Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]([NH2:54])(=[O:53])[C:46]1[C:47](=[CH:49][CH:50]=[CH:51][CH:52]=1)O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH2:1]([C@@H:7]1[C:8](=[O:25])[O:9][C@H:10]1[CH2:11][C@@H:12]([O:24][C:52]1[CH:51]=[CH:50][CH:49]=[CH:47][C:46]=1[C:45]([NH2:54])=[O:53])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: NC(=O)c1ccccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)Oc1ccccc1C(N)=O
Temperature: 0 °C
Yield: 49.5 %

Procedure:
1.1 g of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 1.6 g of triphenylphosphine, 0.825 g of salicylamide and 3 g of molecular sieve (4Å) were treated with 20 ml of THF and cooled to 0° C. Thereupon, 1.4 g of di-t-butyl azodicarboxylate were added. After warming to room temperature and stirring the reaction mixture was concentrated and the residue was partitioned between methanol/water (70:30) and hexane and extracted with hexane. The hexane phase was dried and concentrated and the residue was chromatographed on silica gel with hexane/ethyl acetate (4:1). There were obtained 0.727 g of o-[[(S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl]oxy]-benzamide, MS: 474 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25])[CH:16]=1)[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([CH2:2][CH2:1][NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([C:23]([F:27])([F:28])[C:24]([OH:26])=[O:25])[CH:16]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)C(=O)O)ccc1OC
Product: COc1ccc(C(F)(F)C(=O)O)cc1-c1ccc(C(F)(F)F)cc1CNCCC(C)=O

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-difluoro-acetic acid and acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[C:13]([OH:14])=[CH:12][C:11]3[O:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH:20]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:13]([O:14][CH3:20])=[CH:12][C:11]3[O:15][CH2:16][O:17][C:10]=3[CH:9]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Cc2cc3c(cc2O)OCO3)cc1
Reactant: c1ccccc1
Product: COc1ccc(Cc2cc3c(cc2OC)OCO3)cc1

Procedure:
(4-Methoxybenzyl)-3,4-methylenedioxy-6-methoxybenzene was prepared from 6-(4-methoxybenzyl)-3,4-methylenedioxyphenol (L. Jurd, Tetrahedron, Vol. 33, pp. 163-168 (1977)) by methylation as described above in H. Colorless prisms were obtained from benzene-solve F, m.p. 56°-57° (Found: C, 70.5; H, 5.95. Calc. for C16H16O4 : C, 70.6; H, 5.92%); pmr spectrum: δ3.74, 3H, S; δ3.77, 3H, S; δ3.82, 2H, S; δ5.85, 2H, S; δ5.85, 2H, S; δ6.52, 1H, S; δ6.55, 1H, S; δ6.80, 2H, D (J=9 Hz); δ7.11, 2H, D (J=9 Hz).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH2:35]/[C:36](=[N:39]/[H])/[NH:37]O)[CH:31]=[CH:32][C:33]=1[OH:34])[CH3:26].[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:39]=[C:36]([CH2:35][C:30]3[CH:31]=[CH:32][C:33]([OH:34])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1ccc(O)c(OCC)c1)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccc(O)c(OCC)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 39.2 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-[3-(ethyloxy)-4-hydroxyphenyl]-N-hydroxyethanimidamide (35 mg, 0.165 mmol; entry 11, Table 7) were mixed in EtOH (0.75 ml). Ethanolic sodium ethoxide (21% by wt., 0.083 ml, 0.22 mmol) was added and the mixture was heated in the microwave at 140° C. for 10 min. A further 0.055 ml (0.15 mmol) of NaOEt solution was then added and the mixture heated for a further 10 min period at 140° C. The mixture was partitioned between EtOAc and 2M HCl and the organic phase evaporated and purified by MDAP to give the title compound as a solid (29.6 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].O[C:11]1[CH:21]=[CH:20][CH:19]=[C:13]2[C:14]([NH:16][C:17](=[O:18])[C:12]=12)=[O:15].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>O1CCCC1>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][O:1][N:16]1[C:17](=[O:18])[C:12]2[C:13](=[CH:19][CH:20]=[CH:21][CH:11]=2)[C:14]1=[O:15]
Reactant: COC(=O)C(C)(C)CO
Reactant: O=C1NC(=O)c2c(O)cccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 33.6 %

