Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:25].C(O)C[CH2:28][CH2:29][OH:30].C(OC=C)=C.C1(C(N)C2CCCCC2)CCCCC1.Cl>[Pd].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.C(O)CCC>[Cl:24][C:19]1[CH:18]=[C:17]([C:11]2([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29](=[O:30])[CH3:28])=[C:3]([CH3:25])[CH:4]=3)[CH2:12]2)[CH:22]=[C:21]([Cl:23])[CH:20]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: OCCCCO
Agent: [Pd]
Agent: C=COC=C
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 58.8 %

Procedure:
A mixture of 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (500 mg), 1,4-butandiol-monovinyl ether (385 mg), 1,3-bis(diphenylphosphine)propane (dppp, 9 mg), palladium on charcoal (10%, 23 mg), dicylohexylmethylamine (259 mg) and n-butanol (3 mL) were stirred under an atmosphere of nitrogen at reflux over night. After cooling, ethyl acetate (30 mL) and aqueous hydrochloric acid (1 M, 20 mL) were added and the mixture was stirred at room temperature for 1 h. After filtration, the layers were separated, the organic layer was extracted with 1 M HCl, dried (Na2SO4) and evaporated in vacuum. Purification of the residue on silica gel afforded the title compound (270 mg, 60%).
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:16])[C:10]2[NH:11][CH:12]=[N:13][C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:16])[C:10]2[N:11]=[CH:12][N:13]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:14]=2[N:15]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 10 (2.21 g, 10 mmol) and Na2CO3 (2.12 g, 20 mmol) were suspended in dry DMF, and the mixture was warmed to 80° C. with stirring. After 1 h the heating was terminated, and the reaction mixture was cooled to 0° C. and ethyl bromoacetate (1.22 mL, 11 mmol) was added dropwise for 1 h. The stirring was continued for an additional 2 h. The reaction mixture was filtered and the solid was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography ((DCM/MeOH; 9.5/0.5) to obtain 11 as a white solid: yield 0.77 g (25%); MS(+ESI): m/z 308 [M+H]+; 1H NMR (400 MHz, CDCl3): δ11.99 (s, 1H), 8.50 (s, 1H), 7.71 (s, 1H), 4.80 (s, 2H), 4.26 (q, 2H, J=6.8 Hz), 2.70 (septet, 1H, J=6.8 Hz), 1.31 (t, 3H, J=6.8 Hz), 1.28 (d, 6H, J=6.8 Hz); 13C NMR (400 MHz, CDCl3): δ178.3, 166.9, 155.4, 148.5, 147.6, 139.2, 120.8, 62.3, 44.5, 36.5, 18.9, 14.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:27](Br)=[CH:28][CH2:29][CH3:30].O>CC(=O)CC>[CH:27]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[CH:28][CH2:29][CH3:30]
Reactant: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Reactant: CCC=CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCC=COc1cc(OCCCCCCCC)ccc1C(=O)OC
Yield: 89.9 %

