Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:15][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([NH:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)=[O:10]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)c1ccc([N+](=O)[O-])c(C(=O)NCC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Step 1): A mixture of 5-dimethylamino-2-nitrobenzoic acid [J. Med. Chem., 24, 742 (1981)](9.0 g, 40 mmol), 4-aminomethyl-1-diphenylmethylpiperidine (12.0 g, 40 mmol), 1-(3-dimethylamino-propyl)-3-ethylcarbodiimido hydrochloride (WSC) (8.0 g, 40 mmol) and 4-dimethylaminopyridine (DMAP) (5 g, 40 mmol) in dichloromethane (400 ml) was stirred at 0° C. for 1 hour, then at room temperature for 3 days. The reaction mixture was washed with 1N HCl, then water. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (5% methanol in dichloromethane) to give 5-dimethylamino-2-nitro-N-[(1-diphenylmethyl-piperidin-4-yl)methyl]benzamide (47%) as yellow solid: mp 200° C.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)CO>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])=[CH:17][CH:16]=1
Reactant: C#CCNC(=O)c1cccnc1Cl
Reactant: Nc1ccc(F)cc1
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(F)cc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 99 mg, 0.61 mmol)) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5b (192 mg, 80%); mp: 201-204° C.; 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H), 8.45 (brs, 1H), 8.25 (dd, J=4.7, 1.4 Hz, 1H), 7.94 (dd, J=7.7, 1.4 Hz, 1H), 7.62-7.57 (m, 3H), 7.41 (s, 1H), 7.23 (s, 1H), 6.98 (t, J=8.4 Hz, 2H), 6.88 (t J=8.4 Hz, 2H), 6.69-6.65 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 433 [M+H]+. Yield: 80%
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:19]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: NCCCOc1ccncc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCCOc1ccncc1
Yield: 77.3 %

Procedure:
To a solution of 7.0 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 0.77 ml (5.52 mmol) of triethylamine in 30 ml of methylene chloride, 0.57 ml (4.63 mmol) of pivaloyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 840 mg of the desired compound (yield: 77.3%, colorless crystals).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=O)[CH2:4][CH2:3]1.Cl.[CH2:12]([O:14][C:15]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=1)=[O:16])C.C(=O)(O)[O-].[Na+]>CO.O>[C:15]([CH2:17][C:18]1[CH:23]=[C:22]2[C:21](=[CH:20][CH:19]=1)[NH:24][CH:9]=[C:8]2[CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)([O:14][CH3:12])=[O:16]
Reactant: CCOC(=O)Cc1ccc(NN)cc1
Reactant: CN1CCC(CC=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Temperature: 25 °C
Yield: 39.3 %

Procedure:
A solution of 1-methyl-4 (formylmethyl)piperidine (2.3 g, 16 mmol) and 4-(ethoxycarbonylmethyl)phenyl hydrazine hydrochloride (3.7 g, 16 mmol) in methanol:water (20:1) (25 ml) was stirred at room temperature for 1 hour. Polyphosphoric acid (7 g) was then added and the mixture heated at reflux for 5 hours, under nitrogen. The mixture was then cooled to ambient temperature, basified with saturated sodium bicarbonate to pH9, and extracted with dichloromethane (2×20 ml). The organic phases were combined, dried (MgSO4) and evaporated to give a brown residue. This was chromatographed (eluant 50:8:1 dichloromethane:ethanol:ammonia) to give 4-[5-carbomethoxymethyl-1H-indol-3-yl]N-methylpiperidine (1.8 g, 39%) as a yellow solid. mp 105°-107° C. δ(360 MHz, CDCl3) δ1.85 (2H, m), 2.16 (4H, m), 2.36 (3H, s), 2.81 (1H, m), 3.00 (2H, m), 3.70 (3H, s), 3.73 (2H, s), 6.97 (1H, d, J=2 Hz), 7.10 (1H, dd, J=8 and Hz), 7.31 (1H, d, J=8 Hz), 7.53 (1H, s), 7.97 (1H, brs).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]#N.[OH-:12].[Na+].Cl.C(O)CCC.[OH2:20]>>[CH3:1][C:2]([CH3:11])([CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:3]([OH:20])=[O:12]
Reactant: [OH-]
Reactant: O
Reactant: CCCCC=CC(C)(C)C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCCC=CC(C)(C)C(=O)O

