Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH2:34]([O:36][C:37](=[O:45])C1C=CN=C(N)C=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:45])[C:23]1[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:24]=1)[CH3:35]
Reactant: CCOC(=O)c1ccnc(N)c1
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Product: CCOC(=O)c1ccnc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)c1

Procedure:
The product from Example 11, Part D (100 mg, 0.30 mmol) and 2-aminoisonicotinic acid ethyl ester (75 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E without crystallization (120 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.31 (d, J=5 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=8 Hz, 1H), 7.58 (dd, J=5 Hz, 1 Hz, 1H), 7.47 (m, 1H), 7.32 (m, 2H), 7.20 (t, J=9 Hz, 1H), 7.02 (t, J=9 Hz, 2H), 5.27 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.41 (q, J=7 Hz, 2H), 4.24 (d, J=15 Hz, 1H), 2.55 (m, 2H), 1.97 (m, 2H), 1.41 (t, J=7 Hz, 3H). MS: m/z (MH+) 480.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[CH2:8][C@H:9]1[CH2:14][N:13]([S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])[CH2:12][CH2:11][NH:10]1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:37])([C:33]([F:36])([F:35])[F:34])[CH2:31][OH:32])=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:34][C:33]([F:35])([F:36])[C:30]([C:27]1[CH:26]=[CH:25][C:24]([N:10]2[CH2:11][CH2:12][N:13]([S:15]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:17])[CH2:14][C@@H:9]2[CH2:8][N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:29][CH:28]=1)([OH:37])[CH2:31][OH:32]
Reactant: OCC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(O)(CO)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 20-mL vial was charged with (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (0.750 g, 2.17 mmol, Example 82), 2-(4-bromophenyl)-3,3,3-trifluoro-1,2-propanediol (0.766 g, 2.69 mmol, Example 67), 6 mL of toluene and sodium tert-butoxide (1.426 mL, 11.65 mmol). After stirring at room temperature for 5 min, dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.167 g, 0.359 mmol, Strem Chemicals Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (0.164 g, 0.179 mmol, Strem Chemicals Inc, Newburyport, Mass.) were added. The vial was sealed and heated at 100° C. for 1 h. After that time the mixture was cooled to room temperature, diluted with 50 mL MeOH, and filtered. The filtrate was concentrated, re-dissolved in 10 mL of CH2Cl2 and purified via column chromatography on silica gel (80 g, 0 to 75% EtOAc in hexanes) to give 3,3,3-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,2-propanediol as a mixture of two isomers (0.109 g). 1H NMR (400 MHz, CD3OD) δ=7.91-7.80 (m, 1H), 7.64 (dd, J=1.2, 3.7 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.26 (dd, J=3.7, 4.9 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 4.09-3.98 (m, 3H), 3.93-3.85 (m, 1H), 3.79-3.37 (m, 6H), 3.26-3.10 (m, 2H), 2.89-2.81 (m, 1H), 2.64-2.45 (m, 2H), 2.37-2.25 (m, 1H), 2.14-1.99 (m, 1H), 1.94-1.81 (m, 1H), 1.00 (d, J=6.3 Hz, 3H). m/z (ESI, +ve ion) 550.1 (M+H)+. GK-GKRP EC50 (LC MS/MS-2)=0.019 μM.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1.Br[CH2:16][C:17]#[N:18]>C1COCC1>[C:17]([CH2:16][O:3][CH:4]1[CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7]1)#[N:18]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OCC#N)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.8 %

