Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([OH:9])=[C:4](I)[N:3]=1.C(N(CC)CC)C.[C:18]([C:20]12[CH2:27][CH2:26][CH2:25][N:24]1[CH2:23][CH2:22][CH2:21]2)#[CH:19].Cl>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]2[CH:19]=[C:18]([C:20]34[CH2:27][CH2:26][CH2:25][N:24]3[CH2:23][CH2:22][CH2:21]4)[O:9][C:5]2=[CH:6][C:7]=1[Cl:8]
Reactant: C#CC12CCCN1CCC2
Reactant: Oc1cc(Cl)c(Cl)nc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1cc2oc(C34CCCN3CCC4)cc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
2,3-Dichloro-6-iodo-5-pyridinol (163 mg, 0.56 mmol) from example 25a, copper(I) iodide (20 mg, 0.10 mmol), bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.030 mmol) and triethylamine (176 mL, 0.67 mmol) were combined and allowed to stir for 1 hour at ambient temperature. 7a-ethynyl-hexahydro-1H-pyrrolizine (91 mg, 0.67 mmol) in DMF (1.0 mL) was added to the reaction mixture which was then heated to 60° C. for 18 hours. After cooling to ambient temperature, 2 N aqueous HCl was added and the mixture was washed with Et2O (2×), basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 phases were combined, dried (MgSO4), concentrated and the residue was chromatographed (silica gel; EtOAc/hexane, 1:3) to afford a white solid (116 mg, 70%): 1H NMR (CDCl3, 300 MHz) δ 1.83-1.97 (m, 6H), 2.20-2.31 (m, 2H), 2.67-2.77 (m, 2H), 3.18-3.25 (m, 2H), 6.71 (s, 1H), 7.78 (s, 1H); MS (CI/NH3) m/z: 297 (M+H)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[C:12]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:13]2[O:19][CH2:18][O:17][C:14]2=[N:15][CH:16]=1.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].CN(C=O)C>C(OCC)(=O)C>[Cl:10][C:11]1[C:12]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([C:44](=[O:45])[CH2:43][N:42]([CH3:47])[CH3:41])[CH2:37][CH2:36]4)=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)=[C:13]2[O:19][CH2:18][O:17][C:14]2=[N:15][CH:16]=1
Reactant: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCNCC1
Reactant: CN(C)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Nc3c(Cl)cnc4c3OCO4)ncnc2cc1OCC1CCN(C(=O)CN(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
Diisopropylethylamine (0.118 ml) was added to a mixture of 4-(5-chloro-2,3-methylenedioxypyrid-4-ylamino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (0.15 g), N,N-dimethylglycine (0.042 g), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.154 g) and DMF (3 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic solution was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 100:3 mixture of methylene chloride and a 7M methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.051 g); NMR Spectrum: (DMSOd6) 1.11-1.36 (m, 2H), 1.83 (d, 2H), 2.11 (m, 1H), 2.19 (s, 6H), 2.61 (t, 1H), 3.03 (m, 2H), 3.12 (d, 1H), 3.93 (s, 3H), 4.06 (m, 3H), 4.4 (d, 1H), 6.19 (br s, 2H), 7.19 (brs, 1H), 7.78 (m, 2H), 8.39 (br s, 1H), 9.71 (br s, 1H); Mass Spectrum: M+H+ 529 and 531.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[NH:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22](O)=[O:23])[C:16]=2[CH:15]=[N:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:17]3[C:16]4[CH:15]=[N:14][NH:13][C:21]=4[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc2[nH]ncc12
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc2[nH]ncc12

