Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:17][OH:18]
Reactant: [H][H]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1CO
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1CO
Reaction time: 22 h
Yield: 98.9 %

Procedure:
Palladium on carbon (10 wt. %, 10 mg) was added to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (110 mg, 0.41 mmol) in MeOH (3.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 22 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 110 mg (99%) of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:15]=[O:16])=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Br)c(C(F)(F)F)c1
Reaction time: 18 h
Yield: 86 %

Procedure:
A suspension of 4-bromo-3-(trifluoromethyl)aniline HCl salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichloromethyl chloroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with CH2Cl2 (500 mL), then concentrated under reduced pressure. The CH2Cl2 treatment/concentration protocol was repeated and resulting amber oil was stored at −20° C. for 16 h, to afford 4-bromo-3-(trifluoromethyl)phenyl isocyanate as a tan solid (35.1 g, 86%): GC-MS m/z 265 (M+).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].N1C=CN=C1.[Si:60](Cl)([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.2 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (3.01 g) in dry methyl ene chloride (70 ml) was added an excess of imidazole (809 mg) followed by tert-butyldimethylsilyl chloride (716 mg). After 3 days of stirring at room temperature, the mixture was diluted with ethyl acetate which in turn was washed with 1N HCl, saturated sodium bicarbonate and brine, dried over magnesium sulfate and purified by flash chromatography (ethyl acetae:hexane (1:3)) to give the title compound (941 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)=[O:17])[CH3:14].[Cl:30][CH:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:13]([O:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Cl:30])=[O:28])=[CH:21][CH:20]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)Oc1ccc(/C=C/C(=O)O)cc1
Reactant: CCCCCC(O)Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(/C=C/C(=O)OCCCCCCCl)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 73.4 %

Procedure:
69.2 g (343 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added to a solution of 95.4 g (343 mmol) of (2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoic acid, 4.27 g (34.3 mmol) of 4-dimethylaminopyridine in 1.5 L of dichloromethane at 0° C. To this mixture, 46.7 mL (343 mmol) of chlorohexanol in 100 mL of dichloromethane are incorporated at 10° C. The solution is allowed to stir at room temperature for 22 hours. The reaction mixture is then partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation. Chromatography of the residue using toluene yielded 89.3 g (72%) of pure 6-chlorohexyl(2E)-3-{4-[(ethoxycarbonyl)oxy]phenyl}prop-2-enoate as a white powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].Cl[CH2:12][CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].CC1(C)CCCC(C)(C)N1>C(#N)C>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:2]([CH2:12][CH2:13][CH:14]([OH:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:1]
Reactant: CNCc1ccccc1F
Reactant: OC(CCCl)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: CN(CCC(O)c1ccccc1)Cc1ccccc1F
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A mixture of N-methyl-o-fluorobenzylamine (27.8 g), 3-chloro-1-phenylpropan-1-ol(34.2 g), 2,2,6,6-tetramethylpiperidine (34.4 ml) and acetonitrile (500 ml) was refluxed for 48h. The mixture was cooled to room temperature, filtered and the solvent removed. The residue was partitioned between chloroform and aqueous sodium bicarbonate. The organic phase was dried and the solvent removed. The residue was dissolved in 60°-80° petrol (150 ml) and allowed to crystallise yielding the title compound (32.4 g) which is cyclodehydrohalogenated as in Example 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:18][N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:7][C:6]1[O:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:23]1[N:19]([CH3:18])[N:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(Br)c(C)o1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A solution of methyl 4-bromo-5-methyl-2-furancarboxylate (2.1 g, 9.59 mmol), potassium carbonate (6.63 g, 47.9 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) [prepared according to Preparation 7] and bis(tri-t-butylphosphine)palladium(0) (0.24 g, 0.48 mmol) in 1,4-dioxane (40 ml) and water (8 ml) was stirred at 80° C. in a sealed tube for 1 h. 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.19 g, 10.55 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.245 g, 0.48 mmol) were added and the reaction stirred an additional 1 h and was partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-40% EtOAc in hexanes) affording methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (1.7 g, 7.72 mmol, 81% yield) as a yellow oil: LCMS (ES) m/e 221 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:14][C:15]1[CH:20]=[C:19]([S:21](C)=O)[CH:18]=[CH:17][C:16]=1[NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28]>>[Cl:14][C:15]1[CH:20]=[C:19]([SH:21])[CH:18]=[CH:17][C:16]=1[NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:28])[F:29]
Reactant: CS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@@](O)(C(=O)Nc1ccc(S)cc1Cl)C(F)(F)F
Yield: 103.6 %

