Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[CH:17]=[CH:18][CH:19]=1.Cl>>[F:13][C:14]1[CH:15]=[C:16]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH:17]=[CH:18][CH:19]=1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3cccc(F)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(3-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.79 (s, br, 1H), 7.63-6.82 (m, 11H), 5.24-5.15 (m, 1H), 3.70-3.56 (br, 2H), 3.04-2.84 (br, 2H), 2.82-2.60 (m, br, 4H), 2.60-2.42 (m, br, 2H), 2.20-1.83 (m, br, 6H), 1.70-1.44 (m, br, 2H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 589.3 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[C:5]([OH:10])[C:4]=1[CH3:11].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[Cl:2][C:3]1[NH:8][C:7](=[O:9])[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([OH:10])[C:4]=1[CH3:11]
Reactant: Cc1c(O)cc(=O)[nH]c1Cl
Reactant: O=[N+]([O-])O
Agent: Cl
Agent: O=S(=O)(O)O
Product: Cc1c(Cl)[nH]c(=O)c([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6—Chloro-4-hydroxy-5-methyl-1H-pyridin-2-one hydrochloride (64 g) was dissolved in sulfuric acid (325 mL) while cooling in an ice bath. Nitric acid was added dropwise over a period of 90 minutes. The reaction mixture was allowed to stir for an additional 30 minutes and then it was poured into ice water (2 L). The resulting precipitate was isolated by filtration, washed with water and then dried to provide 42.5 g of 6-chloro-4-hydroxy-5-methyl-3-nitro-1H-pyridin-2-one as a light yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][N:17]1[CH2:33][CH2:32][C:20]3([N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][NH:22][C:21]3=[O:31])[CH2:19][CH2:18]1)[CH2:7]2.[BH4-].[Na+]>CO.O>[OH:15][C@@H:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:7][C@H:8]1[CH2:16][N:17]1[CH2:18][CH2:19][C:20]2([N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][NH:22][C:21]2=[O:31])[CH2:32][CH2:33]1
Reactant: COc1cc2c(cc1OC)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-[(2,3-Dihydro-5,6-dimethoxy-1-oxo-1H-inden-2-yl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (20.0 g finely ground) is slurried in methanol (400 ml), cooled in ice, and treated dropwise with an excess of sodium borohydride dissolved in water (75 ml). The resulting mixture is stirred for 16 hours at room temperature. Dilution with water (400 ml), extraction with methylene chloride, and concentration of the dried methylene chloride extracts in vacuo yield the crude product. Crystallization of this material from absolute ethanol yields 13.3 g of isomerically pure title compound, melting point 189°-190° C.
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH3:11][C:12]1(O)[C:17]([Cl:19])([Cl:18])[CH2:16][CH2:15][CH2:14][C:13]1([Cl:21])Cl.[OH-].[Na+]>O>[Cl:21][C:13]12[O:8][CH:14]1[CH2:15][CH2:16][C:17]([Cl:19])([Cl:18])[CH:12]2[CH3:11]
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: CC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 3.97 g (15.75 mmol) of crude alcohol 1j, 20 cm3 of distilled water and 2.4 g (60 mmol) of sodium hydroxide; reaction time was 1 h 15 min; ether extraction (5×40 cm3); 3.29 g of epoxide 2h were obtained having a 95.5% yield based on the ketone (macrobore GC purity>99%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH2:17][C:18]([OH:20])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:6]=1[C:18](=[O:20])[CH2:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]12
Reactant: COc1cc(OC)cc(N2CCCCC2CC(=O)O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(OC)c2c(c1)N1CCCCC1CC2=O

Procedure:
Under a nitrogen atmosphere, a mixture of 12.1 g. (0.043 mole) dl-2-[1-(3,5-dimethoxyphenyl)piperidin-2-yl]acetic acid, 100 ml. glacial acetic acid, 6.0 g. sodium acetate and 100 ml. acetic anhydride was stirred at room temperature overnight. The acetic acid and acetic anhydride were removed by evaporation in vacuo, the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution, and the organic phase washed with sodium bicarbonate, water, brine and dried (MgSO4). The extracts were evaporated to dryness to give 13 g. of a green oil. The oil was purified by chromatography on a column containing 300 g. of silica gel, eluting with ethyl acetate. Product fractions were combined and evaporated to afford 5.5 g. of the desired dl product, M.P. 91°-94° C. 1H-NMR (CDCl3) ppm (delta): 2.50 (m, 2H, CH2CO), 3.79 (s, 3H), 3.81 (s, 3H), 5.90 (m, 2H). After recrystallization from isopropyl ether, 2.6 g. of crystals were obtained, M.P. 92°-93° C.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:40]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:41])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)N2CCOCC2)CC1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
Under a N2 atmosphere, a solution of of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl]-ethyl}-methyl-amine (0.17 g, 0.48 mmole described as intermediate 12 above) and triethylamine (0.15 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. 4-Morpholinecarbonyl chloride (0.06 mL, 0.51 mmole) was added and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated to give a brown residue. Flash chromatography (elution with 7:3 EtOAc-hexane) gave 0.17 g (74% yield) of morpholine-4-carboxylic acid {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydro-4H-pyridin-1-yl]-ethyl}-methyl-amide. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([F:44])=[C:39](B(O)O)[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([F:44])=[C:37]([C:7]2[CH:8]=[C:9]3[C@@:20]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[N:15][CH:16]=[C:17]([CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:18]=4)[O:13][C:10]3=[CH:11][CH:12]=2)[CH:36]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1ncc(C3CCOCC3)cc12
Reactant: OB(O)c1cc(Cl)ccc1F
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: [K+]
Product: NC1=N[C@@]2(CO1)c1cc(-c3cc(Cl)ccc3F)ccc1Oc1ncc(C3CCOCC3)cc12
Reaction time: 1.5 h

