Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[CH:4]([CH3:13])[CH:3]1[CH3:14].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C1(C)C=CC=CC=1>O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[C:4]([CH3:13])=[C:3]1[CH3:14]
Reactant: CC1c2cc(C=O)ccc2N(C)C1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1c(C)n(C)c2ccc(C=O)cc12
Yield: 12.1 %

Procedure:
1,2,3-Trimethylindoline (21.5 g) was formulated in a similar manner to that described in Step 2 of Example 1 to obtain 20.1 g of 1,2,3-trimethylindoline-5-carbaldehyde. The obtained aldehyde (7.5 g) was dissolved in 200 ml of 1,4-dioxane, followed by the addition of 18 g of DDQ. The obtained mixture was heated under reflux for 2.5 hours, followed by the addition of 100 ml of toluene. Insolubles were filtered out and the organic phase was concentrated in a vacuum. The obtained residue was purified by flash column chromatography to give 900 mg of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:10][C:9]3[CH:12]=[CH:13][C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[CH:7][CH:8]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(-n4cncn4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(1H-1,2,4-triazol-1-yl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 404.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[O:12]1[CH2:13][CH2:14][CH:10]([O:9][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11]1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1CCOC1
Product: Brc1ccc(OC2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and 3-hydroxytetrahydrofuran by the method of Example 10 (b). 1H NMR (DMSO-D6) 2.0 (m, 1H), 2.2 (m, 1H), 3.8 (m, 4H), 5.4 (m, 1H), 6.8 (d, 1H), 7.8 (m, 1H), 8.2 (m, 1H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([CH3:34])=[C:22]([C:27]2[CH:31]=[CH:30][S:29][C:28]=2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[CH3:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[NH2:33][CH2:32][C:28]1[S:29][CH:30]=[CH:31][C:27]=1[C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:21]=1[CH3:34]
Reactant: Cc1ccc(-c2ccsc2C#N)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cl
Product: Cc1ccc(-c2ccsc2CN)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
A mixture of 3-(3-tert-butyldiphenylsilyloxymethyl-2,4-dimethylphenyl)-2-cyanothiophene (471 mg) and 1M borane-tetrahydrofuran complex (3 ml) was stirred for 30 minutes at 0° C. under nitrogen atmosphere and allowed to stand at ambient temperature overnight. To the mixture was added 4N hydrochloric acid (1.5 ml) under ice-cooling, and the mixture was stirred for 1 hour. The mixture was partitioned between ethyl acetate and water, and the separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol =50:1, V/V) to give 2-aminomethyl-3-(3-tert-butyldiphenylsilyloxymethyl-2,4-dimethylphenyl)thiophene (415 mg) as oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O>CN(C)C=O>[CH2:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCc1ccc2ncnc(N)c2c1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1ncnc2ccc(CC)cc12)C(=O)OCC
Temperature: 110 °C
Reaction time: 3 h
Yield: 66.7 %

Procedure:
A mixture of 4-amino-6-ethylquinazoline (6.35 g) and diethyl ethoxymethylenepropanedioate (9.52 g) in N,N-dimethylformamide (25 ml) was stirred for 3 hours at 110° C. and then cooled to ambient temperature. A small volume of water was added to the resultant mixture to precipitate crystals, which were separated by filtration and washed with water. The crystals were dissolved in chloroform, washed with an aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crystalline residue, which was recrystallized from a mixture of ethyl acetate and hexane to give crystalline diethyl [(6-ethyl-4-quinazolinylamino)methylene]propanedioate (8.40 g). Further, crystals (2.75 g) of the same compound were recovered from the mother liquor in the same manner as mentioned above.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>O1CCCC1>[N+:1]([C:21]1[CH:20]=[CH:19][C:18]([OH:23])=[C:17]([O:16][C:15]([F:14])([F:25])[F:24])[CH:22]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1OC(F)(F)F
Agent: [Bi+3]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(O)c(OC(F)(F)F)c1
Temperature: 50 °C
Yield: 31 %