Procedure:
NaH (60% dispersion in mineral oil, 276 mg, 6.89 mmol) was added to an ice cold solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.92 mg, 5.30 mmol) in THF (8 mL) and stirred for 15 mins. Bromoacetonitrile (0.52 mL, 7.43 mmol) was added dropwise and the reaction mixture allowed to warm to room temperature. After 2.5 h, bromoacetonitrile (0.074 mL, 1.06 mmol) was added and the reaction mixture stirred at rt. After 17 h, NaH (60% dispersion in mineral oil, 0.085 mg, 2.12 mmol) and bromoacetonitrile (0.074 mL, 1.06 mmol) were added. After 2 h the reaction mixture was evaporated to dryness and the crude product purified on a Biotage Horizon HPFC system eluting with 5-90% EtOAc in petroleum ether (40-60° C.) to give the title compound (0.47 g, 42%) as an oil. 1H NMR (CDCl3): δ 4.46-4.40 (m, 1H), 4.24 (s, 2H), 4.17 (dd, 2H), 3.92 (dd, 2H), 1.45 (s, 9H); 13C NMR (CDCl3): δ 156.3, 115.6, 80.2, 69.3, 56.3, 54.6, 28.6.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C[Al](C)C.[Br:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C@H:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])=[CH:22][CH:21]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[Br:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C@@H:27]([CH2:31][CH2:30][OH:29])[C:28]([NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)=[O:32])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C1OCC[C@@H]1Oc1ccc(Br)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)[C@H](CCO)Oc2ccc(Br)nc2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-aminopiperidine-1-carboxylate (0.93 g, 4.65 mmol) in DCM (15 mL) was added dropwise 2M trimethylaluminum (2.8 mL, 5.7 mmol) in toluene. The resulting mixture was stirred for 15 minutes, and (S)-3-(6-bromopyridin-3-yloxy)dihydrofuran-2(3H)-one (1.0 g, 3.87 mmol) in DCM (10 mL) was added slowly over 5 minutes and the reaction stirred at ambient temperature for 2 hours. The reaction was slowly quenched by the addition of 5% tartaric acid (5 mL), saturated NaHCO3 (5 mL) and DCM (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo to provide (S)-tert-butyl 4-(2-(6-bromopyridin-3-yloxy)-4-hydroxybutanamido)piperidine-1-carboxylate. The crude material was taken on without a further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:17][CH2:18]O)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([OH:20])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH2:17][CH2:18][O:20][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Br)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.1 %

Procedure:
To a solution of tert-butyl N-[(4-bromo-2-hydroxy-phenyl)methyl]-N-(2-hydroxyethyl)carbamate (3 g, 8.67 mmol) and triphenylphosphine (3.4 g, 13.0 mmol) in dichloromethane (85 mL) was added diisopropyl azodicarboxylate (2.69 g, 13.0 mmol) and the reaction was stirred at ambient temperature for 12 hours. The reaction was then washed with water, brine, dried with MgSO4 and purified by silica gel column chromatography (0-40% EtOAc in heptane) to give tert-butyl 8-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2.45 g, 86% yield). LCMS (m/z) ES+ 328 [M+1]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]#[C:34][CH2:35][CH2:36]O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:39]>>[Br:39][CH2:36][CH2:35][C:34]#[C:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCC#CCCOCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: BrCCC#CCCOCCCCc1ccccc1
Reaction time: 1 h
Yield: 88 %

Procedure:
Triphenylphosphine (4.5 g) in dry MC (20 ml) was added dropwise to the product of stage (i) (3.8 g) and carbon tetrabromide (5.8 g) in dry MC (50 ml) at 0°. The solution was stirred at 0° for 1 h and MC was evaporated. The residue was treated with ER (100 ml), filtered and the filtrate was evaporated. The residue was purified by FCC eluting with CX followed by CX-ER (4:1) to give the title compound as a colourless oil (4.2 g). T.l.c. (CX-ER 9:1) Rf 0.4.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[C:7]([Cl:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[C:4]1[Cl:11].C(=O)([O-])O.[Na+].[CH3:19][C:20]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH3:27])[O:22][N:21]=1.C1(C=CC(O)=CC=1)O>C(OCC)(=O)C>[CH3:27][CH:26]1[C:4]2([Cl:11])[C:3]([O:2][CH3:1])([O:12][CH3:13])[C:7]([Cl:8])([C:6]([Cl:9])=[C:5]2[Cl:10])[CH:25]1[C:23]1[O:22][N:21]=[C:20]([CH3:19])[CH:24]=1
Reactant: C/C=C/c1cc(C)no1
Reactant: COC1(OC)C(Cl)=C(Cl)C(Cl)=C1Cl
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C(c1cc(C)no1)C2C
Temperature: 180 °C
Reaction time: 7 h
Yield: 44.6 %