Procedure:
To methyl hydroxypivalate (1.31 g, 9.89 mmol) were added tetrahydrofuran (40 ml), hydroxyphthalimide (3.23 g, 19.78 mmol) and triphenylphosphine (6.48 g, 24.73 mmol). After this solution was cooled to 0° C., diisopropyl azodicarboxylate (4.87 ml, 24.73 mmol) was added dropwise to the solution. While being allowed to warm gradually, the reaction mixture was stirred for 12 hours, and concentrated under reduced pressure. The residue was roughly purified by silica gel column chromatography to give the title compound (922 mg).
Reaction SMILES: [C:1]([N:4]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C@@H:11]2[C:6]([C:7]3[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:8]=3[CH2:9][CH2:10]2)=[N:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br.Cl>ClCCl>[C:1]([N:4]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C@@H:11]2[C:6]([C:7]3[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:8]=3[CH2:9][CH2:10]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C1=NN(C(C)=O)[C@@H](c3ccc(O)cc3)[C@H]1CC2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1N=C2c3cc(O)ccc3CC[C@@H]2[C@@H]1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (175) (0.100 g, 0.28 mmol) under an argon atmosphere in dichloromethane (5 mL) was added BBr3 (1.0 mL, 1.0 M solution in dichloromethane) at −78° C. The reaction mixture was stirred at room temperature for 1 h and then poured into an ice cold solution of HCl (1.0 N). The mixture was extracted in ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The solid obtained was recrystallized from ethyl acetate to give (176): (62 mg, 67%): mp 164-67° C., 1H NMR (400 MHz, DMSO-CDCl3): δ 0.70-0.90 (m, 1H), 1.41-1.46 (m, 1H), 2.41-2.57 (m, 5H), 3.15-3.22 (m, 1H), 5.29 (d, J=11.2 Hz, 1H), 6.43 (d, J=6.8 Hz, 2H), 6.53-6.57 (m, 3H), 6.68 (d, J=8.4 Hz, 1H), 7.19 (s, 1H). HFABMS m/z 323.1399 (calc for C19H18N2O3, MH+, 323.1396).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:21]([C:20]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=O)Cl
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Agent: Cl
Product: CCCCC(=O)Nc1ccc(-c2cc3[nH]c(=O)[nH]c3nc2C)cc1

Procedure:
[I; Ar 4-CH3 (CH2)3CONHC6H4, R1 and R3H, R5 =CH3 ]was prepared from 3 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one hydrochloride and 1.86 ml valeryl chloride according to the procedure of Example 7, and was obtained (1.16 g) as a colorless solid, m.p. above 300° C. when recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.B(F)(F)F.C[CH2:18][O:19][CH2:20][CH3:21]>C(#N)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:3]2[C:4]3[C:21](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:20]([O:19][CH3:18])=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CCOCC
Reactant: COc1cccc2ccccc12
Agent: FB(F)F
Solvent: CC#N
Product: COc1ccc(-c2ccc(OC)c3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In synthetic route `A3`, 1-methoxynaphthalene and a solution of tris(trifluoroacetato)thallium[III] in acetonitrile are charged to a reaction vessel. Boron trifluoride etherate is added and the reaction mixture stirred at room temperature for between approximately 1-2 h to provide the intermediate 4,4'-dimethoxy-1,1'-binaphthyl. The 4,4'-dimethoxy-1,1'-binaphthyl intermediate is subsequently demethylated using boron tribromide (BBr3) which is added slowly to a dichloromethane solution of the intermediate to maintain the temperature at about -78° C. The reaction mixture is then warmed to room temperature and stirred for approximately 16 h in an inert atmosphere, then poured into water. The white crystals that form are 4,4'-Dihydroxy-1,1'-binaphthyl.
Reaction SMILES: [C:1]1([C:7]2[O:12][C:11](=O)[NH:10][C:9](=[O:14])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][NH2:16]>>[CH3:15][N:16]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9](=[O:14])[NH:10][C:11]1=[O:12]
Reactant: CN
Reactant: O=c1cc(-c2ccccc2)oc(=O)[nH]1
Product: Cn1c(-c2ccccc2)cc(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
To 189 mg (1 mM) of 6-phenyl-1,3-oxazine-2,4-dione from Preparation Ia(1) is added 10 ml of a 40 percent aqueous CH3NH2 solution. The reaction mixture is allowed to heat at reflux for 18 hours. The resulting solution is cooled to room temperature and the precipitate filtered, washed well with water, and dried at 60° C. under vacuum. The yield is 146 mg (72 percent) (m.p. 183°-185° C.) of 1-N-methyl-6-phenyl-2,4-pyrimidine-dione.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].CC1(C)C(C)(C)OB([C:21]2[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])O1.C1(C)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:21]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1-c1ccc(C(=O)OC)cc1C
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Under a nitrogen atmosphere, to a mixture of methyl 4-bromo-3-methylbenzoate (2.291 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.313 g), toluene (20 ml), water (10 ml) and tripotassium phosphate (4.246 g) was added tetrakis(triphenylphosphine)palladium(0) (0.578 g) at room temperature, and the mixture was stirred with heating under reflux overnight. The reaction mixture was cooled to room temperature, and partitioned in a separatory funnel. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5) to give the title compound (2.404 g, 81%)
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:33]4[CH:34]=[CH:35][C:36]([O:42][CH2:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[C:37]([NH:39][CH:40]=[O:41])[CH:38]=4)[O:25][Si](C(C)(C)C)(C)C)=[CH:16][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:33]4[CH:34]=[CH:35][C:36]([O:42][CH2:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)=[C:37]([NH:39][CH:40]=[O:41])[CH:38]=4)[OH:25])=[CH:18][CH:19]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(OCCC23CC4CC(CC(C4)C2)C3)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CNCCc2ccc(OCCC34CC5CC(CC(C5)C3)C4)cc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a solution of Intermediate 25 (1.23 g, 1.44 mmol) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride on silica gel (1-1.5 mmol/g, 2 g). The reaction mixture was stirred first at room temperature overnight and then at 45° C. for 3 hours. Silica was filtrated and the solvent was removed under reduced pressure. The crude was dissolved in ethyl acetate and the organic layer was washed several times with water. The solvent was removed under reduced pressure and the crude was purified by column chromatography with silica gel, eluting with chloroform/methanol (75:1) to give the title compound as a solid (0.36 g, 61%). MS (M+): 569.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1>>[CH3:1][N:3]1[CH2:4][CH2:5][CH:6]([O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(OC2CCNCC2)cc1
Reactant: C=O
Product: COC(=O)c1ccc(OC2CCN(C)CC2)cc1