Procedure:
A vial was charged with (S)-2′-amino-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (70.0 mg, 0.144 mmol), 5-chloro-2-fluorophenylboronic acid (75 mg, 0.433 mmol), potassium carbonate (100 mg, 0.721 mmol), and Pd(PPh3)4 (8.33 mg, 7.21 μmol). The vial was flushed with Ar (g), then Dioxane (721 μL) and water (0.3 mL) were added in sequence. The vial was sealed and placed in an 80° C. for 1.5 hours. The mixture was diluted with brine (20 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 24-g Redi-Sep Gold column with 0-60% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-7-(5-chloro-2-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4]1)[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:8][CH:5]1[CH2:6][CH2:7][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: CCN1CCC(O)C1
Reactant: Oc1ccccc1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1CCC(Oc2ccccc2Br)C1
Temperature: 25 °C

Procedure:
1-Ethyl-3-pyrrolidinol (0.5 ml), 2-bromophenol (0.37 ml) and triphenylphosphine (1.02 g) were dissolved in tetrahydrofuran (10 ml) and the mixture cooled in an ice bath before dropwise addition of diisopropyl azodicarboxylate (0.77 ml). The mixture was allowed to warm to room temperature over 3 h. The mixture was concentrated in vacuo and partitioned between ether (50 ml) and water (50 ml) and the aqueous phase was extracted further with ether (50 ml). The combined organic phases were washed with water (2×25 ml), brine (2×25 ml), dried (MgSO4) and concentrated in vacuo. The product was dissolved in ethyl acetate (50 ml) and extracted with 2M aqueous hydrochloric acid (3×20 ml). The aqueous washings were combined and basified by the addition of solid sodium hydroxide and extracted with ethyl acetate (3×20 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures. This gave the title compound as a pale orange oil (529 mg).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:20][CH2:19][CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11]1>>[CH2:17]([O:16][C:14]([CH:13]1[CH2:19][CH2:20][N:10]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:11][CH2:12]1)=[O:15])[CH3:18]
Reactant: N#Cc1cccc(F)c1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(c2cccc(C#N)c2)CC1

Procedure:
According to a similar manner to that in Reference Example 17, the title compound was synthesized from 3-fluorobenzonitrile and ethyl isonipecotate.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[C:16]1([CH2:15][CH2:14][CH2:13][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCc1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CCCn2cnc3ccccc32)cc1

Procedure:
To a flask were added 5 g benzimidazole and 75 ml tetrahydrofuran under nitrogen and the solution was cooled to 10 C with stirring. 2.2 g Sodium hydride were added in small portions and the reaction was stirred for 10 minutes. 1-Bromo-3-phenylpropane was added and the reaction mixture was heated to 40 C for 5 hrs. After cooling to 5 C, the reaction was quenched with slow addition of 100 ml water. After the tetrahydrofuran was removed of by rotovap, the mixture was extracted with 100 ml ethyl acetate and washed with 25 ml water and the solvent was removed on the rotovap. The product was purified by column chromatography using 40% ethyl acetate in hexane resulting in a light yellow oil which crystallized in the freezer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].C(=O)([O-])[O-].[Cs+].[Cs+].[N:26]1([C:32]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.COCCOC>O.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>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:37]4[CH:36]=[CH:35][C:34]([C:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:33])=[CH:39][CH:38]=4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Temperature: 85 °C
Yield: 13.3 %

