Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.I[CH3:16]>CC(C)=O>[CH3:16][O:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1
Reactant: CI
Reactant: O=c1cc(-c2ccccc2)occ1O
Solvent: CC(C)=O
Product: COc1coc(-c2ccccc2)cc1=O
Temperature: 60 °C
Yield: 93 %

Procedure:
To a solution of crude 5-hydroxy-2-phenyl-4H-pyran-4-one (0.4 mmol) in acetone (10.9 mL) is added iodomethane (0.7 mL, 1 1.3 mmol) and the reaction mixture was heated at 60° C. for 2 h. After being cooled to room temperature, the reaction was concentrated under reduced pressure and diluted with CHCl3 (10 mL) and water (10 mL). The layers were separated and the organic fraction washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide (93%) of 5-methoxy-2-phenyl-4H-pyran-4-one as tan crystals which were used in the subsequent step without further purification. LC/MS (M+H)+ 203.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 85 °C
Yield: 34.6 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-methoxyphenol (21 μL, 0.19 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 85° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-methoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (12 mg, 35%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.91 (d, J=8.4 Hz, 2H), 7.53-7.63 (m, 3H), 6.78-7.07 (m, 3H), 5.14 (s, 2H), 3.25-3.37 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]#[N:24])[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: N#Cc1ccccc1B(O)O
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: COCCOC
Solvent: O
Product: N#Cc1ccccc1-c1cccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c1
Yield: 46.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 2-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.033 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-cyanobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9](=[O:30])[CH2:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:6]([C:31]([N:33]2[CH2:37][CH2:36][CH2:35][C@@H:34]2[C:38]([NH:40][CH2:41][C@H:42]2[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[CH2:43]2)=[O:39])=[O:32])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(Cl)(Cl)Cl>[NH2:1][C@@H:4]1[CH2:8][N:7]([C:9](=[O:30])[CH2:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]([C:31]([N:33]2[CH2:37][CH2:36][CH2:35][C@@H:34]2[C:38]([NH:40][CH2:41][C@H:42]2[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]3)[CH2:43]2)=[O:39])=[O:32])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a solution of 24 mg of (2R)-1-{(2S,4S)-4-azido-1-(3,3,3-triphenyl-propanoyl)pyrrolidin-2-yl}carbonyl-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}pyrrolidine-2-carboxamide in 0.5 ml of 20% hydrous tetrahydrofuran, 13 mg of triphenylphosphine was added at room temperature, followed by 3 hours' refluxing under heating. The reaction liquid was diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=90/10/1) to provide 16 mg of the title compound in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.Cl.[NH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2g; 3.47 mmol) in THF (100 ml) was treated with tert-butyl 3-aminopropanoate hydrochloride (800 mg; 4.4 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:6][CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH3:19][O:20][CH2:21]Cl.O>CN(C=O)C>[CH3:19][O:20][CH2:21][N:12]([C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][CH:6]=1)[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Nc1cccc2c1CCCC2=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(c1cccc2c1CCCC2=O)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 15A (4.0 g, 17 mmol) in anhydrous DMF (40 mL) under a nitrogen atmosphere was treated with a 60% dispersion of sodium hydride (0.74 g, 18 mmol) in portions over 5 minutes, stirred for 45 minutes, cooled to 0° C., treated dropwise with chloromethyl methyl ether (1.3 mL, 18 mmol), stirred at ambient temperature for 2 hours, treated with cold water (250 mL) and extracted with diethyl ether (3×). The combined diethyl ether extracts were washed with water, washed with brine, dried (MgSO4), filtered and concentrated. Purification of the residue on silica gel with 1:1 hexanes:ethyl acetate provided the desired product.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:6][CH3:7])=[O:5].[F:8][C:9]([F:30])([F:29])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25](OC)=[O:26])[CH:13]=[CH:12][CH:11]=1.O>C1(C)C=CC=CC=1>[F:29][C:9]([F:8])([F:30])[C:10]1[N:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2/[C:24](=[CH:25]\[OH:26])/[C:4]([O:6][CH3:7])=[O:5])[CH:13]=[CH:12][CH:11]=1
Reactant: COC=O
Reactant: COC(=O)Cc1ccccc1COc1cccc(C(F)(F)F)n1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)/C(=C/O)c1ccccc1COc1cccc(C(F)(F)F)n1
Reaction time: 6 h
Yield: 94.8 %