Procedure:
3.0 g (7.5 mmol) of anh. bismuth nitrate was added to a solution of 891 mg (5.0 mmol) of 2-trifluoromethoxyphenol in 20 mL of tetrahydrofuran (redistilled) under argon atmosphere with stirring. The mixture was slowly heated to 50° C. and allowed to react at this temperature for 10 min. The reaction was stopped, cooled, filtered under reduced pressure and the filter cake was washed with 20 mL of tetrahydrofuran. The filtrate was concentrated, and 40 mL of water and 45 mL of ethyl acetate were added. The organic layer was isolated, and the water layer was extracted with 40 mL×2 of ethyl acetate. The organic layers were combined, successively washed with 110 mL of water and 110 mL of saturated saline, dried over anh. MgSO4, filtered and concentrated. The residue was purified by silica column chromatography (mobile phase: petroleum ether: ethyl acetate=15:1) to obtain 346 mg of a yellow oil. Yield 31.4%.
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([C:44](=[O:54])[CH2:45][NH:46]C(=O)OC(C)(C)C)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].FC(F)(F)C(O)=O>ClCCl>[NH2:46][CH2:45][C:44]([N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1)=[O:54]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CNC(=O)OC(C)(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CN)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
The resulting tert-butyl 2-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)-2-oxoethylcarbamate was dissolved in dichloromethane (2 mL), and stirred at room temperature for 1.5 hours after adding trifluoroacetic acid (0.256 mL, 3.33 mmol). The aqueous layer was extracted with chloroform after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 85/15) to give compound 61 (60.5 mg, 55.3%).
Reaction SMILES: [CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([NH2:20])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3].[C:25](Cl)(Cl)=[O:26].C1(C)C=CC=CC=1>O1CCOCC1>[CH2:1]([N:4]([CH3:24])[C:5](=[O:23])[C:6]1[C:18]([I:19])=[C:17]([N:20]=[C:25]=[O:26])[C:16]([I:21])=[C:8]([C:9]([N:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])=[O:10])[C:7]=1[I:22])[CH:2]=[CH2:3]
Reactant: C=CCN(C)C(=O)c1c(I)c(N)c(I)c(C(=O)N(C)CC=C)c1I
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: C=CCN(C)C(=O)c1c(I)c(N=C=O)c(I)c(C(=O)N(C)CC=C)c1I
Temperature: 60 °C

Procedure:
To a solution of N,N′-diallyl-5-amino-2,4,6-triiodo-N,N′-dimethyl-isophthalamide (5 g, 7.5 mmol) in 1,4-dioxane (10 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (35 mL, 70 mmol) at ambient temperature, the solution was heated at 60° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (50 mL×2) was added and removed slowly at reduced pressure to give an off white, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:15]=1[CH2:16][NH:17][O:18][CH3:19]>>[Cl:13][C:14]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:15]=1[CH2:16][N:17]([O:18][CH3:19])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(F)cc1Cl
Product: CON(Cc1ccc(F)cc1Cl)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-chloro-4-fluoro-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 127-128° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.70 (3H, s, OCH3), 4.95 (2H, s, NCH2), 6.41 (1H, s, CH), 6.96 (1H, m, aromatic), 7.13 (1H, dd, J=2.5 Hz and J=8.7 Hz, aromatic), 7.38 (1H, dd, J=6.1 Hz and J=8.6 Hz, aromatic). Anal. calcd for C15H15ClFNO5: C, 52.41; H, 4.39; N, 4.07. Found: C, 52.49; H, 4.15; N, 3.76.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:10]([C:3]1[C:2](/[CH:15]=[CH:14]/[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:7]([F:8])[C:6]([Cl:9])=[CH:5][CH:4]=1)(=[O:12])[CH3:11]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(Cl)c(F)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a mixture of Intermediate 12C (50 g, 198 mmol), tert-butyl acrylate (50.9 g, 397 mmol) and TEA (55 mL, 397 mmol) in DMF (500 mL) was added Pd(OAc)2 (8.9 g, 39.7 mmol). The resulting mixture was stirred at 90° C. overnight. The reaction was cooled to rt, filtered, and the filtrate was concentrated. Purification by column chromatography gave Intermediate 12D (30 g, 51%) as a light yellow solid. MS (ESI) m/z: 242.7 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C@H:12]([C:24]([O:26][CH3:27])=[O:25])[CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C@H:12]([C:24]([O:26][CH3:27])=[O:25])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(C(=O)O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 2 h
Yield: 68.7 %