Procedure:
Prepared using essentially the same procedure used in reference example 114a except using formaldehyde and Methyl 4-(piperidin-4-yloxy)-benzoate (reference example 123) as substrates. 1H NMR (CDCl3): d 8.01 (d, 2H), 6.91 (d, 2H), 4.80 (s, 1H), 3.89 (s, 3H), 3.35 (brd, 2H), 3.13 (q, 2H), 2.80 (d, 3H), 2.65 (t, 2H), 2.18 (d, 2H). MS (ion spray) m/z 250 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[OH:8][C@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CC(=O)c1ccccc1
Solvent: CO
Product: COC(=O)C[C@H](O)c1ccccc1
Yield: 94.9 %

Procedure:
In a 1 liter autoclave was charged a mixture of 0.84 g of (1.0 mmol) of Ru2Cl4((R)-Tol-BINAP)2.NET3, 178 g (1.00 mol) of methyl benzoylacetate, and 500 ml of methanol, and the mixture was stirred at 50° C. under a hydrogen pressure of 1000 kPa for 16 hours. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure (99° C./100 Pa.) to yield 171 g (95%) of the title compound as liquid. Optical purity: 87%e.e.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.[Cl:21]C1C=C2C(C=CC(COC3C=CC(CO)=CC=3)=N2)=CC=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:21]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: OCc1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 72 %

Procedure:
The procedure from Example 6, part B was used except 3-(quinolin-2-ylmethoxy)benzyl alcohol was substituted for 4-(7-chloroquinolin-2-ylmethoxy)benzyl alcohol. The intermediate was obtained in 72% yield: mp 39°-43° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M75) (0.34 g, 0.62 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (222 mg, 83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 2 tR=1.049 min, m/z=391; 1H NMR (CDCl3) 1.06-1.19 (d, 6H), 1.50 (s, 3H), 2.11-2.38 (m, 6H), 2.80 (m, 1H), 5.66 (m, 1H), 6.97 (m, 2H), 7.04 (d, 2H), 7.18 (m, 1H), 7.23 (m, 2H), 7.58 (m, 1H), 7.73 (m, 3H), 8.60 (d, 1H).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:14])[CH:12]=1)[O:9][C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:7]([CH3:30])[C:6]2=[O:31]>>[Cl:1][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([C:13]([O:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:14])[CH:12]=1)[O:9][C:8]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:7]([CH3:30])[C:6]2=[O:31]
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)OCCN3CCOCC3)cc(Br)cc2c1=O
Reactant: Cl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)OCCN3CCOCC3)cc(Cl)cc2c1=O