Procedure:
Trifluoroacetic anhydride (5 ml) was added to (R)-N-(2-chloro-4-methylsulphinylphenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 32)(0.188 g). The mixture was stirred and heated under reflux for 45 minutes then cooled and evaporated to dryness. A mixture of triethylamine (5 ml) and methanol (5 ml) was added to the residue. This mixture was stirred for a further 45 minutes then evaporated to dryness. The residue was dissolved in chloroform (50 ml), washed with saturated aqueous ammonium chloride solution (50 ml), dried and concentrated by evaporation to give the title compound (0.177 g) as a gum which was used without purification. MS 298 (M−H)−.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:37][C:38]1[C:46]([O:47][C@@H:48]2[CH2:53][CH2:52][CH2:51][C@H:50]([NH2:54])[CH2:49]2)=[CH:45][CH:44]=[C:43]2[C:39]=1[CH:40]=[N:41][NH:42]2>CN(C)C=O>[CH3:3][CH:2]([CH3:4])[C:1]([NH:54][C@H:50]1[CH2:51][CH2:52][CH2:53][C@@H:48]([O:47][C:46]2[C:38]([CH3:37])=[C:39]3[C:43](=[CH:44][CH:45]=2)[NH:42][N:41]=[CH:40]3)[CH2:49]1)=[O:5]
Reactant: CC(C)C(=O)O
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(O[C@@H]2CCC[C@H](NC(=O)C(C)C)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
Isobutyric acid (36.2 μL, 0.39 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (74.8 mg, 0.39 mmol), hydroxybenzotriazole (52.8 mg, 0.39 mmol) and triethylamine (0.18 ml, 1.28 mmol) were added to a solution of monohydrochloride (100 mg, 0.35 mmol) of the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine obtained in Example 411 in N,N-dimethylformamide (5 ml), and the resulting mixture was stirred overnight at room temperature. The reaction solution was partitioned by the addition of ethyl acetate, toluene and water, and then extracted twice with ethyl acetate-toluene (1/1). The extract solution was washed with a saturated aqueous sodium hydrogencarbonate solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=1/1 to 0/1) to obtain 2-methyl-N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}propanamide (86.3 mg, 77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:40][O:41][C:42]1[CH:61]=[CH:60][C:45]([C:46](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:44][CH:43]=1.CO>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][O:37][C:46]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]3[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:61][CH:60]=3)[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](CO)O2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Yield: 71.9 %