Procedure:
Prepared using General Procedure 4: To a stirred solution of (S)-methyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (316.6 mg, 0.79 mmol) in dioxane (15 mL) and water (1 mL) at 0° C. was added lithium hydroxide monohydrate (93.52 mg, 2.23 mmol). After 2 h, the solution was neutralized with 1 M HCl to pH 7.0. The mixture was partitioned between DCM (15 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was washed with saturated aqueous NaHCO3 (3×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated to afford 208 mg (69%) of (S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic acid, INT-1. LCMS-ESI (m/z) calculated for C22H25NO5: 383.2. found 384.1 [M+H]+, tR=2.13 min. (Method 1). 1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 8.80 (d, J=8.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.75-7.65 (m, 2H), 7.50-7.35 (m, 4H), 4.72 (ddd, J=10.3, 8.0, 5.1 Hz, 1H), 3.65 (s, 3H), 3.28-3.05 (m, 2H), 1.29 (s, 9H). 13C NMR (101 MHz, DMSO) δ 173.00, 167.21, 166.29, 154.39, 143.10, 130.85, 129.34, 129.27, 129.21, 129.03, 127.21, 125.39, 125.10, 53.75, 52.04, 34.64, 30.92, 30.88.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[C:5]([Mg]Cl)([CH3:8])([CH3:7])[CH3:6].[CH3:11][CH:12]([Mg]Cl)[CH2:13][CH3:14]>C(OCC)C>[CH3:11][CH:12]([P:1]([C:5]([CH3:8])([CH3:7])[CH3:6])[Cl:4])[CH2:13][CH3:14]
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C)[Mg]Cl
Reactant: CCC(C)[Mg]Cl
Solvent: CCOCC
Product: CCC(C)P(Cl)C(C)(C)C
Temperature: -25 °C
Reaction time: 0.75 h

Procedure:
To a solution of phosphorus trichloride (55 g) in dry diethyl ether (200 cm3) stirred and maintained at between -25° C. and -30° C. in an atmosphere of dry nitrogen, a 2 molar solution of tert-butyl magnesium chloride in diethyl ether (200 cm3, solution supplied by Aldrich Chemical Co.) was added during 45 min. After a further 15 min. a 2 molar solution of 2-butyl magnesium chloride (200 cm3, solution supplied by Aldrich Chemical Co.) was added in the same way. The suspension was stirred at -25° C. for a further 45 min., then allowed to reach ambient temperature, and finally boiled under reflux for 30 min., cooled, filtered to remove magnesium chloride, and distilled, yielding 2-butyl-tert-butylchlorophosphine (47 g), b.p. 74° C. under a pressure of 15 mm of mercury.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:13])=[O:14])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)[CH:17]=1)(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)CC(C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ccccc12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.18 g, 0.34 mmol) in dichloromethane (10 mL) and water (0.1 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred for 2 hours at room temperature. The reaction was then concentrated under reduced pressure to yield a colorless oil. The residue was purified by HPLC using a gradient of 10% to 50% acetonitrile containing 0.1% TFA and water at containing 0.1% TFA over 140 minutes to yield 3-[4-carbamoyl-2-(2-naphthalen-1-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid as a lyophilized as a white solid (0.045 g, 28%). MS(APCI) m/z 471.0 (M+1).
Reaction SMILES: N[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[I:12]CI.N(OCCC(C)C)=O>C(OCC)(=O)C>[I:12][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (10.0 g, 64.5 mmol) in diiodomethane (130 mL, 1.61 mol) at −10° C. was added isoamyl nitrite (156.0 mL, 1.16 mol). The mixture was allowed to warm to ambient temperature then heated to 100° C. After 2 h, ethyl acetate was added. The mixture was washed with saturated aqueous Na2SO3, HCl (1N in water) then water. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (9.63 g). MS 267.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:24])([F:23])[F:22])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]([F:22])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[C:16]([NH:20][C:31](=[O:36])[CH2:32][CH2:33][CH2:34][CH3:35])[CH:17]=[CH:18][CH:19]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCCCC(=O)Cl
Reactant: Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 3-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenylamine (0.150 mg, 0.40 mmol) (Example I3) in tetrahydrofuran (4 ml) was added pyridine (0.085 ml, 1.06 mmol). Pentanoyl chloride (0.063 ml, 0.53 mmol) was added under vigorous stirring at ambient temperature. The reaction mixture was stirred for 3 hours at ambient temperature. Aqueous sodium hydrogen carbonate (saturated) and ethyl acetate was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. A6 of Table A (0.165 g, 89% yield). 1H-NMR (400 MHz, CDCl3): 8.00 (s, 1H), 7.70 (s, 1H), 7.53 (d, 1H), 7.49 (s, 2H), 7.42 (m, 2H), 7.35 (m, 1H), 4.09 (d, 1H), 3.72 (d, 1H), 2.40 (t, 2H), 1.70 (m, 2H), 1.40 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [BrH:1].[NH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O.Br.N1CCCC1>C(Cl)(Cl)Cl>[Br-:1].[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=[N+:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Br
Reactant: C1CCNC1
Reactant: O=Cc1ccc[nH]1
Solvent: ClC(Cl)Cl
Product: C(c1ccc[nH]1)=[N+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 81.0 g (1.00 mole) of hydrogen bromide in 1000 ml of absolute chloroform is added dropwise with cooling and stirring a solution of 80.0 g (1.12 mole) of pyrrolidine in 100 ml of absolute chloroform. Then 95.1 g (1.00 mole) of pyrrole-2-carboxaldehyde is added to the above pyrrolidine hydrobromide solution along with 1 pound of Linde Molecular sieve 5A. The reaction mixture is stirred at ambient temperature for 3 hours, then is filtered through filter aid, washing well with chloroform. The combined filtrate and washings are evaporated in vacuo and the residue is recrystallized twice from acetonitrile to give 1-(pyrrol-2-ylmethylene)pyrrolidinium bromide; m.p. 113°-116° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[CH2:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6]1
Reactant: BrCCCC1=CCc2ccccc21
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: C1=C(CCCN2CCCCC2)c2ccccc2C1
Yield: 89 %