Procedure:
A sealable tube was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 0.200 g, 0.518 mmol), cesium carbonate (0.253 g, 0.777 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.183 g, 0.777 mmol) and DME (2 mL). The mixture was degassed under nitrogen for 10 minutes and Pd(PPh3)4 (0.0299 g, 0.0259 mmol) was added as a solid. The mixture was heated to 85° C. for 18 hours. The crude was diluted with water (300 mL), extracted with EtOAc/MeOH (4:1, 2×300 mL), dried organic over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (2.0 mm thickness) eluting with EtOAc/MeOH (9:1) to give product (31 mg, 12%) as a white solid. LRMS (APCI+) 450 m/z (M+1) detected.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: NCCCCC(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)NCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
5-Aminopentanoic acid hydrochloride (2 g, 13 mmol), and potassium carbonate (13 g, 94 mmol) were dissolved in water (30 ml) and dioxane (10 ml) then cooled to 0° C. Methyl chloroformate (5 ml, 65 mmol) was added over 30 seconds, then the mixture was stirred for 2.5 hours at 0° C. Concentrated HCl was added until the mixture became acidic then the mixture was diluted with water and extracted with ether. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)amino]pentanoic acid as a white powder (1.5 g).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:30])[CH:28]=[CH2:29]>O>[CH2:27]([O:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH:28]=[CH2:29]
Reactant: C=CCO
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of allyl alcohol was stirred while heating at 100° C. for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-allyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 74”).
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C(N(CC)CC)C>C(#N)C>[CH3:13][C:8]1[CH:7]=[C:6]([C:4]2[N:20]=[C:21]([NH2:23])[S:22][C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: Cc1cc(C)cc(C(=O)C(Br)c2ccncc2)c1
Reactant: NC(N)=S
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To a solution of 2-bromo-1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone hydrobromide (5.0 g, 13 mmol) and thiourea (1.0 g, 14 mmol) in acetonitrile (60 mL) was added dropwise triethylamine (1.9 ml, 14 mmol) and the mixture was stirred at room temperature for 3 h. The solvent was concentrated under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and the solvent was evaporated. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (2.0 g, 7.2 mmol, yield 55%).
Reaction SMILES: C1([Se][CH2:8][CH2:9][O:10][C:11](=[O:24])[C@H:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:13][C:14](=[O:16])[CH3:15])C=CC=CC=1.OO>C1COCC1.C(Cl)(Cl)Cl>[CH:9]([O:10][C:11](=[O:24])[C@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH:13][C:14](=[O:16])[CH3:15])=[CH2:8]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)OCC[Se]c1ccccc1
Agent: OO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.6 g (6.66 mmol) of N-acetylphenylalanine 2-(phenylseleno)ethyl ester in 20 ml of THF, 8 ml of a 30% H2O2 solution were added dropwise within 10 minutes at 0° C., and the solution was stirred at 0° C. for another 30 minutes. After stirring the mixture for 12 hours at room temperature, it was diluted with 80 ml of CHCl3 and extracted with 3×50 ml of water. The organic phases were then dried over sodium sulfate, and the solvent was removed. The residue was taken up in 70 ml of chloroform and was refluxed for 24 hours. After cooling, the solvent was removed. Flash column—chromatography (PE:EE=3:1) yielded 1.3 g (84% of th., 93% of lit.) of a light-yellow liquid.
Reaction SMILES: [CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:25](O)=[O:26])=[CH:23][N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:34]1([NH:37][C:25]([C:22]2[S:21][C:20]([NH:19][C:12]3[N:11]=[C:10]4[N:28]([CH2:29][CH3:30])[C:7]([C:5](=[O:6])[N:4]([CH:1]5[CH2:3][CH2:2]5)[CH:31]5[CH2:32][CH2:33]5)=[CH:8][C:9]4=[C:14]4[N:15]([CH3:18])[CH:16]=[N:17][C:13]=34)=[N:24][CH:23]=2)=[O:26])[CH2:36][CH2:35]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)NC4CC4)s3)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a mixture of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A, 13.97 mg, 0.030 mmol) in DMF (300 μL) was added cyclopropylamine (4.16 μL, 0.060 mmol), HATU (14.83 mg, 0.039 mmol), and Hünig's Base (15.72 μL, 0.090 mmol). The reaction mixture was stirred at rt 1 h and concentrated in vacuo: The residue was taken up in MeOH and purified by preparative HPLC. N-Cyclopropyl-2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxamide (3 mg, 19.82% yield) was isolated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@H:35]([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: C[C@@H](N)CO
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2[(M+H)+] 543.2196, observed 543.2201.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([CH2:13][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OCC1CC1

Procedure:
A solution of 3-hydroxy-4-methoxybenzaldehyde (400 g, 2.63 mole) and bromomethylcyclopropane (426 g, 3.2 mole) in 1 L dimethylformamide (DMF) was stirred with potassium carbonate (K2CO3) (483 g, 3.5 mole) at 55° C. for 3.5 h. Then, 1 L of water was added, the mixture chilled on ice, and Intermediate 1 filtered as a white solid, (535 g, 99%). m/z 207 (MH+).