Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15].O.C(=O)([O-])[O-].[K+].[K+].N1([C:56]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[O:57])C=CN=C1>C(#N)C>[CH3:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][O:58][C:56](/[N:33]=[C:31](\[NH2:32])/[C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH2:23][C:21]2[N:20]([CH3:34])[C:19]3[CH:35]=[CH:36][C:16]([C:14]([N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:15])=[CH:17][C:18]=3[N:22]=2)=[CH:30][CH:29]=1)=[O:57]
Reactant: CCCCCCOC(=O)n1ccnc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-6a (100 g) was added to acetonitrile (1200 ml) and water (800 ml) at 25-35° C. and then cooled to 12-18° C. Potassium carbonate (117 g) was added to the reaction mixture and stirred for 15 minutes at 12-18° C. A solution of hexyl 1H-imidazole-1-carboxylate compound of formula-4 (60 g) in acetonitrile (150 ml) was slowly added to the reaction mixture over a period of 25 minutes at 12-18° C. and stirred for 14 hours at 15-20° C. After completion of the reaction, water was added to the reaction mixture and stirred for 30 minutes. Filtered the solid, washed with acetonitrile followed by aqueous acetonitrile and then dried to get title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Further the obtained solid, recrystallized from ethylacetate and ethanol.
Reaction SMILES: [F:1][C:2]([F:29])([C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:6]([O:8]CC)=[O:7].C(OCC)(=O)CC(OCC)=O.BrCCCCCCC=C.ICCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F.[CH2:66]([C:68]1([C:105]2[CH:110]=[CH:109][C:108]([OH:111])=[CH:107][CH:106]=2)[CH:77]([CH2:78]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:76]2[C:71](=[CH:72][C:73]([OH:104])=[CH:74][CH:75]=2)[O:70][CH2:69]1)[CH3:67]>>[CH2:66]([C:68]1([C:105]2[CH:106]=[CH:107][C:108]([OH:111])=[CH:109][CH:110]=2)[CH:77]([CH2:78][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:5]([CH2:4][CH2:3][C:2]([F:29])([F:1])[C:19]([F:27])([F:28])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:6]([OH:8])=[O:7])[C:76]2[C:71](=[CH:72][C:73]([OH:104])=[CH:74][CH:75]=2)[O:70][CH2:69]1)[CH3:67]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: C=CCCCCCCBr
Agent: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Solvent: CCOC(=O)CC(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate prepared from diethyl malonate, 8-bromo-1-octene and 1-iodo-3,3,4,4,5,5,6,6,6-nonafluorohexane as in Example 5 and the allyl compound prepared in Example 21, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:28])[F:29])[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4CNC4)cc3N21

Procedure:
A solution of 3-(4(S)-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 6), Rt=8.78 min., 0.270 g, 0.59 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at ambient temperature for 1 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(S)-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale yellow solid (Example #53-1, Enantiomer 1, SFC (Table 1, Method 7), Rt=6.44 min, 0.275 g, 99%). LC/MS (Table 1, Method 5) Rt=2.070 min.; MS m/z: 356 [M+H]+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[C:9]([O-:12])(=[S:11])[CH3:10].[K+].Cl>CN(C)C=O>[C:9]([O:12][CH2:2][CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])(=[S:11])[CH3:10]
Reactant: CC([O-])=S
Reactant: FC(F)(F)CCCI
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OCCCC(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture of 23.80 g of 1-iodo-4,4,4-trifluorobutane, 100 ml of N,N-dimethylformamide and 11.42 g of potassium thioacetate was heated and stirred at 80° C. for 4 hours under a nitrogen atmosphere. A reaction vessel was cooled in an ice bath. To the reaction mixture was added an aqueous 1N hydrochloric acid solution, and the mixture was extracted with 100 ml of t-butyl methyl ether twice. Organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 18.20 g of 4,4,4-trifluorobutyl thioacetate represented by the formula:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][CH:7](O)[C:6]=2[CH:16]=1.P(Br)(Br)[Br:18].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[Br:18][CH:7]1[C:6]2[CH:16]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][C:10]2=[CH:12][CH:13]=[CH:14][N:9]2[CH2:8]1
Reactant: OC1Cn2cccc2Sc2ccc(F)cc21
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Fc1ccc2c(c1)C(Br)Cn1cccc1S2
Yield: 48 %

Procedure:
To a solution of 24c (0.17 g 0.71 mmol) in dry ethyl ether (3 ml) was added dropwise a solution of phosphorus tribromide (μL 33.5, 0.36 mmol) in dry ethyl ether (0.7 ml); the reaction mixture was refluxed for 2 hours under argon atmosphere. After cooling to room temperature dry ethanol (μL 143) was added and the resulting solution was heated at reflux for 1 hour. Then 4 ml of aqueous sodium carbonate was added; the organic phase was separated, dried and evaporated. The crude product was chromatographed (50% petroleum ether 40-60° in dichloromethane) to give 0.103 g of pure 25c (48% yield). 1H NMR (CDCl3) δ7.35-7.16 (m, 2H); 6.92-6.82 (m, 2H); 6.39-6.37 (m, 1H); 6.13-6.09 (m, 1H); 5.69-5.64 (m, 1H); 5.10-5.01 (dd, 1H, J=14.57, 2.65 Hz); 4.70-4.59 (dd, 1H, J=14.88, 7.05 Hz).
