Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[CH2:15](Cl)[CH2:16][Cl:17].[CH:19]1[CH:20]=C[C:22]2[N:27](O)N=[N:25][C:23]=2[CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:17].[N:27]12[CH2:16][CH2:15][CH:24]([CH2:19][CH2:20]1)[C@@H:23]([NH:25][C:12]([C:9]1[S:10][C:11]3[C:3]([C:1]#[N:2])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=1)=[O:14])[CH2:22]2
Reactant: On1nnc2ccccc21
Reactant: ClCCCl
Reactant: N#Cc1cccc2cc(C(=O)O)sc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cl
Product: N#Cc1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.5 g (7.38 mmol) of 7-cyano-1-benzothiophene-2-carboxylic acid and 1.47 g (7.38 mmol) of R-3-aminoquinuclidine dihydrochloride are initially charged in 25 ml of DMF. At 0° C., 1.70 g (8.86 mmol) of EDC, 1.20 g (8.86 mmol) of HOBt and 3.70 ml (26.6 mmol) of triethylamine are added to the solution. The mixture is stirred at RT for 18 h. The reaction is terminated by addition of a 10% strength aqueous sodium bicarbonate solution, and ethyl acetate is added. The resulting precipitate is filtered off with suction. The mother liquor is extracted twice with ethyl acetate. The organic phases are combined and concentrated. The crude product is purified by silica gel column chromatography (mobile phase: dichloromethane/methanol/25% ammonia 100:20:4). The product fractions are concentrated, dissolved in a mixture of methanol and 1N hydrochloric acid, then again concentrated and dried under high vacuum. 655.1 mg (24.5% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(=[C:34]([C:44]2[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][CH:45]=2)[C:35]2[CH:42]=[CH:41][C:38](C=O)=[C:37]([F:43])[CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O.[CH2:52](Cl)Cl>>[C:28]1(=[C:34]([C:44]2[CH:45]=[CH:46][C:47]([OH:50])=[CH:48][CH:49]=2)[C:35]2[CH:42]=[CH:41][C:38](/[CH:52]=[CH:8]/[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[C:37]([F:43])[CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCCl
Reactant: O=Cc1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1F
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A solution of (tert-butoxycarbonylmethylene)triphenylphosphorane (610 mg, 1.62 mmol) in CH2Cl2 (10 mL) was added dropwise to 89 (200 mg, 0.644 mmol) dissolved in CH2Cl2 (10 mL) at RT. After stirring for 2 h at RT, water (50 mL) was added and the mixture was extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with brine (50 mL) and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) and recrystallization (hexanes:EtOAc) afforded 180 mg (68%) of 90 as a white crystalline solid. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.59 (br s, 6H), 2.22 (br s, 4H), 5.24 (s, 1H), 6.40 (d, J=16.3 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 6.80-6.89 (m, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.37 (t, J=7.9 Hz, 1H), 7.67 (d, J=16.3 Hz, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]Cl>CN(C=O)C>[Cl:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][N:1]=[N+:2]=[N-:3]
Reactant: ClCc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cold (0° C.) solution of sodium azide (1.45 g, 22.3 mmol) in 50 ml of DMF was treated with 2-chlorobenzyl chloride (2.4 ml, 18.6 mmol). The reaction mixture was stirred at room temperature for 2 days, under N2 and then partitioned between EtOAc and H2O. The resultant layers were separated and the organic layer was dried over Na2SO4, filtered and then concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.O.O.