Procedure:
Sodium methoxide (0.725 g, 13 mmol) and methyl formate (0.8 ml, 13 mmol) were added portionwise to a stirred solution of methyl 2-(6-trifluoromethylpyrid-2-yloxymethyl)phenylacetate (2.0 g, 6.0 mmol) in dry toluene (15 ml) under a nitrogen atmosphere at room temperature. After 6 hours at room temperature, the mixture was poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the ether removed to give (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (2.01 g, 95%) as a yellow gum which was used in the next stage without further purification; 1H NMR (270 MHz)δ: 3.75(3H,s), 5.34(2H,s), 6.90(1H,d), 7.15-7.75(7H,m), 11.95(1H,d) ppm.
Reaction SMILES: C1(C([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH:28]([OH:49])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:51]1[N:56]=[CH:55][CH:54]=[CH:53][N:52]=1>>[CH:43]1([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH:28]([O:49][C:51]2[N:56]=[CH:55][CH:54]=[CH:53][N:52]=2)[CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][OH:20])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1
Reactant: Clc1ncccn1
Reactant: OC(COCCCCCCCCCCCCC1CCCCC1)COCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: OCCOCCOCC(COCCCCCCCCCCCCC1CCCCC1)Oc1ncccn1
Yield: 83.9 %

Procedure:
The procedure of Reference Example 2 was applied for a reaction of 2-[2-[3-(12-cyclohexyldodecyloxy)-2-hydroxypropoxy]ethoxy]ethyl triphenylmethyl ether (7.69 g) with 2-chloropyrimidine (3.36 g) to yield the desired compound (4.88 g).
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O>C1(C)C=CC=CC=1>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][N:14]1[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]1=[O:8]
Reactant: COC(CN)OC
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(CN1C(=O)C(C)=C(C)C1=O)OC

Procedure:
84 g (0.66 mol) of dimethylmaleic anhydride are dissolved in 150 ml of toluene, and 70 g (0.66 mol) of aminoacetaldehyde dimethyl acetal are added. The solution is heated to the boil, and the water formed is separated off by means of a water separator. When the reaction is complete, the solvent is removed by distillation, and the residue is distilled, giving 127 g (90% of theory) of the product of boiling point 160° C. at 0.03 mbar which is a single product according to TLC and GC. NMR data: 2.97 (s) 6-methyl protons, 3.34 ppm (s) 6 methoxy protons, 3.61 ppm (d) 2 methyl protons, 4.66 ppm (t) 1 acetal proton.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH:4]([Br:28])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc(S(=O)(=O)C2CCOCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(S(=O)(=O)C2CCOCC2)cc1
Yield: 37.1 %

Procedure:
[4-(Tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (1.60 gm, 5.36 mmol), NBS (1.04 g, 5.90 mmol) and benzoyl peroxide (0.130 g, 0.53 mmol) in carbon tetrachloride (50 ml) was refluxed for 7 hrs. Reaction mixture was diluted with DCM (50 ml), washed with water and brine (100 ml each), dried over anhydrous sodium sulfate, fliltered and concentrated. Crude compound was purified by column chromatography over silica gel using 30% ethyl acetate hexane as eluent to give the pure bromo-[4-(tetrahydro-pyran-4-sulfonyl)-phenyl]-acetic acid methyl ester (0.75 gm).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[CH:7][CH:6]=2.[N-:13]=[N+:14]=[N-:15].[Na+]>C(O)C>[CH3:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]1[N:13]=[N:14][N:15]=[C:2]1[CH:3]=[N:4]2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2ncc(Cl)nc12
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2ncc3nnnn3c12
Reaction time: 3 h

