Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[OH-].[Na+]>CC(C)=O.CO>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([C:1]([OH:13])=[O:12])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A solution of dimethyl isophthalate (25 g, 128.75 mmol) was dissolved in acetone (250 mL) and a solution of NaOH (5.4 g, 135 mmol) in methanol (50 mL) was added dropwise. A white precipitated was observed and the slurry was stirred for 18 h at room temperature. Then powdered NaOH (0.5 g) was added. The acetone was evaporated until dryness and the white residue was dissolved in water (250 mL), extracted with diethylether (2×100 mL). The aqueous solution was acidified with concentrated HCl to pH 4˜5 and the white precipitate was filtered, dried under vacuum and the desired monoacid obtained (17 g, 94.36 mmol, 73% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[N:20]=[C:21]=[O:22])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:18])[CH3:19])[C:12]=1[NH:20][C:21]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:22])([CH3:9])[CH3:10]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1ccncc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
4-Aminopyridine (100 mg, 1.06 mmol) and 2,6-diisopropylphenyl isocyanate (216.0 mg, 1.06 mmol) were dissolved in toluene, and the mixture was then stirred at 110° C. for 4 hr.
Reaction SMILES: Br[C:2]([CH3:16])=[C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1COCC1.C([Li])CCC.Cl[P:28]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[C:4]1([C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([P:28]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Br)=C(c1ccccc1)c1ccccc1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Temperature: -70 °C
Reaction time: 1.25 h
Yield: 72.5 %

Procedure:
Into a reactor were introduced 8.50 g (31.1 mmol) of the 2-bromo-1,1-diphenylpropene obtained in Example 1 (2) and 85 ml of THF under a nitrogen atmosphere. The contents were cooled to −70° C. Thereto was gradually added dropwise 21.4 mL (34.2 mmol; 1.6 M hexane solution) of butyllithium. The resultant mixture was stirred for 30 minutes. Thereafter, 8.25 mL (37.3 mmol) of chlorodicyclohexylphosphine was added, and this mixture was stirred for 75 minutes, subsequently heated to room temperature, and then further stirred for 15.5 hours. Water was added to the reaction mixture. The organic layer was extracted with ethyl acetate, and the extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol to obtain 8.80 g (72%) of the target compound as white crystals.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[CH:11][C:10]([O:13][C@@H:14]([CH:19]([CH3:21])[CH3:20])[C:15](OC)=[O:16])=[CH:9][CH:8]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(OCC)C.O>[C:7]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:11][C:10]([O:13][C@@H:14]([CH:19]([CH3:21])[CH3:20])[CH2:15][OH:16])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](Oc1ccc(-c2ccccc2)cc1)C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)[C@@H](CO)Oc1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A solution of lithium aluminium hydride (1.0M in tetrahydrofuran, 16 ml,) was added dropwise to a stirred (2S)-2-(biphenyl-4-yloxy)-3-methylbutyric acid, methyl ester (4.0 g, Example 8a)) in dry tetrahydrofuran (80 ml) at room temperature and the reaction was left to stir overnight. Water (0.6 ml), then aqueous sodium hydroxide (50%, 0.6 ml) then water (2.4 ml) were cautiously added to the solution at 0° C. Diethyl ether (200 ml) and anhydrous magnesium sulfate (10 g) were added and the solution stirred at room temperature for 10 minutes. The solution was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane then dichloromethane:ether (49:1) to give the sub-title compound as an oil which solidified on standing (3.43 g).
Reaction SMILES: [CH2:1]([C:3]1[CH2:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].NC1C=CC=CC=1.C(CC(OCC)=O)(=O)CC.[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([B:41]2[O:46]CC(C)(C)C[O:42]2)=[CH:37][CH:36]=1.CC1C=CC(B(O)O)=CC=1.CC(C)(CO)CO.BrN1C(=O)CCC1=O.[ClH:74]>CN1C(=O)CCC1.C1CCCCC1.C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N.O>[ClH:74].[CH2:1]([C:3]1[CH:12]=[C:11]([O:13][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([B:41]([OH:46])[OH:42])=[CH:37][CH:36]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CC1(C)COB(c2ccc(CBr)cc2)OC1
Reactant: CCC1=Nc2ccccc2C(=O)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(CO)CO
Agent: CCOC(=O)CC(=O)CC
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc(OCc2ccc(B(O)O)cc2)c2ccccc2n1
Reaction time: 0.33 h