Procedure:
2,2-Dimethyl-3-octenoic acid is prepared by adding 2,2-dimethyl-3-octene nitrile (1.51 g, 0.01 m) to a solution prepared from 15% NaOH in butanol/H2O (2:3) (30 mL). The reaction mixture is stirred and refluxed for 7 hours, is cooled and made acidic with 10% hydrochloric acid. The reaction mixture is extracted with diet hyl ether and the extract washed with saturated NaCl and dried over MgSO4, filtered and concentrated to give 2,2-dimethyl-3-octenoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[CH2:9]1[O:8][C:7]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:23]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1COC(c2ccco2)(c2ccco2)c2cc(Br)ccc2N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C1COC(c2ccco2)(c2ccco2)c2cc(-c3ccc(F)c(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5,5-di(2-furyl)-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluoro benzeneboronic acid generally according to the coupling procedure of example 1. 1H NMR (DMSO-d6): δ 10.28 (s, 1H), 7.77 (dd, J=1.95, 0.98 Hz, 2H), 7.66 (dd, J=8.3, 1.95 Hz, 1H), 7.59 (dd, J=7.32, 2.44 Hz, 1H), 7.45 (dd, JHF=JHH=8.79 Hz, 1H), 7.33-7.36 (m, 1H), 7.32 (d, J=8.79 Hz, 1H), 6.89 (d, J=2.44 Hz, 1H), 6.51 (dd, J=3.42, 1.95 Hz, 2H), 6.27 (dd, J=3.42, 0.98 Hz, 2H), 4.17 (s, 2H); MS (ESI) m/z 422/424 ([M−H]−); Anal. calcd for C23H15ClFNO4: C, 65.18; H, 3.57; N, 3.30. Found: C, 64.16; H, 3.66; N, 2.78.
Reaction SMILES: CI.[C:3](=[O:6])([O-])[O-].[K+].[K+].[Br:9][C:10]1[C:15]([F:16])=[CH:14][NH:13][C:12](=O)[CH:11]=1.O>CN(C)C=O>[Br:9][C:10]1[C:15]([F:16])=[CH:14][N:13]([CH3:12])[C:3](=[O:6])[CH:11]=1
Reactant: O=c1cc(Br)c(F)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(F)c(Br)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (0.9 mL) was added to a mixture of potassium carbonate (2.34 g) and 4-bromo-5-fluoro-1H-pyridin-2-one (2.50 g) in dimethylformamide (25 mL) at room temperature. The mixture was stirred at room temperature overnight and then water was added. The resulting mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated to afford the crude title compound that was recrystallized from Et2O. Yield: 1.22 g (45% of theory); Mass spectrum (ESI+): m/z=206/208 (Br) [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]1([C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([OH:17])[CH2:15]Cl)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[C:18]1([C:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([OH:17])[CH2:15][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1nc[nH]n1
Reactant: OC(CCl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(Cn1cncn1)(c1ccccc1)c1ccccc1

Procedure:
1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to a suspension of sodium hydride (0.03 mol, 0.72 g) in DMF (30 ml) and the solution stirred until effervescence ceased. 1,1-Diphenyl-2-chloro-ethan-1-ol (0.015 mol, 2.94 g) in dimethylformamide (DMF; 10 ml) was added dropwise and the solution warmed at 100° for six hours. The reaction mixture was poured into water and a white solid crystallised out. This was filtered off, washed with water, dried, and recrystallised from ethanol to give the title compound as a white crystalline solid, m.p. 128°-129°.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.C(O)(C)(C)C.[CH2:36]1[CH2:46]CN2C(=NCCC2)[CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH2:46][CH2:36][CH2:37][CH3:38])=[O:28])[CH:17]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
CDI (1.29 g, 7.99 mmol) was added to a solution of diflunisal (2.02 g, 8.07 mmol) in DMF (20 mL). The reaction mixture was stirred at 50° C. for 30 min and tert-butyl alcohol (1.50 mL, 14.97 mmol) and DBU (2.40 mL, 16.064 mmol) were dropwise added. The reaction mixture was stirred at 50° C. for 20 h and allowed to reach r.t. It was poured into NaHCO3 (100 mL, saturated aqueous solution) and extracted with EtOAc (100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (5% EtOAc/hexanes) to furnish 1.677 g of ten-butyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (colourless oil, yield: 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1B(O)O.Br[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[C@H:17]3[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:16]23)[CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:13]1[CH:14]=[C:15]2[C:19]3=[C:20]([CH2:22][S:23][CH2:24][CH2:25][N:18]3[CH:17]3[CH2:26][CH2:27][NH:28][CH2:29][CH:16]23)[CH:21]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Product: Fc1cccc(F)c1-c1cc2c3c(c1)C1CNCCC1N3CCSC2