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1H-indazole-4-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.42-7.52 (m, 1H), 7.58-7.64 (m, 1H), 7.72 (d, J=8.5 Hz, 1H), 8.33 (s, 1H). MS (DCI/NH3) m/z 297.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][N:6]=[CH:5][C:4]=1[CH2:11][CH3:12].[SH:13][C:14]1[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([C:21](F)(F)F)[N:15]=1.C(N(CC)CC)C.CCOCC>C(O)C>[CH2:11]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([CH2:9][CH3:10])[C:3]=1[CH2:2][S:13][C:14]1[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)[CH3:12].[CH2:9]([C:8]1[CH:7]=[N:6][CH:5]=[CH:4][C:3]=1[CH2:2][S:13][C:14]1[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)[CH3:10]
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: CCc1cncc(CC)c1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOCC
Product: CCc1cncc(CC)c1CSc1nc(C)cc(O)n1
Product: CCc1cnccc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of crude 4-(bromomethyl)-3,5-diethylpyridine and 2-sulfanyl-6-(trifluromethyl)pyrimidin-4-ol (0.838 g, 5.89 mmol) in anhydrous ethanol (50 mL) at 0° C. was added triethylamine (3.21 g, 4.42 mL, 31.75 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated to provide a crude residue. Ether was added to precipitate the triethylamine hydrobromide salt. The solid was filtered and washed with ether several times. The combined ether layers were evaporated, and the crude residue was purified by Combiflash using 0-10% MeOH in dichloromethane to provide 2-{[(3,5-diethylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol and 2-{[(3-ethylpyridin-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid; 1H NMR (400 MHz, DMSO-d6): δ 1.19 (t, 6H), 2.64 (q, 4H), 4.55 (s, 2H), 6.70 (s, 1H), 8.30 (s, 2H); M+1 344.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:22]([C:19]2([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH2:21][CH2:20]2)=[O:23])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCOC(=O)C1CCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Yield: 167.5 %

Procedure:
A solution of piperidine-3-carboxylic acid ethyl ester (10.0 g, 0.032 mol), 1-(4-chloro-phenyl)-cyclopropylcarboxylic acid (9.57 g, 0.049 mol), diisopropylethyl amine (21.0 g, 0.16 mol) in dichloromethane (160 mL) was stirred at room temperature. PyBroP (22.6 g, 0.49 mol) was added and the reaction mixture continued stirring at room temperature. After 12 h the reaction mixture was quenched with 10% KOH. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to yield a crude oil. The crude material was purified using silica gel chromatography (80:20 hexane:ethyl acetate) to yield the amide (18.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Mg].Cl[P:14]([C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH3:33])=[C:27]([CH3:34])[CH:26]=1)[C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[C:17]([CH3:24])[CH:16]=1.[OH:35]O>C1COCC1.II.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([P:14](=[O:35])([C:25]2[CH:30]=[C:29]([CH3:31])[C:28]([O:32][CH3:33])=[C:27]([CH3:34])[CH:26]=2)[C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[C:17]([CH3:24])[CH:16]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: OO
Reactant: COc1c(C)cc(P(Cl)c2cc(C)c(OC)c(C)c2)cc1C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)cc(P(=O)(c2cc(C)c(OC)c(C)c2)c2cc(C)c(OC)c(C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Bromo-3,5-dimethoxybenzene (10 g, 46.1 mmol) in THF (60 ml) was added to a flask (250 ml) with magnesium (1.2 g, 49.9 mmol) and I2 (20 mg) in THF (40 ml) at 60° C. The mixture was refluxed for 2 h after the addition was completed. It was cooled to RT. The resulting light brown solution was transferred to another flask (250 ml). It was cooled to −78° C. and chlorobis(4-methoxy-3,5-dimethylphenyl)phosphine (16.8 g, 49.9 mmol) in THF (40 ml) was added dropwise at −78° C. within 1 h. The resulting mixture was stirred at −78° C. for 0.5 h, then slowly warmed up to RT and stirred at RT for 30 min. To the resulting mixture water (50 ml) was added, then H2O2 (13 ml) was added dropwise at 0° C. The mixture was stirred for 0.5 h at RT. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml×2) and CH2Cl2 (100 ml×1). The combined organic layer was washed with brine (200 ml×2), NaHSO3 (200 ml×3) and dried over MgSO4. It was filtered and the solvent was removed. The viscous residues were stirred with CH2Cl2/hexane (5 ml/100 ml) for 1 h. The solid was collected by filtration to give the product as a colorless solid (17.4 g, 83 yield). 1H NMR (300 MHz, CD2Cl2) δ: 7.32 (s, 2H), 7.28 (s, 2H), 6.76 (dd, J=2.4 Hz, J=12.9 Hz, 2H), 6.61 (t, J=2.4 Hz, 1H), 3.78 (s, 6H), 3.75 (s, 6H), 2.28 (s, 12H). 31P NMR (121.5 MHz, CD2Cl2) δ: 28.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1
Reactant: COC(=O)c1cn2c(n1)COc1ccc(Cl)cc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(n1)COc1ccc(Cl)cc1-2
Yield: 97 %

