Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=1)=[CH:6]2.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN(C=O)C>CS(C)=O>[N:28]1([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=2)[NH:8][C:7]([C:15]2[S:16][CH2:17][C@@H:18]([CH2:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=2)=[CH:6]3)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CCl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)OC[C@@H]1CSC(c2cc3cc(CN4CCOCC4)cc([N+](=O)[O-])c3[nH]2)=N1

Procedure:
2,2-Dimethyl-propionic acid [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]methyl ester prepared in Preparation 41 and morpholine were reacted according to the same procedure as Preparation 92 except that DMF was used as the solvent instead of DMSO to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:25])[O:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]([NH:23][CH3:24])=[O:22])[CH2:12]1>N1C=CC=CC=1>[CH3:24][N:23]([S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:21](=[O:22])[O:20][C:17]1[C:18]2[O:19][C:11]([CH3:10])([CH3:25])[CH2:12][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(SCl)cc1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: c1ccncc1
Product: Cc1ccc(SN(C)C(=O)Oc2cccc3c2OC(C)(C)C3)cc1

Procedure:
A solution of 8.75 g of 4-methylbenzenesulfenyl chloride in 25 ml of pyridine was added to a solution of 10.9 g of carbofuran in 25 ml of pyridine. A precipitate formed immediately. The reaction mixture was processed as described in Example I to give a residue which could not be distilled even at 0.005 mm. Passage through a falling film still at 140° at 0.01 mm, then at 168° at 0.01 mm gave a liquid which crystallized on standing to a solid, m.p. 62°. Recrystallization several times from petroleum ether gave 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (methyl)(4-methylphenylthio)carbamate, m.p. 65°.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:15][C:12]1[CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([NH2:14])=[N:10][CH:11]=1
Reactant: BrBr
Reactant: Nc1ncccc1Oc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Phenoxypyridin-2-amine (20.50 g, 110.1 mmol) was placed in acetic acid (50 mL) and cooled to 0° C. Bromine (d 3.12) (7.049 mL, 137.6 mmol) was slowly added and the reaction mixture was stirred for 1 hour. The reaction mixture was poured onto saturated sodium bisulfite and ice and allowed to sit overnight. Solids were removed by filtration and washed with water to give pure 5-bromo-3-phenoxypyridin-2-amine. The filtrate was then extracted with CH2Cl2 several times, combined, and washed with water. Organic layer was dried, filtered, and concentrated. The residue was purified by silica gel (5-20% EtOAc in hexanes) to give additional 5-bromo-3-phenoxypyridin-2-amine (total yield: 22.69 g, 77.74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[C:13]([CH2:25][OH:26])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:27]([CH3:29])[CH3:28])[N:12]=[C:13]2[CH2:25][OH:26])=[CH:17][CH:18]=1
Reactant: CC(C)c1nc(CO)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CO)n(Cc2ccc(N)cc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 77.5 %