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[S:8][C:9]([CH3:23])=[C:10]([NH:12][C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH:11]=1)=[O:6].Cl>CO.O>[CH3:23][C:9]1[S:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][C:10]=1[NH:12][C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: COC(=O)c1cc(NC(=O)NCc2ccccc2)c(C)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc(C(=O)O)cc1NC(=O)NCc1ccccc1

Procedure:
A 2N aqueous potassium hydroxide solution (16 mL) was added to a stirred solution of 5-methyl-4-(3-benzyl-ureido)-thiophene-2-carboxylic acid methyl ester from Step 2 of Example 16 below (0.4 g, 1.3 mmol) in warm methanol (4 mL), and the mixture was heated under reflux. After 1 hour the mixture was cooled, diluted with water (100 mL), and acidified with aqueous HCl. The precipitate was filtered off, rinsed with water, then ethanol, then ether, and dried to afford 0.29 g of 5-methyl-4-(3-benzyl-ureido)-thiophene-2-carboxylic acid; mp 259-260° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[CH2:16][CH2:17][CH3:18].[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:20]([NH:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][C:11]=2[CH2:16][CH2:17][CH3:18])[CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:42])([F:41])[F:43]
Reactant: CCCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a solution of 5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (206 mg, 0.78 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (300 mg, 0.78 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.68 ml, 3.90 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (400 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-4-(1-methyl-4-propyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (283 mg, 0.46 mmol, 60% yield) as a yellow oil: LCMS (ES) m/e 595 (M+H)+.
Reaction SMILES: [CH:1]([CH:4]([C@@H:14]1[CH2:17][C@H:16]([OH:18])[CH2:15]1)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[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>C1COCC1>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:18][C@H:16]2[CH2:15][C@H:14]([CH:4]([CH:1]([CH3:2])[CH3:3])[C:5]([CH:11]([CH3:12])[CH3:13])([CH:8]([CH3:9])[CH3:10])[O:6][SiH3:7])[CH2:17]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C([C@H]1C[C@@H](O)C1)C(O[SiH3])(C(C)C)C(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C([C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a 100 mL flask with cis-3-(triisopropyl-siloxyethyl)cyclobutanol (0.64 g, 2.3 mmol), 4-nitrobenzoic acid (0.79 g, 4.6 mmol) and Ph3P (1.29 g, 4.83 mmol) inside, dry THF 10 mL was added under argon to give a colorless solution. This was cooled to 0° C. and DIAD (1.0 mL, 4.83 mmol) was added drop by drop. After 15 hr, the volatile materials were evaporated and the crude mixture was purified by silica gel flash chromatography (Hexane: EtOAc=20:1 to Hexane: EtOAc=12:1) to give yellow oil contaminated with some DIAD (0.96 g, 97.4%, Rf=0.48 (Hexane: EtOAc=12:1)). 1H NMR (CDCl3, 400 MHz): δ 1.02-1.07 (m, 21H), 1.74-1.79 (m, 2H), 2.24-2.33 (m, 2H), 2.35-2.42 (m, 2H), 2.48-2.60 (m, 1H), 3.67-3.71 (t, J=6.4, 2H), 5.30-5.38 (m, 1H), 8.19-8.28 (m, 4H). 