Procedure:
Using 2,6-difluorophenyl boronic acid and following the procedures described in EXAMPLE 9, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate was converted into the title compound of EXAMPLE 14. 1H NMR (CDCl3, 300 MHz): δ 7.19 (m, 1H), 6.93 (m, 2H), 6.83 (m, 3H), 3.81 (m, 2H), 3.59 (m, 1H), 3.41 (m, 1H), 3.21 (m, 2H), 3.0 (m, 2H), 2.82 (m, 3H), 2.60 (m, 1H), 1.80 (m, 2H). LRMS (ES+): 359 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[F:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:17](Cl)=[O:18].Cl>O.CC(C)=O>[F:15][C:16](=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:17]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:18]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(C=C(F)C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(C=C(F)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 0.5 h

Procedure:
L-phenylalanine (13.2 g, 0.080 mole) and 6N NaOH (43 ml, 0.086 mole) were dissolced in a solvent prepared by mixing water (77 ml) with acetone (240 ml). To the mixture, while cooling to less than 10° C., the acetone solution of α-fluoro-4-methyl cinnamic acid chloride prepared as above and 2N NaOH (38 ml, 0.076 mole) were alternately added over 20 minutes. Next, the mixture was stirred at normal temperature for 30 minutes, and the reaction solution was made acidic by the addition of 2N HCl. Then, water (200 ml) was gradually added thereto. The thus precipitated crystals were recovered by filtration and dried to give crude crystals (16.7 g). The crude crystals were recrystallized from a mixture of methanol and water to obtain N-(α-fluoro-4-methylcinnamoyl)-L-phenylalanine (yield 15.5 g) in the form of white needle-like crystals having a melting point of 163° to 163.5° C.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([C:12]1[C:13]([OH:34])=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:17]2)[CH3:11].ClC(Cl)(Cl)C(=N)O[C@H:39]1[C@@H:44]2[O:45][C:46](=[O:48])[O:47][C@@H:43]2[C@@H:42]([O:49][CH3:50])[C:41]([CH3:52])([CH3:51])[O:40]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:10]([C:12]1[C:13]([O:34][C@H:39]2[C@@H:44]3[O:45][C:46](=[O:48])[O:47][C@@H:43]3[C@@H:42]([O:49][CH3:50])[C:41]([CH3:52])([CH3:51])[O:40]2)=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:17]2)[CH3:11]
Reactant: CCc1c(O)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1c(O[C@@H]2OC(C)(C)[C@H](OC)[C@H]3OC(=O)O[C@@H]23)ccc2cc(NC(=O)OCc3ccccc3)c(=O)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.2 %