Procedure:
In ethyl acetate was dissolved 800 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(p-nitrobenzyl)-1H-imidazole (103a), and platinum sulfided carbon was added. After replacement with hydrogen atmosphere, the mixture was catalytically hydrogenated under atmospheric pressure at room temperature. After 1 hour, the mixture was filtered through Celite, the filtrate was distilled off under reduced pressure, and to the residue, diethyl ether was added. The precipitated crystals were filtered, and 579 mg of 1-(p-aminobenzyl)-5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1H-imidazole (104a) was obtained (yield 78%). mp 130° C. (decomp.).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]4[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=4[F:33])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([CH3:35])[CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][C:38]=1[CH3:46].C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]Cl>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:3]=[C:4]([CH3:35])[C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]5[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=5[F:33])(=[O:21])=[O:20])=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]3=[O:34])=[CH:6][C:7]=2[F:8])=[CH:39][C:38]=1[CH3:46]
Reactant: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Cc1cc(B(O)O)ccc1Cl
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2cc(C)c(-n3c(=O)ccc4cc(S(=O)(=O)Oc5c(F)c(F)c(F)c(F)c5F)ccc43)cc2F)ccc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-5-fluoro-2-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.20 g, 2.075 mmol), (4-chloro-3-methylphenyl)boronic acid (1.061 g, 6.23 mmol), copper(i) chloride (0.616 g, 6.23 mmol), cesium carbonate (2.70 g, 8.30 mmol), and bis(di-tert-butyl(4-ethylaminophenyl)phosphine)-dichloropalladium(ii) (0.036 g, 0.05 mmol). The flask was flushed with Ar (g), then Dioxane (10.38 ml) was added. The reaction was heated to 50° C. and stirred for one hour. The reaction was diluted with ethyl acetate and washed three times with water containing excess n-(2-hydroxyethyl)ethylenediaminetriacetic acid, trisodium salt hydrate. The organic layer was washed with water, washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 120 g, gradient elution 0-30% EtOAc:Heptane) to afford perfluorophenyl 1-(4′-chloro-2-fluoro-3′,5-dimethyl-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.01 g, 1.619 mmol, 78% yield) as an off-white solid. m/z (ESI) 624.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([I:21])[C:10]3=[O:22])=[C:5]2[NH:4][N:3]=1.[C:23](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:6]2=[CH:7][CH:8]=[C:9]3[C:14]([O:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([I:21])[C:10]3=[O:22])=[C:5]2[N:4]([CH3:23])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1c(Cl)n[nH]c12
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc(Cl)c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.3 %

Procedure:
To a stirred ice-cooled solution of 3-chloro-7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (42 mg, 0.10 mmol) in DMF (2 mL), was added cesium carbonate (65 mg, 0.2 mmol). After 5 min, iodomethane (0.0185 mL, 0.3 mmol) was added. After a further 5 min, the reaction mixture was allowed to warm to RT. After a further 15 min, the resulting mixture was partitioned between EtOAc and water. The resulting biphasic mixture was separated, the organic phase was further extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30 to 50% EtOAc in cyclohexane) to afford the title compound as a white solid (25 mg, 58%), LCMS (Method H): RT=4.19 min, [M+H]+=437/439.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:44])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:39])[CH:22](Br)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[CH2:16][C:15]2[CH:40]=[CH:41][CH:42]=[CH:43][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][SH:52])=[CH:49][CH:48]=1>>[CH3:1][NH:2][C:3](=[O:44])[CH:4]([N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:39])[CH:22]([S:52][CH2:51][C:50]2[CH:53]=[CH:54][C:47]([O:46][CH3:45])=[CH:48][CH:49]=2)[CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])[CH2:16][C:15]2[CH:40]=[CH:41][CH:42]=[CH:43][C:14]=2[CH2:13]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(Br)CCCCN2C(=O)c3ccccc3C2=O)C1=O
Reactant: COc1ccc(CS)cc1
Product: CNC(=O)C(Cc1ccccc1)N1Cc2ccccc2CC(NC(=O)C(CCCCN2C(=O)c3ccccc3C2=O)SCc2ccc(OC)cc2)C1=O

Procedure:
Prepare by the method of Example 3.2 using 2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionic acid, N-methyl amide and p-methoxybenzylmercaptan to give the title compound.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:25]([NH2:27])=[N:24][CH:23]=[N:22][C:21]=3[N:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)=[CH:14][C:13]=1[O:33][CH3:34].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:27][C:25]1[C:26]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[C:13]([O:33][CH3:34])[CH:14]=3)=[CH:19][N:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C=NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)NCc1ccccc1
Reaction time: 24 h