Procedure:
The procedure of Example 13 was repeated with the exception of using 37.3 g (0.10 mole) of methyl 6-bromo-3-methylflavone-8-carboxylate in place of methyl 6-chloro-3-methylflavone-8-carboxylate, giving 44 g (93.2%) of crystals. The hydrochloride of the product melts at 205.0° to 208.0° C. The crystals were found to be identical with the product obtained in Example 9.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[ClH:11]>CCCCCCC>[ClH:11].[CH3:1][NH+:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccccc1
Agent: Cl
Solvent: CCCCCCC
Product: C[NH+](C)Cc1ccccc1

Procedure:
12.12 g of N,N-dimethylbenzylamine and 400 ml of heptane were placed under argon in a 500 ml three-necked flask fitted with internal thermometer and gas inlet stopcock. HCl gas from a gas generation apparatus was passed into this reaction mixture for 1 hour. The N,N-dimethylbenzylammonium hydrochloride formed was separated off via a G4 frit, washed with 100 ml of heptane and dried in an oil pump vacuum. 13.14 g (85%) of the desired product were isolated.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=2)[O:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)O1.[F:22][C:23]1[C:24](C2C=CC(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)=CC=2)=[CH:25][C:26](=[O:42])[N:27]([CH2:29][CH2:30][C@@:31]([CH3:41])([S:37]([CH3:40])(=[O:39])=[O:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=1>>[F:22][C:23]1[C:24]([C:9]2[CH:20]=[CH:19][CH:18]=[C:11]([O:12][C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[CH:10]=2)=[CH:25][C:26](=[O:42])[N:27]([CH2:29][CH2:30][C@@:31]([CH3:41])([S:37]([CH3:40])(=[O:38])=[O:39])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=1
Reactant: CC1(C)OB(c2cccc(Oc3nccs3)c2)OC1(C)C
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)cc1=O)S(C)(=O)=O
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2cccc(Oc3nccs3)c2)cc1=O)S(C)(=O)=O

Procedure:
The title compound (534 mg) was prepared as a crude brown oil from 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1,3-thiazole (1.33 g, 4.39 mmol) and T2 (400 mg, 0.90 mmol) using a procedure analogous to that described for ethyl (2R)-4-[5-fluoro-2-oxo-4-(4-{[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate, Example 18, Step D. MS (LCMS) m/z 495.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[F:1][C:2]1[C:9]([F:10])=[C:8]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[CH:32][CH:31]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(OS(=O)(=O)C(F)(F)F)c(F)c1F
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
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: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)c(F)c2F)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A solution of 2,3-difluoro-4-trifluoromethylsulfonyloxybenzonitrile in 60 mL of dioxane is admixed under an argon atmosphere with 1.24 g of 4-(tert-butyloxycarbonylamino)phenylboronic acid. A solution of 1.03 g of sodium carbonate in 15 mL of water is added, followed by 0.48 g of tetrakistriphenylphosphinepalladium. The reaction mixture is stirred at 90° C. for 3 hours and then poured into 80 mL of distilled water. Following extraction with ethyl acetate and then washing with saturated sodium chloride solution, the organic phase is concentrated under reduced pressure, to give 0.8 g of 2,3-difluoro-4-(4-tert-butoxycarbonylaminophenyl)benzonitrile, whose characteristics are as follows:
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Br)=[CH:3][CH:2]=1.[Mg].[CH:10]12[O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C1COCC1>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:3][CH:2]=1
Reactant: Cc1ccc(Br)cc1
Reactant: C1CCC2OC2C1
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C2CCCCC2=O)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
To a solution of p-tolylbromide (17.1 g, 100 mmol) in dry THF (100 mL) was added magnesium (2.43 g, 100 mmol) and then the resulting mixture was cooled to −20° C. and (CuBr-dimethylsulfide complex (2.0 g, 10 mmol) was added and the mixture stirred at −20° C. for 10 min. Then a solution of cyclohexene oxide (10 mL, 100 mmol) in dry THF (10 mL) was added dropwise and the reaction warmed to 0° C. at which point an exothermic reaction initiates. With ice-bath cooling the temperature can be maintained below 25° C. The reaction mixture was then stirred at 0–5° C. for an additional 2 h, then quenched with ammonium chloride solution (saturated, 30 mL) and the product extracted with tert-butyl methyl ether. The combined organic extracts were then washed with water, dried over sodium sulfate, filtered and evaporated. Recrystallisation from hexane afforded the title compound (9.9 g, 52%) as white crystals. MS: m/e=190.1 (M).