Procedure:
Compound 6 (0.62 g, 1.24 mmol) in dry pyridine (25 mL) was treated with 4-monomethoxytrityl chloride (0.46 g, 1.49 mmol) at room temperature for 16 h. After addition of methanol (5 mL), the mixture was concentrated to dryness. The residue was dissolved in dichloromethane (60 mL) and washed successively with water (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and water (3×40 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to give 7 (0.71 g, 72%) as a foam: 1H NMR (DMSO-d6): δ 2.21 (d, 1H, H-2′ J2′,2″=14.3 Hz), 2.6-2.7 (m, 1H, H-2″), 3.1-3.3 (2m, 2H, H-5′ and H-5″), 3.64 and 3.65 (2s, 6H, 2×OCH3), 4.1-4.2 (m, 1H, H-4′), 4.2-4.3 (m, 1H, H-3′), 5.68 (d, 1H, OH-3′, JH,OH=5.2 Hz), 6.24 (d, 1H, H-1′, J1′,2″=7.0 Hz), 6.7-6.8 and 7.1-7.3 (2m, 29H, 2 MMTr and NH-6) 7.83 and 8.21 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 796 [M+H]+, 408 [BH2]+, (FAB−) m/z 794 [M−H]−, 406 [B]−; UV (95% ethanol): λmax 275 nm (ε 30900), λmin 246 nm (ε 12800); [α]D20=+14 (c 1.03, DMSO).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[Cl:36][C:37]1[CH:50]=[CH:49][C:40]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:48][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[CH:49]=[CH:50][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (AMR01030, 417 mg, 1.82 mmol) in dry DCM (8 mL) was stirred under nitrogen, and 4-dimethylaminopyridine (DMPA, 40 mg, 0.327 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.05 g, 5.46 mmol) and triethylamine (0.25 mL) were added. The resulting mixture was stirred for 30 min under nitrogen and 2-(4-chloro-phenoxy)-phenylamine (AMR01029, 400 mg, 1.82 mmol) in dry DCM (4 mL) was added. After stirring at room temperature for 24 h, the mixture was diluted with DCM, washed with HCl 1M (3×25 mL), water, saturated NaHCO3 (2×25 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane/EtOAc 8:2 as eluent gave starting material (104 mg). Further elution using hexane/EtOAc 7:3 gave 4-[2-(4-chlorophenoxy)-phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (430 mg, 55%) as a white solid, mp 97-99° C. Rf: 0.22 (hexane/EtOAc 7:3) LC/MS (APCI) tr=3.83 min, m/z 431.23 (33), 429.21 (M−−H, 100). 1H NMR (270 MHz, CDCl3) δ 1.44 (9H, s, 3CH3), 1.68 (2H, m, CH2), 1.83 (2H, m, CH2), 2.36 (1H, tt, J=11.4, 3.7 Hz), 2.75 (4H, br t, 2CH2), 4.11 (4H, m, 2CH2), 6.81 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (2H, AA′BB′, ArH), 7.01 (1H, td, ArH), 7.12 (1H, td, ArH), 7.31 (2H, AA′BB′, ArH), 7.68 (1H, br s, NH) and 8.40 (1H, dd, J=6.9, 1.5 Hz, ArH).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.O.[NH2:18]N>C(O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:18]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Reaction time: 5 h
Yield: 100.9 %

Procedure:
2.5 g (11 mmol) of (2E)-3-(dimethylamino)-1-(3-nitrophenyl)prop-2-en-1-one were dissolved in 25 ml of ethanol and 2.3 ml of hydrazine hydrate 98% (46 mmol) were added. The resulting solution was refluxed under stirring for 5 hours. The solvent was then evaporated and the crude was dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and the solvent removed in vacuo. The residue was then triturated with diisopropylether and collected by filtration, giving 2.1 g of the title compound (98%).
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][C:21]1[C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[S:24][CH:25]=1>>[CH3:18][C:13]1([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15][B:11]([C:25]2[S:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[C:21]=2[CH3:20])[O:12]1
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Reactant: Cc1csc2ccccc12
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)sc2ccccc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 3-methyl-benzo[b]thiophene.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[O:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]1[C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(N(CC)CC)C>C1COCC1>[NH2:33][C:17]1[N:18]=[CH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:29][CH2:28]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:15]2[C:10]([N:9]=1)=[N:11][CH:12]=[CH:13][CH:14]=2
Reactant: COCC(=O)Cl
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
2-methoxyacetyl chloride (0.023 ml) was added in one portion to a stirred solution of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and triethylamine (0.069 ml) in THF (40 ml). The resulting mixture was stirred at 23° C. for 2 hours and concentrated to dryness. The product was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness and the resulting solid was triturated overnight with acetonitrile, filtered and dried under vacuum at 50° C. overnight to afford 1-[4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]-1-piperidyl]-2-methoxy-ethanone (80 mg) as a solid. Mass spectrum: M+H+ 434; RT 2.23 min
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:13][CH:14](C(OCC)=O)[C:15]([O:17]CC)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1>C(O)(=O)C.Cl>[CH3:1][C:2]1[O:3][C:4]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: CCOC(=O)C(Cc1oc(C)nc1-c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2)c(CCC(=O)O)o1
Reaction time: 3 h