Procedure:
The methyl 8-chloro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate prepared in Example 1 was suspended in 50 ml of ethanol and a solution of 1.15 g (29 mmol) of sodium hydroxide in 50 ml of water was added thereto. The mixture obtained was then heated on a steam bath until a clear solution was obtained and thin layer chromatography indicated no starting ester remaining. The solution was filtered and the filtrate was acidified while still hot to a pH of 2-3 with concentrated hydrochloric acid. On cooling, the acid crystallized out and was collected, was washed with water and dried over P2O5 under vacuum to obtain 3.20 g (97% yield) of 8-chloro-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylic acid in the form of colorless needles with a melting point of 276°-278° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:20](=[O:21])[CH2:19][CH2:18][Cl:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)CCCl)cc1
Temperature: 10 °C
Yield: 66.1 %

Procedure:
A three-necked flask was charged with p-Anisidine (50 g), Et3N (40.43 g) and methyl ethyl ketone (100 ml). The resulting slurry was cooled to 10° C. and 3-chloropropionyl chloride (50.74 g) was slowly added. The temperature was allowed to rise to 60° C. during the addition. The mixture was then refluxed for 1 hour and cooled to 50° C. The solids were collected by filtration, washed with water, and dried at 50° C. to constant weight to give N-(4-methoxyphenyl)-3-chloropropionamide (56.42 g, 86.8%).
Reaction SMILES: [Li].[CH2:2](Cl)[C:3]([CH3:6])([CH3:5])[CH3:4].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](F)[C:10]=1[C:16]1[O:17][CH2:18][C:19](C)(C)[N:20]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:4][C:3]([CH3:6])([CH3:5])[CH2:2][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[C:10]=1[C:16]([NH:20][CH2:19][CH3:18])=[O:17]
Reactant: CC1(C)COC(c2c(F)cccc2F)=N1
Reactant: CC(C)(C)CCl
Agent: O=C([O-])O
Agent: [Li]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)c1c(F)cccc1CC(C)(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
A solution of p,p'-di-t-butyl biphenyl (5.559 g, 0.021 mol) and THF (100 mL) was stirred at 0° C. under an atmosphere of argon. Lithium wire (0.021 mol, 0.15 g) was added in small pieces and the mixture was allowed to stir at 0° C. for 24 h. The mixture was cooled to -78° C. and neopentyl chloride (2.0 g, 0.01875 mol) was added dropwise. The mixture was stirred at -78° C. for 1 h, and the compound of Example g (3.17 g, 0.015 mol) was added all at once. The mixture was continuously stirred for 4 h and 50 mL sat aq NaHCO3 was added. This mixture was extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed twice with water, dried (MgSO4), and concentrated. The crude concentrate was purified by HPLC eluting with 1:4 ethyl acetate/hexanes. The oxazoline was as a clear oil in 27% yield.
Reaction SMILES: [C:1]([CH:4]([CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:5][OH:6])([CH3:3])=[CH2:2].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:6][CH2:5][CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(C)C(CO)CC=C(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(CC=C(C)C)COS(C)(=O)=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
2-Isopropenyl-5-methyl-4-hexen-1-ol (154.25 g, 1.00 mol), toluene (775.6 g) and triethylamine (122.5 g, 1.21 mol) were charged in a four-neck flask (inner volume 2 L) equipped with a thermometer, a stirrer and a dropping funnel, and the mixture was cooled to 5° C. Then, methanesulfonyl chloride (137.5 g, 1.20 mol) was added dropwise to this mixture over 30 min. After the completion of the dropwise addition, the reaction mixture was further stirred at 25° C. for 1 hr. Water (462.4 g) was added to the obtained reaction mixture, the mixture was stirred for 15 min, and the organic layer was separated. The obtained organic layer was washed with 5 mass % aqueous solution of sodium hydrogencarbonate (488.0 g) and water (464.1 g) and concentrated to give 2-isopropenyl-5-methyl-4-hexen-1-yl methanesulfonate (237.73 g, 0.972 mol, yield 97.2%, purity 95%). The result of 1H-NMR measurement of 2-isopropenyl-5-methyl-4-hexen-1-yl methanesulfonate is shown below. The present compound is a novel substance.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:11]=1[NH2:12].C(O)(=O)C>C(#N)C>[Br:1][C:15]1[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[C:11]([NH2:12])=[C:10]([Cl:9])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1c(Cl)cccc1C(F)(F)F
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1c(Cl)cc(Br)cc1C(F)(F)F