13C NMR (CDCl3, 100 MHz): δ 12.13, 18.19, 25.97, 34.87, 39.08, 61.95, 70.81, 123.66, 130.85, 136.01, 150.65, 164.39. MS (FAB): expected for C22H35NO5Si (M+H)+ 422.60. Found 422.23608. IR (neat) νmax 2942, 2865, 1725, 1608, 1530, 1463, 1349, 1276, 1103, 882, 720, 681.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[Li+].[OH-]>CN(C=O)C.Cl.O>[F:33][C:30]([F:31])([F:32])[C:27]1[N:26]=[CH:25][C:24]([NH:23][C:20]2[N:19]=[CH:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([CH:8]4[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[CH:22][N:21]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)nc3)cc2)CC1
Temperature: 50 °C

Procedure:
To a glass vial add 6-trifluoromethyl-pyridin-3-ylamine (35 mg, 0.217 mmol), {4-[4-(2-chloro-pyridin-5-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (50 mg, 0.145 mmol), Pd(OAc)2-(5 mg, 5% mol), X-Phos (7 mg, 10% mol), and Cs2CO3 (118 mg, 0.363 mmol). Flush with N2. Add tBuOH (0.25 mL), toluene (0.75 mL), and seal the tube. The reaction mixture is heated to 150° C. for 30 min by microwave irradiation. The reaction is diluted with EtOAc and filtered. The filtrate is concentrated and chromatographed on silica gel (25-50% EtOAc/Hexanes) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester as 90% pure. (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid methyl ester (45 mg, 0.096 mmol) is taken up in DMF (1.5 mL) and 4 M LiOH (0.5 mL) and stirred at room temperature for 16 h. The reaction is heated to 50° C. for 12 h and then heated to 70° C. for 8 h. The reaction is diluted with 1 N HCl (2 mL) and H2O (2 mL). The precipitate is collected by filtration and purified by HPLC (Xterra C8 30×100 mm, 22-50% ACN/H2O+5 mM NH4OH) to afford (4-{4-[2-(6-Trifluoromethyl-pyridin-3-ylamino)-pyrimidin-5-yl]-phenyl}-cyclohexyl)-acetic acid as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.18 (m, 2H) 1.43-1.56 (m, J=12.95, 12.66, 12.66, 3.16 Hz, 2H) 1.68-1.87 (m, 6H) 2.08 (d, J=6.57 Hz, 2H) 7.35 (d, J=8.34 Hz, 2H) 7.65 (d, J=8.34 Hz, 2H) 7.85 (d, J=8.59 Hz, 1H) 8.55 (dd, J=8.59, 2.02 Hz, 1H) 8.91 (s, 2H) 9.06 (d, J=2.27 Hz, 1H) 10.42 (s, 1H); (M+H)+457.0.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.[F-].[Cs+].N>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: N
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccsc2)cc1
Temperature: 25 °C

Procedure:
2-Benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone prepared in Example 78 (150 mg, 0.4 mmol), thiophene-3-boronic acid (66.5 mg, 0.52 mmol), CsF (145.8 mg, 0.96 mmol), and tetrakis-(triphenylphosphine)-palladium(0) (13.9 mg, 0.012 mmol) in DME (25 mL) were stirred at reflux for 6 hours TLC (1CH2Cl2:1 hexanes:1.5 ethyl acetate) indicated that all starting materials were consumed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column (0.5:2.5:0.5 CH2Cl2/hexanes/ethyl acetate). A yellow powder was obtained (yield: 50 mg, 31%). 1H NMR (300 MHz, CDCl3) δ 3.09 (s, 3H), 5.41 (s, 2H), 6.72 (dd, J=1.5 Hz, 9 Hz, 1H), 7.13 (dd, J=3 Hz, 3 Hz, 1H), 7.3-7.45 (m, 5H), 7.5-7.6 (m, 3H), 7.78 (s, 1H), 7.92 (d, 9 Hz, 2H). MS (DCI/NH3) m/z 423 (M+H)+. Anal. calc. for C22H18N2O3S2. 0.5 H2O: C, 6.23; H, 4.43; N, 6.49. Found C, 61.29; H, 4.40; N, 6.16.