Procedure:
Diethyl 2-(2-methyl-4-phenyl-5-oxazolylmethyl)malonate (8.0 g) was dissolved in a mixture of acetic acid (50 ml) and 6N hydrochloric acid (20 ml) and the solution was refluxed with stirring for 3 hours. The solvent was then distilled off and the residue was made alkaline with 2N sodium hydroxide and washed with ethyl ether. The alkaline solution was adjusted to pH 2 with concentrated hydrochloric acid to give 2-methyl-4-phenyloxazole-5-propionic acid as crystals, yield 4.85 g (overall yield from the 5-bromomethyl compound=57.5%). Recrystallization from ethanol gave colorless prisms, yield 3.40 g (overall yield from the bromomethyl compound=40.3%), m.p. 156°-157° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>O1CCOCC1>[OH:30][C@:26]([C:23]1[CH:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:3]=[CH:4][C:5]2[O:15][CH2:14][CH2:13][C:12]3[S:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:9][C:8]=3[C:6]=2[CH:7]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: COC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Solvent: C1COCCO1
Product: COC(=O)c1nc2c(s1)CCOc1ccc(C#C[C@@](C)(O)c3cc(C)on3)cc1-2

Procedure:
Methyl 9-bromo-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (0.2 g) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure F but substituting CuI for ZnBr and Dioxane as the solvent to afford 70 mg of methyl 9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate following reverse phase hplc purification. MS (Q1) 411.2 (M)+. Methyl 9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxylate (70 mg) was saponified with LiOH in THF/water followed by similar to as described in Example 2 to afford 39.7 mg of 9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydro-[1]benzoxepino[5,4-d]thiazole-2-carboxamide following reverse phase hplc purification. MS (Q1) 396 (M)+. 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=2.1 Hz, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.31 (dd, J=8.3, 2.2 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.46 (s, 1H), 6.36 (s, 1H), 4.35 (t, J=4.9 Hz, 2H), 3.41 (t, J=4.9 Hz, 2H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: CC([O-])(C)C.[K+].[Br-].[C:8]([O:12][C:13]([C:15]1C=CC=CC=1[P+](C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][C:43]=1[N+:44]([O-:46])=[O:45])[CH:39]=O>O1CCCC1>[C:8]([O:12][C:13](=[O:14])/[CH:15]=[CH:39]/[C:38]1[CH:41]=[CH:42][C:43]([N+:44]([O-:46])=[O:45])=[C:36]([F:35])[CH:37]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1ccccc1[P+](C)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Potassium tert-butylate (0.438 g, 3.9 mmol) was added to a suspension of tert-butoxy carbonyl methyl triphenyl phosphonium bromide (1.61 g, 3.9 mmol; CAS Reg. No. 35000-37-4) in tetrahydrofuran (10 ml). The suspension was stirred for 15 min at ambient temperature. 3-Fluoro-4-nitrobenzaldehyde (600 mg, 3.5 mmol; CAS Reg. No. 160538-51-2) was added, the mixture was stirred for 1.5 h at ambient temperature, poured onto water and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. The solid was filtered off and the filtrate was concentrated under reduced pressure to give a brown oil which was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:methyl tert-butyl ether (100:0 to 80:20 v/v) to afford the title compound as a brown oil (812 mg, 3.04 mmol; 86%).