Procedure:
To a solution of 22.0 g (78.5 mmol) of the compound (29) and 65.0 g (471 retool) of potassium carbonate mixed in 300 ml of 2-butanone were added 32.0 g (236 mmol) of butenyl bromide and the whole was refluxed for 18 hours. Water was added to the solution and the whole was extracted with ethyl acetate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 23.6 g of methyl 2-butenyloxy-4-octyloxybenzoate as a colorless clear liquid (yield: 89.9%). Then, 20.0 g (59.8 mmol) of the resulting compound was dissolved in 100 ml of methanol. The solution was poured into a solution of 12.0 g (300 mmol) of sodium hydroxide dissolved in 40 ml of water and 400 ml of methanol. The whole was refluxed for another 2 hours. After removal of the solvent by distillation, the resulting white solid was dissolved in water and the solution was rendered acidic by adding hydrochloric acid, whereby white precipitate formed. The precipitate was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 15.3 g of 2-butenyloxy-4-octyloxybenzoic acid (30) (yield: 80.0%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:19][CH2:18]1.Cl>>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:22][CH2:21]1
Reactant: Cc1ccccc1N1CCN(CCCCl)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Product: Cc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 73.4 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4 -(2-methylphenyl)-piperazine; yield 73.4% of theory; m.p. of the hydrochloride (recrystallized from water) 243°-245°C;
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C@@H:5]1[C@@H:10]2[CH2:11][CH2:12][N:7]([CH:8]([CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]2=O)[CH2:6]1)=[O:4].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:31]=1[CH2:32][NH2:33].O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:1][N:2]([CH3:27])[C:3]([C@@H:5]1[C@@H:10]2[CH2:11][CH2:12][N:7]([C@@H:8]([CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:9]2[NH:33][CH2:32][C:31]2[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=2[O:29][CH3:28])[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)[C@H]1CN2CC[C@@H]1C(=O)C2C(c1ccccc1)c1ccccc1
Reactant: COc1ccc(OC)c(CN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c(CN[C@H]2[C@H]3CCN(C[C@@H]3C(=O)N(C)C)[C@H]2C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
A mixture of 47 (3.9 g, 10 mmol), 2,5-dimethoxybenzyl amine (1.9 g, 11 mmol) camphor sulfonic acid (120 mg) in toluene (40 ml) was heated at reflux with removal of water for 8 hours and then the solvent was removed. The residue was dissolved in small amount of THF (5 ml) and this solution was added to a solution of sodium triacetoxyborohydride (5.3 g, 25 mmol) in acetic acid (100 ml) at room temperature. The mixture was stirred at room temperature for 4 hours and the solvent was removed. Water (25 ml) was added and the mixture was neutralized with sodium bicarbonate (NaHCO3) and extracted with ethyl acetate (EtOAc) three times. The combined extracts were dried over sodium sulfate (Na2SO4) and concentrated. The crude was purified by recrystallization from EtOAc to give 49 (2.4 g, 4.4 mmol, 44%)
Reaction SMILES: C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[N:13](OCCC(C)C)=O.C([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31]C(=O)C)[C:26]=1[CH3:35])(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>[NH:31]1[C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([OH:24])[C:26]=2[CH:35]=[N:13]1
Reactant: CC(=O)Nc1cccc(OC(C)=O)c1C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
Acetic anhydride (16.4 ml, 174 mmol), tetrabutylammonium bromide (933 mg, 2.90 mmol), potassium acetate (11.4 g, 116 mmol) and isoamyl nitrite (11.7 ml, 86.9 mmol) were added to a solution of 3-(acetylamino)-2-methylphenyl acetate (12.0 g, 57.9 mmol) in ethyl acetate (120 ml) at room temperature, and the resulting mixture was refluxed for 7 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=3/1). Subsequently, the residue purified was dissolved in methanol (50 ml) and a 2N-aqueous sodium hydroxide solution (47.9 ml) was added thereto at room temperature and stirred for 1 hour. The methanol was distilled off under reduced pressure, and the resulting aqueous solution was adjusted to pH 4 to 5 by dropwise addition of hydrochloric acid and then extracted with acetic acid. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain 1H-indazol-4-ol (3.62 g, 47%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 3.5 h
Yield: 116.5 %

Procedure:
To the solution of N-(3-bromopropyl)phthalimide (402 g) in acetone (2.5 l) were added 1-methylpiperazine (225 g) and potassium carbonate (415 g). The resulting mixture was refluxed with stirring for 3.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with acetone (500 ml). The filtrate and washing were combined and evaporated under reduced pressure. The remaining starting materials in the residnal oil were azeotropically removed with benzene to give an oil of N-[3-(4-methyl-1-piperazinyl)propyl]phthalimide (502 g). I.R. (Film): 1770,1700 cm-.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14]C(=O)OC(C)(C)C)[C@H:9]([CH3:22])[N:8]([C:23]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[C:7]=2[CH:31]=1)#[N:2].[ClH:32]>O1CCOCC1>[ClH:32].[NH2:14][C@@H:10]1[C:11](=[O:13])[NH:12][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][C:7]=2[N:8]([C:23]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[C@H:9]1[CH3:22]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)Nc2ccc(C#N)cc2N1C(=O)C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H]1[C@H](N)C(=O)Nc2ccc(C#N)cc2N1C(=O)C1CCOCC1
Yield: 89 %

Procedure:
A rt solution of tert-butyl(2S,3S)-8-cyano-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (289 mg, 674 μmol) in 4 M HCl in dioxane (3.37 ml) was stirred for 1 h. The reaction was diluted with Et20 and the solids were collected by vacuum filtration to provide (3S,4S)-3-amino-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (218 mg, 89%) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]([Br:11])=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:11][C:10]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[CH:3][C:4]2[O:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: Brc1cc2c(cc1Br)OCO2
Reactant: OB(O)c1ccc(F)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: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2cc3c(cc2Br)OCO3)cc1
Yield: 71.1 %