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[N:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[CH3:39])=[C:29]=[S:30]>O1CCCC1>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([NH:28][C:29]([NH:26][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:16]3[N:17]=[CH:18][N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:2]([F:1])([F:27])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=4)[N:15]=3)=[CH:20][CH:21]=2)=[S:30])=[C:32]([CH3:39])[CH:33]=1
Reactant: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reactant: COc1ccc(N=C=S)c(C)c1
Solvent: C1CCOC1
Product: COc1ccc(NC(=S)NCc2ccc(-c3ncn(-c4ccc(OC(F)(F)C(F)(F)F)cc4)n3)cc2)c(C)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
To a solution of (4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)methanamine (0.075 mg, 0.20 mmol) in dry tetrahydrofuran (1 mL) was added 1-isothiocyanato-4-methoxy-2-methylbenzene (0.052 mg, 0.29 mmol) and the resulting mixture was stirred at 50° C. for 24 hours. The mixture was concentrated under reduced pressure to give a brown residue, which was purified by flash column chromatography eluting with mixtures of hexanes and ethyl acetate to afford the title compound as a white solid (0.050 g, 46%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([NH2:30])[N:29]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([NH2:30])[N:29]=1)=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(N)cs3)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(-c3nc(N)cs3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
Tert-butyl[6-(4-amino-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.14 g, 0.5 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 3-(aminomethyl)-6-(4-amino-1,3-thiazol-2yl)-2-isobutyl-4-phenyl-1(2H)-isoquinolinone dihydrochloride (0.13 g, 92.9%) as crystals.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[N:6][OH:7])[CH2:4][CH3:5].[Cl:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:10]=1[C:11](O)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(OCC)C>[Cl:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:10]=1[C:11]([O:7][N:6]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:12]
Reactant: CCC(CC)=NO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Product: CCC(CC)=NOC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.9 g of 3-pentanone oxime is added at room temperature to a suspension of 3.0 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoic acid in 50 ml of diethyl ether. Thereafter, a solution of 1.9 g of dicyclohexylcarbodiimide and 0.1 g of 4-pyrrolidinopyridine in 15 ml of diethyl ether is added dropwise over 10 minutes. The reaction mixture is stirred at room temperature for 12 hours. Subsequently, it is filtered and evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica gel with n-hexane/diethyl ether (4:1) as the eluent. In this manner there is obtained 3-pentanone O-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoyl}oxime, m.p. 128°-130° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([C@@H:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH:31]C(=O)OC(C)(C)C)[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].Cl>C(Cl)Cl.CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[C:12]([C:15]1[N:19]3[CH:20]=[C:21]([C@@H:24]([N:26]4[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]4)[CH3:25])[CH:22]=[CH:23][C:18]3=[N:17][N:16]=1)[CH:11]=[CH:10]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@@H](c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.2 %

Procedure:
To a solution of tert-butyl (S)-1-((S)-1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.203 g, 0.39 mmol) in DCM (1 mL) was added 4 N HCl (1.97 mL, 7.89 mmol) in IPA. The mixture was stirred at ambient temperature for 1 hour. The solvent was removed under reduced pressure and ether (5 mL) was added. The suspension was stirred at ambient temperature for 10 minutes and the solid formed was collected by filtration to give (S)-1-((S)-1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl) pyrrolidin-3-amine (0.204 g, 98.7%) as solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][CH:21]([CH3:42])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][C:26]=1[CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:23]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:39]2[CH2:40][CH2:41][CH:36]([C:26]3[CH:27]=[C:28]([O:31][C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:30][C:25]=3[NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:42])[CH2:37][CH2:38]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Product: CC(C)C(=O)Nc1ccc(OC(F)(F)F)cc1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Prepared by Procedure G and Scheme AI using 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[2-(4-piperidinyl)-4-(trifluoromethoxy)phenyl]propanamide: ESMS m/e: 574.8 (M+H)+.