Procedure:
3-(3'-Bromopropyl)indene (94.8 g, 0.4 M) and piperidine (76 g, 0.9 M) are dissolved in 400 ml toluene. The mixture is heated under reflux 2 hours. After cooling, a large amount of solid is removed by filtration and washed with ether. The combined filtrate and washes are concentrated in vacuo. The residue is dissolved in ether and filtered to remove a small amount of insoluble material. The ether is removed in vacuo and the product is distilled collecting a fraction of 87.3 g (89% yield) boiling 132°-153°/0.05 mm.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5]C)=[O:4].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:16]=[C:17]([C:22]3[S:26][C:25]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[N:24][CH:23]=3)[CH:18]=[C:19]([CH3:21])[CH:20]=2)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>>[CH3:21][C:19]1[CH:20]=[C:15]([NH:14][C:10]2[N:9]=[C:8]([O:1][CH2:2][C:3]([OH:5])=[O:4])[CH:13]=[CH:12][N:11]=2)[CH:16]=[C:17]([C:22]2[S:26][C:25]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[N:24][CH:23]=2)[CH:18]=1
Reactant: Cc1cc(Nc2nccc(Cl)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Reactant: COC(=O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(OCC(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
Methyl hydroxyacetate (22 mg, 0.24 mmol) and 2-(5-(3-[(4-chloropyrimidin-2-yl)amino]-5-methylphenyl)-1,3-thiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 98, 50 mg, 0.12 mmol) were taken up in N,N′-dimethylacetamide (1.2 mL). Cesium carbonate (118 mg, 0.36 mmol) was added and the mixture was stirred for 24 h at 70° C. The reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate (2×). The combined organics were concentrated under reduced pressure and purified by reverse phase HPLC (10-80% acetonitrile/water+0.05% TFA modifier). Desired fractions were combined and lyophilized to afford {[2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}acetic acid (10 mg, 0.018 mmol, 15%) as the trifluoroacetic acid salt as a white solid. MS ESI: [M+H]+ m/z 455.1.
Reaction SMILES: [C:1](=[NH:5])(OC)[CH3:2].[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:22])=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[NH:9][N:8]=1>C(#N)C.C(O)(=O)C>[Cl:22][C:12]1[CH:11]=[C:10]2[C:15]([C:7]([NH:6][C:1](=[NH:5])[CH3:2])=[N:8][NH:9]2)=[CH:14][C:13]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(C)=N
Reactant: Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=N)Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Reaction time: 0.08 h

Procedure:
33 mg of methyl acetimidate are added to 50 mg of 3-amino-6-chloro-5-phenyl-1H-indazole in 3 ml of acetonitrile and 12 mg of acetic acid. The reaction is placed under microwave radiation at 180° C. for 5 min. After the usual treatments and purification through silica, 35 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)acetamidine are obtained.