Procedure:
1.07 g of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopenta-1,3-diene, 0.34 g of sodium hydrogen carbonate, 0.50g of trans-1-(3-methylisoxazol-5-yl)-1-propene and 0.05 g of hydroquinone were mixed and heated with stirring at 180° C. for 7 hours. The reaction solution was cooled and ethyl acetate was added. Insoluble matter was removed by filtration. Then the solvent was concentrated under reduced pressure. The obtained crude product was purified on silica gel column chromatography (elution with benzene) to give 0.70 g of the title compound as a mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]1[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:26]3[CH2:29][CH:28]([C:30]#[N:31])[CH2:27]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: N#CC1CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#CC1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 59.2 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to −60° C. where azetidine-3-carbonitrile hydrochloride (0.08 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 mL, 2 eq) were added dropwise. The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (3-5% Methanol in DCM). to obtain (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carbonitrile (0.14 g, 60% yield). 1H NMR (400 MHz, DMSO) δ=9.36 (s, 1H), 8.54 (s, 2H), 8.30 (s, 1H), 7.45-7.43 (d, J=10 Hz, 1H), 5.95-5.92 (d, J=10 Hz, 1H), 4.39-4.37 (t, 1H), 4.29-4.11 (m, 3H), 3.84-3.82 (m, 1H); LCMS calcd. for C17H12F6N5O [M+H]+ 416.29. found 416.14, at 2.64 min retention time
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:20][CH:22]4[CH2:23][O:24]4)=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(OCC4CO4)cc3)nc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
4-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)phenol (2 g, 6.89 mmol) was dissolved in DMF (200 ml) and sodium hydride (0.9 g, 20.67 mmol, 55% in oil) was added. The mixture was stirred at 50° C. for 1 h, and epibromohydrin (0.94 ml, 11.37 mmol) was added dropwise followed by stirring for one h at room temperature. Purification by flash chromatography on silica using ethyl acetate/heptane as eluent afforded the title compound (0.55 g, 23%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CCN(C(C)C)C(C)C>Cl.CCCCO>[C:16]1([NH:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[CH:3]=3)=[CH:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cc(Nc2ccc(Nc3ccccc3)cc2)ncn1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: OCCNc1cc(Nc2ccc(Nc3ccccc3)cc2)ncn1
Temperature: 200 °C
Yield: 32 %

Procedure:
176 mg of N1-(6-chloropyrimidin-4-yl)-N4-phenylbenzene-1,4-diamine in the form of a hydrochloride, 72 mg of ethanolamine and 153 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated and the evaporation residue was subjected to MPLC eluting the product with EtOAc. 2-(6-(4-(Phenylamino)phenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[N+:31]([O-:35])=[C:30]([CH3:36])[CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:33]=[C:32]([CH3:34])[N+:31]([O-:35])=[C:30]([CH3:36])[CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccccc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.086, m/z=461.1; 1H NMR (CDCl3) 1.34 (m, 1H), 1.50 (d, 3H), 1.61-1.72 (m, 2H), 1.88-2.00 (m, 2H), 2.18 (m, 1H), 2.22-2.34 (m, 2H), 2.62 (s, 6H), 2.88 (m, 1H), 3.51 (t, 2H), 5.65 (m, 1H), 6.93 (d, 2H), 7.21 (m, 1H), 7.26 (m, 4H), 7.29-7.38 (m, 4H).
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC3(C(F)(F)F)CCCC3)=CC=2F)(=O)=O)CCC1.[N:30]1([S:34]([NH:37][C:38](=[O:57])[C:39]2[CH:44]=[C:43](Cl)[C:42]([O:46][CH2:47][CH:48]3[C:50]4([CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)[CH2:49]3)=[CH:41][C:40]=2[F:56])(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1>>[N:30]1([S:34]([NH:37][C:38](=[O:57])[C:39]2[CH:44]=[C:43]([CH:15]3[CH2:10][CH2:9]3)[C:42]([O:46][CH2:47][CH:48]3[C:50]4([CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]4)[CH2:49]3)=[CH:41][C:40]=2[F:56])(=[O:36])=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CC23CCCCC3)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2(C(F)(F)F)CCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC2CC23CCCCC3)cc1F