Procedure:
Boron trifluoride etherate (19.0 μL, 0.15 mmol) was added to 23h (171 mg, 0.51 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (183 mg, 0.51 mmol) in anhydrous CH2Cl2 (11.0 mL). After stirring at room temperature for 24 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25h as a colorless foam (138 mg, 51%): 1H NMR (CD2Cl2, 400 MHz) δ 8.29 (s, 1H), 7.62 (s, 1H), 7.47-7.38 (m, 5H), 7.36 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.25 (s, 2H), 5.10 (dd, J=8.0, 2.0 Hz, 1H), 5.02 (t, J=7.8 Hz, 1H), 3.55 (s, 3H), 3.41 (d, J=7.2 Hz, 1H), 2.87 (q, J=7.4 Hz, 2H), 1.42 (s. 3H), 1.28 (s, 3H), 1.21 (t, J=7.4 Hz, 3H); 13C NMR (CD2Cl2, 100 MHz) δ 158.5, 154.8, 153.2, 153.1, 148.4, 136.0, 128.6 (2C), 128.4, 128.1, 125.6, 122.4, 121.5, 120.7, 114.8, 111.4, 94.8, 82.7, 77.9, 77.2, 76.6, 67.3, 60.3, 27.3, 22.3, 16.4, 13.6; IR (film) νmax 3400, 2980, 2937, 2359, 2339, 1817, 1711, 1607, 1524, 1383, 1366, 1227, 1205, 1175, 1101, 1040, 906, 768, 737, 700 cm−1; [M+Na]+ calcd for C28H29NO10, 562.1689. found, 562.1689.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:2]1.[Cl:12][C:13]1[CH:31]=[CH:30][C:16]2[O:17][C:18]3[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=3[CH2:20][N:21]([C:22]([NH:24][NH2:25])=[O:23])[C:15]=2[CH:14]=1>>[O:11]=[C:9]([NH:25][NH:24][C:22]([N:21]1[CH2:20][C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]=2[O:17][C:16]2[CH:30]=[CH:31][C:13]([Cl:12])=[CH:14][C:15]1=2)=[O:23])[CH2:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=C(O)CCCc1ccsc1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCCc1ccsc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-4-(3-thienyl)butyl]hydrazide (33) was prepared in the manner described in Example 7 on a 5.2 mmol scale from 3-thiophenebutanoic acid (32), prepared as described above in Example 32, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, to yield 0.87 g (37%) product. Analysis calculated for C22H20N3O3SCl (M.W. 441.94): C, 59.79; H, 4.56; N, 9.51; Cl, 8.02. Found: C, 59.76; H, 4.58; N, 9.54; Cl, 8.06; S, 7.25.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[C:50]([Si:52]([CH3:55])([CH3:54])[CH3:53])#[CH:51]>CN1CCCC1=O.C(OCC)(=O)C.[Cu](I)I>[CH3:17][O:16][C:14]1[CH:13]=[C:12]([O:18][CH3:19])[C:8]2[C:9](=[O:11])[CH2:10][C:4]3[C:3]([C:51]#[C:50][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:2][CH:21]=[CH:20][C:5]=3[O:6][C:7]=2[CH:15]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(OC)c2c(c1)Oc1ccc(Br)cc1CC2=O
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(c1)Oc1cccc(C#C[Si](C)(C)C)c1CC2=O
Temperature: 80 °C
Yield: 80.1 %

Procedure:
2-Bromo-7,9-dimethoxy-10,11-dihydrodibenzo[b,f]oxepin-10-one 500 mg (F. W. 349.18, 1.43 mmol) prepared in the first stage of Production Example 79, triphenylphosphine 75 mg (F. W. 262.29, 0.062 mmol), trisbenzylidene acetone dipalladium chloroform complex 74 mg (F. W. 1035.08, 0.015 mmol), diisopropylethylamine 575 μl (F. W. 98.22, d=0.742, 2.86 mmol), ethynyl trimethylsilane 350 μl (F. W. 98.22, d=0.742, 2.86 mmol) and copper iodide 27.5 mg (F. W. 190.44, 0.143 mmol) were dissolved in N-methyl-2-pyrrolidone (5 ml) and, after substituting with argon atmosphere, they were stirred with heating at 80° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography to give the title compound 420 mg (F. W. 367.419, 66%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1](=[N:17][OH:18])([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1nccc(OCC(F)(F)F)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1nccc(OCC(F)(F)F)n1
Yield: 69.7 %