Procedure:
The crude 3-chloro-5-methylquinoxaline obtained in the step above was stirred for 3 hours at reflux temperature in 75 ml. of ethanol containing 1.8 g. of sodium azide and 20 ml. of 1N HCL. When the reaction mixture was cooled, the product precipitated as needles. Recrystallization of the product from ethanol produced highly purified 9-methyltetrazolo[1,5-a]quinoxaline, m.p. 166°-68°C. The product was identified by NMR analysis and elemental microanalysis.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[CH3:10][NH:11][C:12]([NH:14][CH3:15])=[O:13].C(OC(=O)C)(=O)C>>[CH3:10][N:11]1[CH2:7][CH:3]([C:2]([F:9])([F:8])[F:1])[C:4](=[O:5])[N:14]([CH3:15])[C:12]1=[O:13]
Reactant: CNC(=O)NC
Reactant: C=C(C(=O)O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CN1CC(C(F)(F)F)C(=O)N(C)C1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (4.31 g; 30.8 mmoles), 1,3-dimethylurea (2.75 g; 31.2 mmoles) and acetic anhydride (17 ml) was heated at 100° C. with stirring for one hour. The solvent was evaporated under reduced pressure, and the residue was purified by a column chromatography on silica gel (CHCl3) to give 5.50 g (yield: 84%) of 1,3-dimethyl-5-trifluoromethyldihydrouracil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (50.00 g, 354.36 mmol) in DMF (450 ml) was added 3-hydroxypyridine (33.70 g, 354.36 mmol) under nitrogen. The reaction mixture was heated to 35° C. and then potassium carbonate (102.85 g, 744.15 mmol) was added in one portion. The reaction was very exothermic, and the temperature rapidly increased to 115° C., then gradually increased to 125° C. The mixture was then cooled to 90° C. and stirred at 90° C. for 2 h. The mixture was cooled to room temperature and poured into 2.5 L of water. The mixture was extracted with ethyl acetate (3×), and the combined organic phases were washed with water (3×) and brine (1×), dried over sodium sulfate, and evaporated at reduced pressure. The brown solid residue was stirred in MTBE at reflux, then filtered, and the filtrate was concentrated at reduced pressure to give a yellow crystalline solid that was triturated with ether to give 23.79 g (31%) of the desired product. The brown solids that did not dissolve in MTBE (43.89 g, 57%) were also of sufficient purity for use in the next step (i.e., total yield 88%). 1H-NMR (DMSO-d6) δ 8.50 (m, 2H), 8.24 (d, J=9.1 Hz, 2H), 7.67 (ddd, J=8.4, 2.9, 1.3 Hz, 1H), 7.52 (dd, J=8.3, 4.7 Hz, 1H), 7.18 (d, J=9.0 Hz, 2H); MS LC-MS [M+H]+=217, RT=1.67 min. In a subsequent experiment, the potassium carbonate was added to the 1-fluoro-4-nitrobenzene in DMF under nitrogen. To this stirred solution was dropwise added a solution of the 3-hydroxypyridine in DMF, and the exotherm caused the mixture to gradually warm up to 38° C. The reaction mixture was then heated to 60° C. for 2 h. Reaction work up as described above gave the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[O:17][CH2:18][C:19]2([N:41]=1)[C:28]1([CH2:31][O:30][CH2:29]1)[CH2:27][O:26][C:25]1[C:20]2=[CH:21][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:24]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:43]1[CH:44]=[N:45][CH:46]=[C:47]([C:49]#[C:50][CH2:51][O:52][CH3:53])[CH:48]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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>[CH3:53][O:52][CH2:51][C:50]#[C:49][C:47]1[CH:48]=[C:43]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[O:26][CH2:27][C:28]2([CH2:31][O:30][CH2:29]2)[C:19]23[CH2:18][O:17][C:16]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[N:41]2)[CH:44]=[N:45][CH:46]=1
Reactant: COCC#Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(B3OC(C)(C)C(C)(C)O3)ccc1OCC21COC1
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: C1COCCO1
Solvent: O
Product: COCC#Cc1cncc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Under argon atmosphere, a mixture of di-tert-butyl[6′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (213 mg, 0.372 mmol), 3-bromo-5-(3-methoxyprop-1-yn-1-yl)pyridine (252 mg, 1.12 mmol), Na2CO3 (158 mg, 1.49 mmol), tetrakis(triphenylphosphine)palladium(0) (21.5 mg, 0.019 mmol), dioxane (3.4 mL) and water (0.85 mL) was stirred for 3 hours at 110° C. The reaction mixture was cooled down to ambient temperature, and water was added to the mixture. The mixture was extracted with MeOH—CHCl3 (1:9), and the organic layer was dried over Na2SO4 prior to filtration. The filtrate was concentrated at reduced pressure to give crude di-tert-butyl {6′-[5-(3-methoxyprop-1-yn-1-yl)pyridin-3-yl]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl}imidodicarbonate, which was used for the next reaction without further purification.
Reaction SMILES: Cl[C@H:2]1[CH2:7][C@@H:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:3]1.[CH:22]1[C:32]2[CH2:31][O:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]=2[CH:25]=[CH:24][CH:23]=1>>[CH3:11][O:10][CH2:9][O:8][C@H:6]1[CH2:5][N:4]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C@@H:2]([CH2:3][N:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:32]=3[CH2:31][O:30][C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]2=3)[CH2:7]1
Reactant: COCO[C@@H]1C[C@H](Cl)CN(CCc2ccc(OC)cc2)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Product: COCO[C@@H]1C[C@H](CN2c3ccccc3COc3ccccc32)N(CCc2ccc(OC)cc2)C1