[Sn](Cl)Cl>C(O)C.O1CCCC1>[NH2:16][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: N#Cc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccccc1-c1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) suspension of crude 4′-fluoro-3′-nitrobiphenyl-2-carbonitrile (10.7 g, 44 mmol) in ethanol (80 ml) and tetrahydrofuran (80 ml) was treated with tin(II) chloride dihydrate (29.8 g, 132 mmol) and this mixture was stirred at ambient temperature for 12 h. The solvent was removed in vacuo and the residue treated with ice-cold 2N sodium hydroxide (400 ml). The resulting slurry was stirred at ambient temperature for 60 min then extracted with dichloromethane (2×400 ml). The organics were combined, washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (5-40%) gave 3′-amino-4′-fluorobiphenyl-2-carbonitrile as a cream-coloured solid (4.3 g, 46% over 2 steps): δH (400 MHz, CDCl3) 3.85 (2H, br), 6.84 (1H, ddd, J 8, 4 and 2), 6.95 (1H, dd, J 8 and 2), 7.07 (1H, dd, J 11 and 8), 7.40-7.46 (2H, m), 7.57-7.62 (1H, m), 7.72-7.74 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:24])[CH2:9][NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42]>C(C(C)=O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]\[C:41]([OH:43])=[O:42].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:24])[CH2:9][NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cccc([C@@H]2CCC[C@@H](NC[C@H](O)c3cccc(Cl)c3)C2)c1

Procedure:
A methyl ethyl ketone mixture liquid of 1 equivalent of (1R)-1-(3-chlorophenyl)-2-[(1R,3R)-3-(3-hydroxyphenyl)cyclohexylamino]ethanol 1/3 toluene-solvate and from 2.0 to 3.0 equivalents of potassium carbonate was heated under reflux. With heating, a methyl ethyl ketone solution of from 1.0 to 1.2 equivalents of ethyl bromoacetate was dropwise added to the mixture liquid, and further heated under reflux for 3 to 4 hours. A part of the reaction liquid was sampled, and subjected to HPLC analysis. After cooled, this was filtered through Celite, and a methyl ethyl ketone solution of 1.0 equivalent of maleic acid was put into the obtained solution, and stirred. The precipitated crystal was taken out through filtration, and dried through aeration to obtain ethyl 3-[(1R,3R)-3-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxyacetate maleate. The obtained crystal was subjected to HPLC analysis, in which the content of (1R)-1-(3-chlorophenyl)-2-[(1R,3R)-3-(3-hydroxyphenyl)cyclohexylamino]ethanol (starting compound) and the content of ethyl 3-[(1R,3R)-3-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]cyclohexyl]phenoxyacetate (target product) in the crystal were determined according to the above-mentioned relative area percentage method.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:34]([NH:33][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:8](=[O:9])[CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:22][CH2:23]2)[CH:32]=[CH:31][CH:30]=1)(=[O:36])[CH3:35]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 3 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.40 (s, 1H), 7.32–7.20 (m, 12H), 6.96 (t, 1H, J=4.8 Hz), 6.91 (d, 1H, J=7.6 Hz), 4.87 (s, 1H), 3.39 (dd, 2H, J=6.0, 12.4 Hz), 2.90 (d, 2H, J=11.6 Hz), 2.43 (m, 1H), 2.36 (t, 2H, J=6.4 Hz), 2.11 (s, 3H), 1.94 (m, 2H), 1.76 (d, 2H, J=12.4 Hz), 1.68 (t, 2H, J=6.8 Hz), 1.60 (dd, 2H, J=1.2, 8.4 Hz); ESMS m/e: 470.3 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)=[N:16][C:15]=12>O1CCCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N:24]3[CH2:25][CH2:26][C:27]([OH:30])([CH3:1])[CH2:28][CH2:29]3)=[N:16][C:15]=12
Reactant: C[Mg]Br
Reactant: O=C1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Reaction time: 2 h
Yield: 46.8 %

Procedure:
Methylmagnesium bromide (3M in diethyl ether, 0.24 ml, 0.72 mmol) was added to a stirred solution of 3-(2-fluorophenyl)-5-(4-oxopiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (Example 22) (0.107 g, 0.3 mmol) in dry tetrahydrofuran (2 ml) at room temperature under nitrogen. After stirring for 2 h, the mixture was diluted with water (20 ml) and 1M aqueous citric acid (5 ml). The mixture was extracted with dichloromethane (20 ml) and the organic extract was dried (Na2SO4), filtered and concentrated. Preparative thin layer chromatography on silica, eluting with 2% methanol:dichloromethane, gave 3-(2-fluorophenyl)-5-(4-hydroxy-4-methylpiperidin-1-yl)-[1,2,3]triazolo[1,5-α]quinazoline (0.053 g, 47%). δH (360 MHz; CDCl3) 1.38 (3H, s), 1.75-1.85 (2H, m), 1.90-2.00 (2H, m), 3.56-3.64 (2H, m), 3.83-3.89 (2H, m), 7.20-7.30 (2H, m), 7.30-7.40 (1H, m), 7.60 (1H, dd, J=7 and 7), 7.88 (1H, dd, J=7 and 7), 8.02 (1H, d, J=7), 8.15 (1H, dd, J=7 and 7), 8.68 (1H, d, J=7); m/z (ES+) 378 (M+H+).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([I:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([I:10])[CH:8]=1)[C:3](=[O:14])[N:22]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH2:12]2
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cc(Cl)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3cc(Cl)cc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-iodo-benzoic acid methyl ester (0.389 g, 1.0 mmol), 4-methoxy-benzylamine (0.169 mL, 1.2 mmol), and K2CO3 (0.276 g, 2.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-7-iodo-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.111 g, 27%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.79 (s, 3H), 4.12 (s, 2H), 4.71 (s, 2H) 6.86 (d, 2H), 7.25 (m, 2H), 7.36 (s, 1H), 7.90 (s, 1H). GC-MS: m/z 413 (M)+, 382 (M−31)+.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]([C:10]([CH3:16])([CH:14]=[CH2:15])[C:11]([OH:13])=[O:12])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26]([C@H:30]([O:32][C:33](=[O:35])[CH3:34])[CH3:31])=[N:27]2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:33]([O:32][C@@H:30]([C:26]1[CH:25]=[CH:24][C:23]2[C:28](=[CH:29][C:20](/[CH:15]=[CH:14]/[C:10]([C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])([CH3:8])[CH3:9])([CH3:16])[C:11]([OH:13])=[O:12])=[CH:21][CH:22]=2)[N:27]=1)[CH3:31])(=[O:35])[CH3:34]
Reactant: C=CC(C)(C(=O)O)C(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(Br)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C(=O)O)C(C)(C)O[Si](C)(C)C(C)(C)C)cc2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 65 %

Procedure:
A solution of 2-[1-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-methyl-but-3-enoic acid (258 mg, 0.95 mmol), acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (279 mg, 0.95 mmol), palladium(II) acetate (43 mg, 0.19 mmol), tris-(o-tolyl)phosphine (87 mg, 0.29 mmol) in anhydrous acetonitrile (3 mL) was treated with triethylamine (265 μL, 1.90 mmol). After stirring at 100° C. under microwave for 20 min, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The residue was partitioned between dichloromethane and a saturated potassium hydrogen sulfate solution. The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 0:1 to afford the title compound (300 mg, 65%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.20 (s, 3H), 0.22 (s, 3H), 0.94 (s, 9H), 1.44 (s, 3H), 1.45 (s, 3H), 1.50 (s, 3H), 1.68 (d, J=6.7 Hz, 3H), 2.17 (s, 3H), 6.06 (q, J=6.7 Hz, 1H), 6.76 (m, 2H), 7.43 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 8.11 (d, J=8.5 Hz, 1H). LCMS (m/z) 486.3 [M+H], Tr=3.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=O.CC[N:18]=[C:19]=[N:20]CCCN(C)C.C1C=CC2N(O)N=NC=2C=1.ONC(=N)[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH2:49][CH2:50][C:51]([O:53]CC)=[O:52])[CH:44]=[CH:43]2>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:20]=[C:19]([C:41]3[CH:40]=[CH:48][CH:47]=[C:46]4[C:42]=3[CH:43]=[CH:44][N:45]4[CH2:49][CH2:50][C:51]([OH:53])=[O:52])[N:18]=2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: CCOC(=O)CCn1ccc2cc(C(=N)NO)ccc21