Procedure:
Following the procedure as described in Example 165 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclopentyl)methoxy)benzamide with N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-(spiro[2.5]octan 1-ylmethoxy)benzamide, the title compound was obtained (0.03 g, 7%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.67 (br s, 1H), 7.58 (d, J=9.1 Hz, 1H), 6.58 (d, J=14.4 Hz, 1H), 4.24 (t, J=7.7 Hz, 5H), 3.86 (t, J=9.6 Hz, 1H), 2.26 (q, J=7.7 Hz, 2H), 2.15-2.05 (m, 1H), 1.79-1.18 (m, 10H), 1.14-1.04 (m, 1H), 0.96-0.92 (m, 2H), 0.77-0.58 (m, 3H), 0.28 (t, J=5.0 Hz, 1H); MS (ES−) m/z 435.2 (M−1).
Reaction SMILES: [CH:1]([NH:3][NH:4][S:5]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])=[O:6])=O.O.[C:17]([OH:21])(=[O:20])C=O>Cl.O>[CH:8]([S:5]([NH:4][N:3]=[CH:1][C:17]([OH:21])=[O:20])(=[O:7])=[O:6])=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CNNS(=O)(=O)C=Cc1ccccc1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)C=NNS(=O)(=O)C=Cc1ccccc1
Reaction time: 4.5 h
Yield: 53.6 %

Procedure:
In this operation a suspension of 1-formyl-2-(β-styrenesulfonyl)hydrazine (4.98 g, 22 mmol) in 6 N HCl (44 cc) was stirred for 4.5 hr at 50°-55° C. After cooling a small amount of insoluble material was removed by filtration. The filtrate was added all at once to a stirred solution of glyoxylic acid monohydrate (2.4 g, 26 mmol) in water (180 cc), and stirring was continued for 3 hr. The white crystalline solid which had precipitated was collected by filtration and air dried to give 3.0 g of the product compound, m.p. 141° (dec.).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1Br.[CH2:20]([N:27]1[CH2:32][CH2:31]C(=O)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCCC>[CH2:20]([N:27]1[CH2:32][CH2:31][C:1]2([C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:10][CH3:11])[CH:8]=3)[CH:3]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:2]2)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C(OC)c2ccc(F)cc2)c(Br)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCCCCCC
Product: COc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2c1ccc(F)cc1

Procedure:
By following the manipulative procedure described above in Example 45, 2-bromo-4'-fluoro-4-methoxybenzhydryl methyl ether and 1-benzyl-4-piperidone are reacted to produce a white solid, m.p. 86°-88°, form heptane.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([OH:18])[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10](=[O:18])[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])=[CH:2]1
Reactant: CCCCOC(=O)C(O)c1coc2ccccc12
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: CCCCOC(=O)C(=O)c1coc2ccccc12