Procedure:
A solution of 2-ethyl-4-quinolone (6.9 g; 0.04 mole), (prepared using a similar procedure to that described in Org. Syn., Coll., Vol. III, p. 374 and p. 593 from aniline and ethyl propionylacetate) in (NMP) (50 ml) was added over 30 minutes to a stirred suspension of sodium hydride (1.6 g of a 60% dispersion in mineral oil; 0.04 mole) in NMP (50 ml) and the mixture stirred for 30 minutes. A solution of 2-(4-bromomethylphenyl)-5,5-dimethyl-1,3,2-dioxaborinane in cyclohexane [previously prepared by heating a mixture of 4-methylphenylboronic acid (6.8 g) and 2,2-dimethylpropan-1,3-diol (5.2 g) in cyclohexane (150 ml) at reflux with azeotropic removal of water, followed by the addition of N-bromosuccinimide (8.9 g) and azo(bisisobutyronitrile) (0.2 g), heating the mixture at reflux for 3 hours, and removing suspended succinimide by filtration] was added and the mixture was heated at 60°-70° C. for 18 hours. The mixture was allowed to cool and acetic acid was then added until the mixture was at pH 4, followed by water (200 ml) and ethyl acetate (200 ml). The mixture was stirred for 20 minutes and then the organic phase was separated, washed with water and dried (MgSO4). Volatile material was removed by evaporation to give a crystalline solid. The solid was dissolved in ethyl acetate (150 ml), concentrated hydrochloric acid (3 ml) and water (3 ml) were added and the mixture was stirred for 18 hours. The resultant precipitate was collected by filtration, washed with ethyl acetate and dried to give 4-[(2-ethylquinolin-4-yloxy)methyl]phenylboronic acid hydrochloride (7 g) as a solid; NMR (d4 -methanol): 1.5(t,3H), 3.21(q,2H), 5.78(s,2H), 7.55(s,1H), 7.6-8.15(m,7H), 8.40(d,2H).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1)(=O)C.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[OH-]>CO>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH:12]=[CH:11][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1
Reactant: CC(=O)Oc1ccc(C=Cc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(C=Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 28.2 g of 2-(2-(4-acetoxyphenyl)ethenyl)quinoline in 500 ml of methanol is added 2.58 g (0.25 equiv.) of Na2CO3. This is stirred for 24 hours at room temperature. To this reaction mixture is then added 200 ml of pH7 buffer (25% NH4OH) and the precipitate that forms is filtered off, washed with methanol and dried to give 4-[2-(quinolin-2-yl)ethenyl]phenol (M.P. 268°-270° C.).
Reaction SMILES: [CH2-]C(C)=O.[CH2:5]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH2:18][C@@H:19]([OH:22])[CH2:20][OH:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C@H:19]([OH:22])[CH2:20][OH:21])=[CH:23][CH:24]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: OC[C@H](O)COc1ccc(OCc2ccccc2)cc1
Agent: [CH2-]C(C)=O
Solvent: O
Product: OC[C@@H](O)COc1ccc(OCc2ccccc2)cc1

Procedure:
The methanolic solution of (2S)-3-(4-benzyloxyphenoxy)-1,2-propanediol acetonide (~2 L) from the previous example was diluted with 120 ml water and combined with Dowex 50W-8X ion exchange resin (50 ml) in a flask fitted for distillation. The stirred mixture was heated to boiling and 1.8 L of distillate was collected over 3 hours. The reaction was diluted with ethanol (500 ml) and benzene (500 ml) filtered free of the resin and concentrated to dryness in vacuo. The residue was crystallized from ether and from ethyl acetate to give 137.0 g of (2R)-3-(4-benzyloxyphenoxy)-1,2-propanediol in several crops.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([SiH2][O:24][C:25](C)(C)[C:26]1[CH:27]=[C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])[CH:29]=[CH:30][C:31]=1[Cl:32])(C)(C)C.[NH4+].[Cl-]>C1COCC1>[Cl:32][C:31]1[CH:30]=[CH:29][C:28]([CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])=[CH:27][C:26]=1[CH2:25][OH:24]
Reactant: CC(=O)NCCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)NCCc1ccc(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
TBAF (1M in THF, 1.12 mL, 1.12 mmol) was added to a sol. of N-{2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-acetamide (190 mg, 0.555 mmol) in THF (7.10 mL) at 0° C. The mixture was stirred for 1 h while warming up to rt. Aq. sat. NH4Cl was added, and the mixture was extracted with EtOAc (3×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (100 mg, 79%). LC-MS: tR=0.67 min; ES+: 284.11.
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16](C)[C:17](=O)OC(C)(C)C)[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:5]1=2)(=[O:3])[CH3:2].[ClH:49]>O1CCOCC1.CCOCC>[ClH:49].[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([NH:16][CH3:17])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:29]=[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])[CH:31]=[CH:32][C:33]=2[O:34][CH3:35])[C:6]2[CH:43]=[CH:44][C:45]([C:47]#[N:48])=[CH:46][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2ccccc2F)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2cc(-c3ccccc3F)ccc2OC)c2ccc(C#N)cc2N(C(C)=O)[C@H]1C
Yield: 68 %