Procedure:
2-Acetyl-4-(2,2,2-trifluoroethoxy)-pyrimidine (0.47 g) was dissolved in a mixture of ethanol (10 ml) and water (5 ml) and heated to 40° C. for 1 hour with hydroxylamine hydrochloride (0.16 g) and sodium acetate (0.43 g). The reaction mixture was poured into water and extracted with ethyl acetate (3×50 ml). The combined extracts were dried and concentrated. The residue was washed with hexane to give 2-acetyl-4-(2,2,2-trifluoroethoxy)-pyrimidine oxime (0.35 g, 70% yield) as a white solid, m.p. 179°-181° C.; 1H NMR (270 MHz): δ2.39(3H,s), 4.87(2H,q), 6.88(1H,d), 8.60(1H,d) ppm.
Reaction SMILES: C[Si](I)(C)C.C([O:13][C@@H:14]([C@H:16]1[CH2:21][O:20][CH2:19][C@@H:18]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[NH:17]1)[CH3:15])C1C=CC=CC=1.[OH-].[Na+]>ClCCl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C@H:18]2[NH:17][C@@H:16]([C@H:14]([OH:13])[CH3:15])[CH2:21][O:20][CH2:19]2)=[CH:27][CH:26]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Agent: C[Si](C)(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reaction time: 10 h
Yield: 86.1 %

Procedure:
Trimethylsilyl iodide (3.07 mL) was added to a dichloromethane (20 mL) solution of (3R,5R)-3-((R)-1-benzyloxyethyl)-5-(4-chlorophenyl)morpholin (1.44 g). Stirring was continued for 10 hours at room temperature. Additional trimethylsilyl iodide (3.07 mL) was added, and the resultant was stirred at room temperature for 4 days. Additional trimethylsilyl iodide (3.07 mL) was further added, and stirring was continued for 1 day. Additional trimethylsilyl iodide (3.07 mL) was further added, and stirring was continued for 10 hours at room temperature. A 5 N sodium hydroxide solution was added, and the organic layer was partitioned. The organic layer was dried over anhydrous magnesium sulfate. The resultant was purified with silica gel column chromatography (heptane/ethyl acetate). The title compound (903 mg) was obtained. The physical property values are as follows.
Reaction SMILES: [Cl-].[C:2]1([PH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:18])C=C.N1C=C[CH:22]=[CH:21][CH:20]=1>CCOCC>[CH2:20]([P:8](=[O:18])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:21]=[CH2:22]
Reactant: c1ccncc1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CCO
Agent: [Cl-]
Solvent: CCOCC
Product: C=CCP(=O)(c1ccccc1)c1ccccc1
Temperature: 178 °C
Reaction time: 0.67 h

Procedure:
A mixture of diphenylphosphine chloride (11 g, 0.05 mol), allyl alcohol (2.9 g, 0.05 mol) in 50 ml of anhydrous ether is stirred at room temperature while slowly adding pyridine (4.0 g, 0.05 mol) to it. After 40 minutes, the pyridine hydrochloride is filtered off and the ether removed by distillation. The liquid residue is heated to 150°, whereupon an exothermic reactions sets in raising the temperature quickly to 178° C. The material is then distilled, b.p. 168°-175° C/0.4 mm, whereupon it crystallizes, m.p. 108° identical to the allyl diphenylphosphine oxide made by oxidation of the phosphine. Allyl diphenylphosphine oxide prepared by this method is reported; b.p. 200°-202° C/2 mm; m.p. 94°-96° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11](=O)/[CH:12]=[CH:13]/[N:14](C)[CH3:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([N:21](CC)CC)C.Cl.C(N)=N>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][N:21]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CN(C)/C=C/C(=O)C1(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: N=CN
Product: CC(C)(C)OC(=O)NC1(c2ccncn2)CC1
Temperature: 77.5 °C
Reaction time: 14 h
Yield: 20.4 %

Procedure:
To a solution of [1-((E)-3-Dimethylamino-acryloyl)-cyclopropyl]-carbamic acid tert-butyl ester (600 mg, 2.4 mmol) was added triethylamine (1.3 mL, 9.4 mmol) and formamidine hydrochloride (570 mg, 7.1 mmol) at room temperature. The reaction was stirred at 75-80° C. for 14 h. The volatiles were removed in vacuo to give a crude solid mass that was purified by preparative reversed phase HPLC to give 115 mg of the title compound as a light yellow solid, m/z 236.36 [M+1]+.