Procedure:
14.9 g of butyl benzofur-3-yl-glycolate and 26.6 of lead tetraacetate are refluxed for 8 hours in 125 ml of absolute benzene. After working up as described in Example 15, 8.7 g (59% of theory) of an oil, boiling point 132°-136° C. (1 Torr), nD20 =1.537, are obtained.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([O-])=[O:20])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[CH3:58][C:59]1[C:64]([N+:65]([O-:67])=[O:66])=[CH:63][N:62]=[C:61]([NH:68][CH:69]2[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]2)[CH:60]=1>CN(C)C=O.ClCCl.O1CCCC1>[CH3:58][C:59]1[C:64]([N+:65]([O-:67])=[O:66])=[CH:63][N:62]=[C:61]([NH:68][CH:69]2[CH2:74][CH2:73][N:72]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([F:23])([F:2])[F:22])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:71][CH2:70]2)[CH:60]=1
Reactant: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: Cc1cc(NC2CCNCC2)ncc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)ncc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyric acid lithium salt (122 mg; 0.39 mmol, prepared in accordance with Example 3), diisopropylethyl amine (175 μL; 1.0 mmol) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (133 mg; 0.35 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (1.5 mL) and the resulting solution is stirred for 5 minutes. A solution of (4-methyl-5-nitro-pyridin-2-yl)-piperidin-4-yl-amine hydrochloride (95 mg; 0.35 mmol, prepared in accordance with Example 70) in dimethylformamide (0.5 mL) is added and the reaction is then stirred for 3 hours at room temperature. Following dilution with dichloromethane (10 mL), the organic layer is sequentially washed with water (5 mL), aq. sat. sodium hydrogen carbonate (3×5 mL), is dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is finally purified by preparative HPLC to deliver the desired product in pure form (33 mg; 0.06 mmol). The structure was confirmed using Protocol II-A. Calculated mass=535; observed mass=535; HPLC retention time=3.29 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:13][C:14]([NH:16][N:17]=[C:18]=[O:19])=O.P(Cl)(Cl)(Cl)=O.O>C(#N)C.CCOCC>[CH2:29]([O:28][C:22]1[CH:21]=[C:20]([CH:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH2:13][C:14]2[O:19][CH:18]=[N:17][N:16]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH3:30]
Reactant: CCOc1cc(C(CC(=O)NN=C=O)N2C(=O)c3ccccc3C2=O)ccc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CC#N
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 43.5 %

Procedure:
A mixture of 3-(1,3-dioxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.0 g, 8.1 mmol) and carbonyidiimidazole (1.45 g, 8.94 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. To the solution was added formic hydrazide (644 mg, 10.7 mmol). The mixture was stirred for 18 hours. The resulting suspension was filtered and washed with ether. The isolated solid was stirred in a mixture of ethyl acetate (40 mL) and water (10 mL) for 1 hour. The suspension was filtered and washed with water and ether to give crude 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (1.3 g, 39% yield). A solution of 3-(1,3-dioxoisoindolin-2-yl)-N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)propanamide (600 mg, 1.46 mmol) and phosphorus oxychloride (POCl3, 0.54 mL, 5.8 mmol) in acetonitrile (20 mL) was heated to reflux for 2 hours. This solution was poured into water (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and dried over magnesium sulfate. Removal of solvent and chromatography gave an oil. The oil was slurried in ether (10 mL). The resulting suspension was filtered to yield 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione as a white solid (250 mg, 43% yield): mp, 132.0-134.0° C.; 1H NMR (CDCl3); δ 1.46 (t, J=6.9 Hz, 3H, CH3), 2.82 (dd, J=6.0, 15.6 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.11 (q, J=7.0 Hz, 2H, CH2), 4.37 (dd, J=10.3, 15.7 Hz, 1H, CHH), 5.81 (dd, J=6.0, 10.3 Hz, 1H, NCH), 6.62 (d, J=7.9 Hz, 1H, Ar), 7.13-7.17 (m, 2H, Ar), 7.67-7.72 (m, 2H, Ar), 7.75-7.62 (m, 2H, Ar), 8.29 (s, 1H, Ar); 13C NMR (CDCl3)δ 14.69, 27.70, 51.85, 55.90, 64.42, 111.32, 112.51, 120.32, 123.44, 130.14, 13163, 134.13, 148.39, 143.43, 153.03, 163.99, 167.93; Anal Calcd for C21H29N3O5: C, 64.12; H, 4.87; N, 10.68. Found: C, 63.84; H, 4.90; N, 10.48.