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(Cl)c1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(O)CCn1ccc2c(-c3noc(-c4ccc(OC(F)(F)F)c(Cl)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
3-Chloro-4-[(trifluoromethyl)oxy]benzoic acid (commercial source) (131 mg), EDCI (114 mg) and HOBT (81 mg) were dissolved in DMF (2.5 ml) and stirred at RT for 10 minutes. Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D57) (150 mg) in DMF (2.5 ml) was added and stirring continued at RT for 2 hours. The mixture was then heated at 80° C. overnight. The reaction mixture was evaporated to dryness then extracted with EtOAc (2×25 ml) from H2O (25 ml). The combined organic solutions were evaporated to dryness and the residue treated with EtOH and 2 M aq. NaOH (1:1 mixture, 20 ml). This mixture was stirred at 50° C. for 2 hours then evaporated to remove the EtOH. The resultant precipitate was filtered off and washed with a mixture of H2O and EtOH then 2 M HCl. The residue was recrystallised from hot EtOH to give the title compound (62 mg) as a white solid. δH (d6-DMSO, 400 MHz): 2.81 (2H, t), 4.50 (2H, t), 7.08 (1H, d), 7.36 (1H, apparent t), 7.61 (1H, d), 7.83 (1H, d), 7.89 (1H, d), 7.96 (1H, d), 8.32 (1H, dd), 8.50 (1H, d). MS (ES−): C20H1335CIF3N3O4 requires 451; found 450 (M−H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[H-].[Na+].[CH2:18](I)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C)C=O.O1CCCC1.CCOCC>[CH2:35]([O:1][CH2:2][CH:3]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18]
Reactant: CC(=O)NC(CO)COC1CCCCO1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOCC(COC1CCCCO1)NC(C)=O
Reaction time: 24 h
Yield: 34.1 %

Procedure:
A solution of about 10.85 g of N-[1-(hydroxymethyl)-2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]acetamide in about 240 ml of dry dimethylformamide was added dropwise to a suspension of about 3.12 g of about 50% sodium hydride (pre-washed with anhydrous ether). After stirring about one hour a solution of about 22.8 g of octadecyl iodide in about 150 ml of tetrahydrofuran was added, stirring was continued for about 24 hours, then the mixture was diluted with ether and washed with a minimum amount of brine. The organic layer was dried, the solvents evaporated and the crude material purified by chromatography on silica gel, eluting with ethyl acetate:hexane:ethanol (about 1:1:0.2), giving about 8 g of the desired title compound, mp 52°-55° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].COCCOC.Br[C:14]1[N:19]=[C:18]([C@@H:20]([OH:25])[CH2:21][O:22][CH2:23][CH3:24])[CH:17]=[CH:16][CH:15]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>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>[CH2:23]([O:22][CH2:21][C@@H:20]([C:18]1[N:19]=[C:14]([C:31]2[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=2)[CH:15]=[CH:16][CH:17]=1)[OH:25])[CH3:24]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCOC[C@H](O)c1cccc(Br)n1
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: CCOC[C@H](O)c1cccc(-c2ccc(C#N)cc2)n1
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 130 %

Procedure:
Pd(PPh3)4 (187 mg, 0.162 mmol) and Na2CO3 (1.29 g, 12.2 mmol) was treated with DME (20 mL) and stirred under nitrogen for 2 min. Water (10 mL), (1R)-1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (1.0 g, 4.1 mmol) and (4-cyanophenyl)boronic acid (656 mg, 4.47 mmol) were added and the stirred reaction mixture heated at 80° C. for 17 h. The mixture was then allowed to cool to ambient temperature and the residue partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organic extracts washed with brine (100 mL), dried (Na2SO4) and evaporated to give a yellow oil (1.43 g). Purification by Biotage™ chromatography (silica, 40 g cartridge) eluting with cyclohexane:EtOAc (4:1) afforded the title compound as a pale yellow oil (945 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[S:15][C:14]=1Br)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:10][C:11](=[O:12])[C:13]3[CH:17]=[C:16]([CH3:18])[S:15][C:14]=3[O:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(NC(=O)c2cc(C)sc2Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)Oc1sc(C)cc1C(=O)N2