Procedure:
Under nitrogen, 1.1 g of Pd(PPh3)4 was added to a stirred solution of 10.4 g (37.2 mmol) of 5,6-dibromo-1,3-benzodioxole and 2.6 g (18.6 mmol) of 4-fluorophenylboronic acid in 100 mL of toluene, 60 mL of ethanol, and 40 mL of M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried over Na2 SO4. Purification by silica gel chromatography (Waters Prep-500A) with hexane as the eluent gave 3.9 g (71%) of 5-bromo-6 (4-fluorophenyl)-1,3-benzodioxole as a colorless solid: mp 86.0°-87.5° C.; NMR (CDCl3) δ 6.02 (s, H), 6.77 (s, 1H), 7.04-7.13 (m, 3H), 7.28-7.35 (m, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.O[C:37]1[CH:41]=[CH:40][S:39][N:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[S:39]1[CH:40]=[CH:41][C:37]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][O:32][CH2:33][CH:34]=4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:38]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Reactant: Oc1ccsn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccsn2)CN1c1ccc(C2=CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
Diisopropylazodicarboxylate (227 mg, 1.12 mmol) was added dropwise, at ambient temperature, to a stirred solution of 5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (300 mg, 1.02 mmol ; see Example 1), 3-hydroxyisothiazole (114 mg, 1.13 mmol) and triphenylphosphine (304 mg, 1.16 mmol) in THF (8.0 ml). The resulting solution was stirred at room temperature for 30 minutes before evaporating the solvent to give an orange oil. It was purified by flash chromatography (Merck 9385 silica, EtOAc/isohexane (3:2)) to give the title product (257 mg, 67%) as a colourless crystalline solid. MS: ESP+ (M+H)+=377.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.CN.[CH:22]([N:25](CC)C(C)C)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH3:22])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)COC2
Agent: CN
Agent: Cl
Solvent: CO
Product: CNc1nc(Cl)nc2c1COCC2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation I) (194 mg, 0.690 mmol) in MeOH (6901 μL) was added methanamine hydrochloride (69.9 mg, 1.035 mmol) and N,N-Diisopropylethylamine (301 μL, 1.725 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 2-chloro-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (126 mg, 0.457 mmol, 66.2% yield). LC-MS (M+H)+=276.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.28 (2H, t, J=7.32 Hz), 7.20-7.25 (1H, m), 7.14-7.20 (2H, m), 4.47-4.62 (2H, m), 4.47 (1H, s), 4.00-4.11 (2H, m), 3.95 (1H, d, J=3.36 Hz), 3.08 (3H, d, J=4.88 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][CH:9]1[N:14]=[C:13]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[C:12]([C:27]([O:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])=[O:28])=[C:11]([CH3:35])[NH:10]1.C(N(CC)C1C=CC=CC=1)C.C(O)C#CCCCC.[Cl:55][C:56]([O:58][CH:59]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH3:60])=[O:57]>O1CCCC1.ClC(OC(Cl)(Cl)Cl)=O>[Cl:55][C:56]([O:58][CH:59]([CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH3:60])=[O:57].[CH3:60][CH:59]([O:58][C:56]([N:14]1[CH:13]([C:15]2[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=2)[C:12]([C:27]([O:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])=[O:28])=[C:11]([CH3:35])[N:10]=[C:9]1[CH3:8])=[O:57])[CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: COc1cc(C2=NC(C)NC(C)=C2C(=O)OCC=C(C)C)cc(OC)c1OC
Agent: CCCCC#CCO
Agent: CCCCCC(C)OC(=O)Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(C)OC(=O)N1C(C)=NC(C)=C(C(=O)OCC=C(C)C)C1c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
0.5 ml of Triethylamine was added to a solution of 200 mg of 2,6-dimethyl-5-(3-methyl-2-butenyloxycarbonyl)-4-(3,4,5-trimethoxyphenyl)-dihydropyrimidine in 5 ml of tetrahydrofuran (THF) and 2-heptyl chloroformate dissolved in 6 ml of THF was added dropwise. The 2-heptyl chloroformate was prepared by adding 0.25 ml of N,N-diethylaniline dissolved in 2 ml of THF to a solution of 0.15 g of 2-heptyn-1-ol and 0.1 mg of trichloromethyl chloroformate in 4 ml of THF in a separate reaction vessel. After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was purified on silica gel by column chromatography (silica gel 20 g, eluant:benzene/ethyl acetate 9:1) to obtain 187 mg (69% yield) of title product.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](O)=[O:22])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH:26]([N:29](CC)[CH:30](C)C)(C)C.CNC.CCO.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[CH3:26][N:29]([CH3:30])[C:21](=[O:22])[CH2:20][O:19][CH:16]1[C:12]2[CH:13]=[N:14][CH:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([F:2])([F:24])[F:25])=[CH:5][CH:6]=3)[C:11]=2[CH2:18][CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)C(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (70 mg, 0.19 mmol) in THF (0.6 mL) was added N,N-diisopropylethylamine (131 μL, 0.75 mmol), N,N-dimethylamine 33% solution in EtOH (67 μL, 0.38 mmol) and 1-propanephosphonic acid cyclic anhydride (284 μL, 0.47 mmol). The reaction was stirred at room temperature for 16 h. The mixture was evaporated and purified by flash chromatography (20 g SiO2, Telos-cartridge, 4% 2-propanol in CH2Cl2) to give the title compound (49 mg, 72%) as yellow oil. MS: 365.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[N:3]=1.[I-].C[N+]1C=CN([C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C=1.C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: Cc1cc(C)nc(O)n1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(OC(=O)N(C)c2ccccc2)n1
Yield: 59.6 %