Procedure:
Benzylisocyanate (24 uL, 0.194 mmol) in dichloromethane (1 mL) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.155 mmol) in N,N-diisopropylethylamine (153 uL, 0.881 mmol) and methylene chloride (2 mL) under nitrogen. The resulting mixture was stirred for 24 hours. The solvent was evaporated and the solid was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give N-(4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)-N′-benzylurea. 1H NMR (CDCl3) δ 1.78 (m, 2H), 1.90 (m, 4H), 2.26 (m, 2H), 3.86 (s, 3H), 4.48 (d, J=6 Hz, 3H), 5.24 (m, 4H), 6.93 (s, 1H), 6.98 (s, 1H), 7.00 (s, 1H), 7.04 (d, J=8 Hz, 1H), 7.29 (m, 5H), 8.17 (d, J=8 Hz, 1H), 8.31 (s, 1H); LC/MS (MH+=457).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:33]=[C:32]([N+:34]([O-])=O)[CH:31]=[CH:30][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:34][C:32]1[CH:31]=[CH:30][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH2:21][CH2:20]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:33]=1
Reactant: [H][H]
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 9 h
Yield: 104 %

Procedure:
After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(2-dimethylaminoethyl)piperazine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (94 mg) under a nitrogen atmosphere, 10% palladium-carbon (46 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 9 hours. The atmosphere in the reaction vessel was then replaced with nitrogen, and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of 4-(2-dimethylaminoethyl)piperazine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (91 mg) as a pale yellow amorphous substance.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[NH2:23]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methoxy-5-trifluoromethylaniline (55 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (27 mg, 34%). 1H NMR (CDCl3): 9.65-9.64 (m, 1H), 8.75-8.70 (m, 2H), 7.46-7.41 (m, 2H), 7.36 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 3.91 (s, 3H).
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[C:48]([CH3:49])=[CH:47][C:42]([C:43]([O:45]C)=[O:44])=[CH:41][C:40]=4[CH3:50])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O1CCOCC1>[F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[C:40]([CH3:50])=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:47][C:48]=4[CH3:49])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C
Yield: 75.4 %

Procedure:
To a stirred solution of methyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (Step A, 82 mg, 0.118 mmol) in dioxane (2.4 mL) was added an aqueous solution of lithium hydroxide (1.2 mL, 0.5 M). The mixture was heated at 60° C. for one hour. The reaction mixture was cooled and acidified by the addition of TFA (0.090 mL, 1.17 mmol). Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC reverse phase (C-18) to give 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoic acid (60.7 mg, 0.089 mmol) as a white solid following lyophilization. LCMS (M+H)+: 684.1. 1H NMR (500 MHz, CD3OD): δ 8.19 (s, 1H), 8.03 (s, 1H), 7.80 (s, 2H), 7.50 (m, 3H), 7.40 (m, 1H), 5.80 (d, 1H, J=8.4 Hz), 5.49 (br s, 0.5H), 5.42 (br s, 0.5H), 4.64 (d, 1H, J=16.9 Hz), 4.50 (m, 2H), 4.40 (m, 1H), 4.24 (m, 2H), 4.14 (d, 1H, J=16.9 Hz), 4.02 (s, 3H) 2.17 (s, 3H), 2.16 (s, 3H), 0.76 (d, 3H, J=6.6 Hz). RTA IC50: 15 nM.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[CH3:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[ClH:23]>>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:14])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16](=[O:21])[CH2:17][C:18]([Cl:23])([CH3:20])[CH3:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reactant: Cl
Solvent: O
Product: CC(C)(Cl)CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2

Procedure:
A solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-methyl-2-buten-1-one (Example 12) (2.0 g, 6.2 mmol) in HCl-saturated Et2O (30 mL) is stirred at 25° C. overnight. The solution is treated with H2O (20 mL), and partitioned against CH2Cl2 (3×20 mL). The combined organic layers are dried (MgSO4), filtered, and evaporated to a cream-colored solid which is crystallized from hexane to give 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-chloro-3-methylbutan-1-one.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([O:16][CH3:17])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH2:18]([O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([O:25][C:26]1[C:31]([C:2]2[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([O:16][CH3:17])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OB(c2cccnc2OCc2ccccc2)OC1(C)C
Reactant: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 100.7 %