Procedure:
N-bromosuccinimide (910 mg, 5.1 mmol) was added to a solution of 2-chloro-6-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) and acetic acid (3 mL) in acetonitrile (10 mL) at room temperature. The mixture was stirred at reflux for 18 h. The reaction mixture was then filtered through Celite and concentrated to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]([CH3:14])([OH:13])[C:4]#[C:5][Si](CC)(CC)CC.[C:15](=[O:18])([O-])[O-].[K+].[K+].C(=O)([O-])[O-].Br[C:26]1[CH:27]=[CH:28][C:29]2[O:35][CH2:34][CH2:33][N:32]3[C:36]([CH2:42][N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[C:37]([C:39]([NH2:41])=[O:40])[N:38]=[C:31]3[C:30]=2[CH:49]=1>CO>[F:1][CH2:2][C:3]([OH:13])([CH3:14])[C:4]#[C:5][C:26]1[CH:27]=[CH:28][C:29]2[O:35][CH2:34][CH2:33][N:32]3[C:36]([CH2:42][N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[C:37]([C:39]([NH2:41])=[O:40])[N:38]=[C:31]3[C:30]=2[CH:49]=1.[OH:13][C:3]([CH3:14])([CH2:2][O:18][CH3:15])[C:4]#[C:5][C:26]1[CH:27]=[CH:28][C:29]2[O:35][CH2:34][CH2:33][N:32]3[C:36]([CH2:42][N:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[C:37]([C:39]([NH2:41])=[O:40])[N:38]=[C:31]3[C:30]=2[CH:49]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1nc2n(c1CN1CCOCC1)CCOc1ccc(Br)cc1-2
Reactant: CC[Si](C#CC(C)(O)CF)(CC)CC
Agent: [K+]
Solvent: CO
Product: CC(O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CCOCC3)n1CCO2)CF
Product: COCC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CCOCC3)n1CCO2

Procedure:
Fluoro-2-methyl-4-triethylsilyl-but-3-yn-2-ol (80 mg) was stirred for 24 hrs at room temperature with potassium carbonate (3 eq) in Methanol (1 mL) after which the carbonate was filtered and the resulting methanol was dried down to a viscous oil. This intermediate 1-fluoro-2-methyl-but-3-yn-2-ol was reacted (in accordance with a procedure described in Procedure E) with 10-bromo-3-(morpholinomethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (30 mg) to afford 1.9 mg of (±) 10-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)-3-(morpholinomethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide [MS (Q1) 429 (M)+] and 6.4 mg of (±) 10-(3-hydroxy-4-methoxy-3-methyl-but-1-ynyl)-3-(morpholinomethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide [MS (Q1) 441 (M)+]. 1H NMR (400 MHz, DMSO) δ 8.49 (d, J=2.1 Hz, 1H), 7.56 (s, 1H), 7.29 (dd, J=8.5, 2.2 Hz, 1H), 7.10 (s, 1H), 7.02 (d, J=8.5 Hz, 1H), 5.53 (s, 1H), 4.54-4.42 (m, 5H), 3.98 (s, 2H), 3.57-3.48 (m, 6H), 3.37 (s, 4H), 2.41-2.37 (m, 4H), 1.43 (s, 4H)] following reverse phase purification.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+].COCCOC>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.O>[N:22]1([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N3CCCC3)nc2)CC1