Procedure:
A solution of 4,6-dimethyl-2-hydroxypyrimidine (0.37 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.46 g, 60% yield) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7]([C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[NH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:4]/[CH:3]=[CH:2]/[C:1]([N:15]1[C@H:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:18][O:17][C:16]1=[O:19])=[O:5]
Reactant: C/C=C/C(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Product: C/C=C/C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
trans-Crotonoyl chloride (Aldrich) was coupled with (R)-4-benzyl-2-oxazolidinone according to the procedure of Example 1c to afford the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: COc1ccc(I)cc1
Reactant: COc1ccccc1B(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: COc1ccc(-c2ccccc2OC)cc1
Yield: 66 %

Procedure:
At 120° C., p-iodoanisole is reacted with 2-methoxyphenylboronic acid in the presence of palladium tetraphenyl phosphate, potassium carbonate and the phase transfer catalyst, tetrabutyl ammonium bromide to yield 2,4′-dimethoxybiphenyl (66%), which is then brominated at 0° C. in ethylene dichloride to produce 5,5′-dibromo-2,4′-dimethoxybiphenyl in 80% yield. n-butyl bromide is reacted with the dibromo intermediate in the presence of magnesium and cuprous iodide at −10° C. to produce in 50% yield 3′,5-dibutyl-2,4′-dimethoxy-1,1′-biphenyl. Demethylation with boron tribromide gives 3′,5-dibutyl-2,4′-dihydroxy-1,1′-biphenyl (17% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccccn1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1c(OC)cccc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)Nc2ccccn2)ccc1C(C)(C)C)c1c(OC)cccc1OC

Procedure:
Following a similar procedure to that described in Example 8, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,6-dimethoxyphenyl)octanamide (prepared as described in Preparation 74E) and 2-aminopyridine, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]1[CH:9]=[CH:10][C:11]([Cl:16])=[C:12]([CH:15]=1)[C:13]#[N:14])[CH2:3][N:4]1[CH2:7][CH2:6][CH2:5]1.O[C:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=2[N:21]=[N:22][N:23]=1>>[N:4]1([CH2:3][C@@H:2]([NH:1][C:18]2[C:19]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=3[N:21]=[N:22][N:23]=2)[C:8]2[CH:9]=[CH:10][C:11]([Cl:16])=[C:12]([C:13]#[N:14])[CH:15]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: N#Cc1cc([C@H](N)CN2CCC2)ccc1Cl
Product: N#Cc1cc([C@@H](CN2CCC2)Nc2nnnc3c(C(N)=O)cccc23)ccc1Cl

Procedure:
Compound 18 was prepared following general synthetic scheme 7 wherein (S)-5-(1-amino-2-(azetidin-1-yl)ethyl)-2-chlorobenzonitrile was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [408 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.82 (d, 1H), 8.63 (d, 1H), 8.55 (d, 1H), 8.12 (d, 1H), 8.03 (t, 2H), 7.85 (dd, 1H), 7.72 (d, 1H), 5.54 (d, 1H), 3.21-3.12 (m, 4H), 3.02-2.97 (m, 1H), 2.83-2.79 (m, 1H).