Temperature: 145 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
To a solution of N-(2-hydroxy-4-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g) in dimethyl sulfoxide (17 ml) was added potassium carbonate (1.7 g), and the mixture was stirred at 145° C. for 2 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration and the obtained crystals were purified by silica gel column chromatography (chloroform:methanol=20:0-20:1). The obtained solid was collected by filtration from diisopropyl ether-ethyl acetate—methanol to give 8-methoxy-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (530 mg).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[CH:15]([C:20]2[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])[CH:10]=[CH:9][C:3]=1[C:4]([N:6](C)[NH2:7])=[O:5].[F:29][C:30]([F:36])([F:35])[CH2:31][C:32](O)=[O:33].[CH3:37]CN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:12]=[C:11](/[CH:13]=[CH:14]/[CH:15]([C:20]2[CH:21]=[C:22]([Cl:28])[C:23]([Cl:27])=[C:24]([Cl:26])[CH:25]=2)[C:16]([F:17])([F:19])[F:18])[CH:10]=[CH:9][C:3]=1[C:4]([NH:6][N:7]([CH3:37])[C:32](=[O:33])[CH2:31][C:30]([F:36])([F:35])[F:29])=[O:5]
Reactant: O=C(O)CC(F)(F)F
Reactant: CCN=C=NCCCN(C)C
Reactant: CN(N)C(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br)C(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 21 %

Procedure:
To a stirred solution of (E)-2-bromo-N-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzohydrazide (200 mg, 0.46 mmol) in DCE (15 mL), was added 3,3,3-trifluoropropanoic acid (59 mg, 0.38 mmol), DMAP (46 mg, 0.42 mmol), EDC.HCl (65 mg, 0.42 mmol) and DIPEA (0.2 mL, 1.16 mmol). The reaction mixture was stirred at 25° C. for 12 h, then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% hexane:EtOAc) afforded the title compound as a yellow solid (50 mg, 25%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C(Br)(Br)(Br)[Br:19].C(=O)=O.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CCOCC.C(O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([Br:19])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: O=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)[C@H]1C[C@H](Br)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (320 g, 1.30 mol) and carbon tetrabromide (540 g, 1.94 mol) in dichloromethane (3.2 L) at 0-5° C. (dry ice/dichloromethane bath) add triphenylphosphine (1.95 mol, 514 g) in portions over 30 min and stir at room temperature for 4 h. Add ethanol (3.2 L) and stir for an additional 2 h. Transfer the reaction to an 18 L carboy and add ether (8 L) until precipitation occurs. Stir the mixture overnight. Filter off the solids and concentrate the ether layer. Dissolve the oily residue in dichloromethane and filter through a silica plug eluting with dichloromethane until no more product can be detected by TLC. Concentrate the dichloromethane layer and treat with 5% ethyl acetate in hexanes (4 L) causing a white solid to form. Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes and collect only the fractions that contain the desired product. Concentrate the solution, dissolve in 5% ethyl acetate in hexanes (2 L) and purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes to obtain the title compound as a yellowish oil (372.4 g, 93%). [α]D20+53.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.33 and 1.39 (two s, 9H), 2.40 (m, 1H), 2.53 (m, 1H), 3.35 (m, 1H), 3.66 (s, 3H), 3.80 (m, 1H), 4.35 (q, 1H), 4.73 (m, 1H).