.59 (ddd, 1H), 4.37 (s, 2H), 3.64 (brs, 1H), 3.45 (m, 2H), 2.87 (m, 1H), 2.09 (m, 1H), 1.21 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:37][N:38]([CH3:43])[CH2:39][CH2:40][CH2:41][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: COC(=O)c1cccc(-c2ncc(O)cn2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1

Procedure:
A solution, kept under nitrogen, of 6.1 g (26.5 mmol) of methyl 3-(5-hydroxypyrimidin-2-yl)benzoate, 10.5 g (39.8 mmol) of triphenylphosphine and 4.76 ml (39.8 mmol) of 3-(dimethylamino)-1-propanol in 200 ml of THF is cooled in an ice bath, and 8.21 ml (39.8 mmol) of diisopropyl azodicarboxylate are subsequently slowly added dropwise with stirring. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo. The residue is partitioned between dichloromethane and saturated aqueous potassium hydrogensulfate solution. The aqueous phase is separated off, adjusted to a pH of 12 using saturated aqueous sodium hydroxide solution and extracted twice with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent:methyl 3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]benzoate as colourless crystals; m.p. 66° C.; ESI 316 (M+H); HPLC: 2.18 min (method B).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:13]=2[N+:26]([O-])=O)=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:5])[CH3:2].Cl>[Zn].O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:13]=2[NH2:26])=[N:8][C:7]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(OCc3ccccc3)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(Nc2cc(OCc3ccccc3)ccc2N)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5.09 g (10 mmole) of 2-(5-benzyloxy-2-nitro-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (VI.25), 100 mL of tetrahydrofuran and 20 mL of 1M hydrochloric acid, was added portionwise, 10 g of zinc powder. The mixture was stirred at ambient temperature for 2 hours. The solid was removed by filtration, the filtrate was concentrated under reduced pressure and 200 mL of water was added to the residue. The pH was adjusted to 9 by addition of 15% sodium hydroxide. The precipitate was collected by filtration to give crude 2-(2-amino-5-benzyloxy-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (VII.25). This material was carried through to next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:26])[C:11](=[O:25])[C:12]2[S:16][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:26])[CH:11]([C:12]2[S:16][C:15]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[N:14][CH:13]=2)[OH:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)C(=O)Nc2ccc(F)c(F)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncc(C(O)C(=O)Nc2ccc(F)c(F)c2)s1
Yield: 91.9 %

Procedure:
N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl) (oxo)acetamide (938 mg, 2.4 mmol) in THF (50 ml) and MeOH (10 ml) was treated with sodium borohydride (93 mg, 2.4 mmol) for 30 minutes. The mixture was evaporated, the residue dissolved in ethanol (3 ml) water (25 ml) was added, and the pH adjusted to 6, more water was added, a solid was recovered, dried, recristalized in ether/petroleum ether to give title compound (850 mg, 90%).