Procedure:
A stirred solution of 1-(6-Bromo-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (0.71 g, 2.0 mmol), pyrrolidine (2.0 g, 20 mmol), potassium tert-butoxide (0.45 g, 4.0 mmol), tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) and 1.2-dimethoxyethane was stirred at reflux overnight. Water (40 ml) was added and the mixture was extracted twice with ethyl acetate (20 ml) Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. Yield 0.21 g, 30%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]([O:15][CH3:16])=[O:14])[C:11](=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.O.[OH-].[Na+].O=P(Cl)(Cl)[Cl:30]>>[Cl:30][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)C1C(=O)ON=C1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)noc1Cl
Temperature: 2.5 °C
Yield: 57 %

Procedure:
A suspension of methyl 3-(4-chlorophenyl)-5-oxo-4,5-dihydroisoxazole-4-carboxylate (518 mg, 2.04 mmol; building block is commercially available) in POCl3 (3 mL) was cooled to 0-5° C., and upon stirring, Et3N (0.3 mL) was added dropwise. The resulting mixture was heated to 100-110° C. and stirred at this temperature for 2-2.5 h, cooled to room temperature, poured into iced water and neutralized with aqueous NaOH (10%). The product was extracted with ether and purified by column chromatography (hexane:EtOAc 25:2) to give 320 mg of a yellow solid. Yield 57%. 1H NMR (DMSO-D6, CCl4): 3.79 (3H, s, OCH3), 7.50 (2H, AB-syst., CH-arom.), 7.65 (2H, AB-syst., CH-arom.).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:14].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C:3]=1[CH3:14]
Reactant: CCCCC(=O)Cl
Reactant: Cc1ccc2oc(C(=O)O)cc2c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1cc2oc(C(=O)O)cc2c(C)c1C
Temperature: 5 °C
Reaction time: 48 h

Procedure:
A stirred suspension of 4,5-dimethylbenzofuran-2-carboxylic acid (18 g.) and valeryl chloride (15 g.) in methylene chloride (300 ml.) is cooled to 5°C. and treated with aluminum chloride (40 g.) in portions during a 1/2 hour period during which time the suspended reactant dissolves. The reaction mixture is stirred at 25° for 2 days then poured into ice water (500 ml.) containing hydrochloric acid (50 ml.). The product (21 g.) separates from the biphasic solution, is filtered and recrystallized from ethanol-water affording 4,5-dimethyl-6-valerylbenzofuran-2-carboxylic acid which melts at 188°-9°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]#[N:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:11][C:12]#[N:13]
Reactant: N#CCBr
Reactant: Oc1cc(F)ccc1F
Product: N#CCOc1cc(F)ccc1F

Procedure:
Analogously to Method F, 2.0 g of 2,5-difluorophenol and 2.1 ml of bromoacetonitrile are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.52 (1:2 EtOAc-heptane); Rt=3.86.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][NH:10][CH:11]=1.C(N(CC)CC)C.[C:20](Cl)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:12])/[CH:5]=[CH:6]/[C:7]1[N:8]=[CH:9][N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:11]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)/C=C/c1c[nH]cn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-imidazoleacrylic acid methyl ester hydrochloride (20.0 g, 106 mmol) and triethylamine (44 ml, 318 mmol) in chloroform (500 ml) was added a solution of trityl chloride (29.5 g, 318 mmol) in chloroform (100 ml). The resulting suspension was stirred at room temperature for 24 h. The reaction mixture was then washed with water and dried over MgSO4. Filtration and removal of the solvent in vacuo to gave the title compound as a tan solid: 1H NMR (CDCl3) d 3.75 (s, 3 H), 6.54 (d, J=16 Hz, 1 H) 7.03 (s, 1 H), 7.13-7.34 (m, 15 H) 7.46 (s, 1 H), 7.51 (d, J=16 Hz 1 H).