Procedure:
step 2—A sealed tube containing 60 (70 mg), 2-benzoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (145 mg), Na2CO3 (62 g) and Pd(PPh3)4 (27 mg) in a mixture of MeOH (4 mL) and DCM (1 mL) was irradiated in a microwave synthesizer at 115° C. for 30 min. The organic volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 40% EtOAc/hexanes to afford 95 mg of 2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-N-methyl-benzamide (62) as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:30])[CH3:29])[CH2:24]2)=[C:19]([F:31])[CH:18]=1>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:29])[CH3:30])[CH2:24]3)=[C:19]([F:31])[CH:18]=2)=[O:12])=[C:8]([CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)O)c(C)c1
Reactant: CN(C)C1CCN(c2ccc(N)cc2F)C1
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(N(C)C)C3)c(F)c2)c(C)c1

Procedure:
4-Butoxy-2-methylbenzoic acid was reacted with [1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]dimethylamine by method P. The product with the molecular weight of 413.54 (C24H32FN3O2) was obtained in this way; MS (ESI): 414 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]1.[H-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:31][CH2:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1
Reactant: OCC1CCOCC1
Reactant: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(Cl)cnc1N(CC(C)C)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
N-(5-chloro-3-methylpyridin-2-yl)-4-fluoro-N-isobutylbenzenesulfonamide (200.5 mg, 0.562 mmol) was dissolved in dimethyl sulfoxide DMSO (2 mL) and to this solution was added (tetrahydro-2H-pyran-4-yl)methanol (98 mg, 0.84 mmol) and sodium hydride (33 mg, 0.84 mmol, 60% wt in mineral oil). The reaction was left to stir overnight at room temperature, under nitrogen. The reaction was concentrated under a stream of nitrogen, then the crude product was extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit and concentrated in vacuo to give the title compound (224 mg). LCMS (2 min, formic) Rt 1.42 min, m/z (ES+) 453 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:8]([O:10]C)=[O:9])[NH:5][C:6]=1[Br:7].CC(C)([O-])C.[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:8]([OH:10])=[O:9])[NH:5][C:6]=1[Br:7]
Reactant: COC(=O)c1[nH]c(Br)c(Br)c1OC(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1c(C(=O)O)[nH]c(Br)c1Br

Procedure:
Methyl 4,5-dibromo-3-(1-methylethoxy)-1H-pyrrole-2-carboxylate (1.5 g, 0.004 moles) is stirred under nitrogen in DMSO (100 mL) at room temperature. Potassium tert-butoxide (2.5 g, 0.022 moles) is added. After 12 hours the mixture is stirred into water (600 mL) and extracted with ether twice. The ether extracts are discarded, and the aqueous phase is acidified with H3PO4, then extracted with CH2Cl2 (3x). The combined extracts are washed with brine and dried over MgSO4. Removal of the solvent under reduced pressure left the product as a clear oil (1.4 g), sufficiently pure for further use.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([CH:20]4[CH2:23][CH2:22][CH2:21]4)=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:26](I)[CH3:27].O>CN(C)C=O>[CH2:26]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18]([CH:20]1[CH2:23][CH2:22][CH2:21]1)=[O:19])[CH3:27]
Reactant: CCI
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)C4CCC4)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)C1CCC1)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]cyclobutanecarboxamide and 0.36 g of sodium hydride (50% in oil) in 200 ml of dry dimethylformamide, under argon, was stirred for 1 hour, then 0.6 ml of ethyl iodide was added. This mixture was stirred overnight, then poured into 200 ml of water and extracted with dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with dichloromethane:methanol (97:3). The fractions containing product were combined and evaporated, giving 0.81 g of the desired compound as yellow crystals, mp 157°-159° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[C:16]([O:20][C:21]([NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([NH:23][CH:24]1[CH2:28][CH2:27][N:26]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:25]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)C2CCN(c3ccncc3)CC2)C1
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 3-(tert-butoxycarbonylamino)pyrrolidine to give 3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]pyrrolidine in 41% yield.