Procedure:
(3S, 5R)-(+)-3-chloro-5-(methoxymethoxy)-1-(4-methoxyphenethyl)piperidine was coupled with 5,11-dihydrodibenzo[b,e][1,4]oxazepine as described in Example 1 to give (+)-5,11-dihydro-5-[[(2R, 4R)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidin-2-yl]methyl]dibenzo[b,e][1,4]oxazepine in 4.30 g (72.6%) yield as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C([O-])O
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-propionic acid (1.98 g, 10.0 =ol) in methanol (25 mL) was added 0.5 mL of conc. sulfuric acid. The resulting solution was stirred at room temperature under argon for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate, the methanol was removed via rotary evaporator and the residue was dissolved in 50 mL of ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate (3×50 nL) and brine (50 -mL), dried over sodium sulfate and the solvent was removed in vacuo to give Methyl 3-(4-fluorobenzoyl)-propionate (2 g, 94%). IR (film) 3448, 3111, 3076, 3003, 3958, 1734, 1678, 1601, 1423, 1300, 1240, 1155, 1099 cm−1; 1H-NMR (CDCl3) δ 7.97 (2H, dd, J=9.0, 5.5 Hz), 7.10 (2H, t, J=8.9 Hz), 3.67 (3H, s), 3.25 (2H, t, J=6.6 Hz), 2.73 (2H, t, J=6.6 Hz); 13C-NMR (CDCl3) δ 196.50, 173.34, 167.54, 164.17, 132.98, 130.77, 115.91, 115.62, 51.91, 33.31, 28.00.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:18])[CH3:17])[CH:13]=[CH:14][CH:15]=1.[H-].[Na+].O>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:18][CH:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH3:17])[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(O)c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1cncc(Cl)n1)c1cccc(F)c1
Yield: 108.8 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and 1-(3-fluorophenyl)ethanol (308 mg, 2.2 mmol) in dioxane (5 mL) was added NaH (55% in oil, 96 mg, 2.2 mmol) at room temperature. The reaction mixture was stirred over night. Water (0.5 mL) was added and the mixture was stirred for 15 min. Drying (K2CO3), filtration, and concentration in vacuo gave the title compound as an oil (0.55 g) that was used directly in the next step. MS m/z 254 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:16][CH2:17]O>C(Cl)(Cl)Cl.[Pd]>[CH2:16]([O:8][C:7](=[O:9])[CH2:6][CH2:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:3]=1[O:2][CH3:1])[CH3:17]
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: CCO
Agent: [Pd]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cccc(OC)c1OC

Procedure:
A mixture of (20 g, 0.0961 mole) of 2,3-dimethoxycinnannic acid in 120 mL of CHCl3 and 200 mL of EtOH was hydrogenated at 30 psig in the presence of 2.0 g of 10% Pd/C catalyst to form ethyl-3-(2,3-dimethoxy-phenyl)propionate (hereinafter, "Compound 1"). The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was distillated under reduced pressure to give 22 g (96% yield) of liquid with a boiling point of 143° C./1.15 mmHg. Elemental analysis gave C13H18O4 (C,H,N).