Procedure:
A rt solution of tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((2′-fluoro-4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (39 mg, 59.3 μmol) in 4 M HCl in dioxane (296 μl) was stirred for 1 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((3S,4S)-5-acetyl-7-cyano-1-((2′-fluoro-4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (23.9 mg, 68%) as a white solid. MS m/z 558 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:58][CH2:59][CH2:60][N:61]4[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]4)=[C:48]([O:51][CH2:52][CH:53]4[CH2:57][CH2:56][CH2:55][CH2:54]4)[CH:49]=3)[N:44]=[CH:43][N:42]=2)[CH:36]=[CH:37][C:38]=1[F:39].C(N(CC)CC)C>CN(C)C=O.O>[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:41]2[C:50]3[C:45](=[CH:46][C:47]([O:58][CH2:59][CH2:60][N:61]4[CH2:62][CH2:63][N:64]([C:7]([C@H:5]5[O:6][C:2](=[O:1])[CH2:3][CH2:4]5)=[O:9])[CH2:65][CH2:66]4)=[C:48]([O:51][CH2:52][CH:53]4[CH2:54][CH2:55][CH2:56][CH2:57]4)[CH:49]=3)[N:44]=[CH:43][N:42]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Fc1ccc(Nc2ncnc3cc(OCCN4CCNCC4)c(OCC4CCCC4)cc23)cc1Cl
Reactant: O=C1CC[C@@H](C(=O)O)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H](C(=O)N2CCN(CCOc3cc4ncnc(Nc5ccc(F)c(Cl)c5)c4cc3OCC3CCCC3)CC2)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
72 mg of (S)-(+)-5-oxo-tetrahydrofuran-2-carboxylic acid are dissolved in 2.5 ml of N,N-dimethylformamide, combined with 183 mg of (benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-tetrafluoroborate and stirred for 30 minutes at ambient temperature. This solution is then added to a mixture of 250 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentylmethoxy-7-[2-(piperazin-1-yl)-ethoxy]-quinazoline and 110 μl of triethylamine in 2.5 ml of N,N-dimethylformamide. The reaction mixture is stirred for five hours at ambient temperature. For working up the mixture is poured onto 50 ml of water. A white precipitate is formed, which is suction filtered and washed with water. The crude product is purified by chromatography over an Alox column (activity stage III) with methylene chloride/methanol (98:2) as eluant. The desired product is obtained as a light-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[C:32]([CH2:34][O:35][Si](C(C)(C)C)(C)C)[CH:31]=[CH:30][N:29]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:33]=[C:32]([CH2:34][OH:35])[CH:31]=[CH:30][N:29]=1)=[O:27]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(CO)ccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-4-(tert-butyldimethylsilyloxymethyl)pyridine*.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:18][C@H:17]([N:19]=[N+]=[N-])[CH2:16][C@H:11]2[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([S:7]([N:10]2[CH2:18][C@H:17]([NH2:19])[CH2:16][C@H:11]2[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](N)CN1S(=O)(=O)c1ccccc1
Yield: 100 %

Procedure:
A solution of 0.35 g (1.13 mmol) of 17 and 10% Pd/C (ca 50 mg) in 5 mL of methanol stirred under hydrogen (60 psi) overnight. The resulting mixture was filtered through a Celite plug and the filtrate concentrated to give 0.32 g (1.13 mmol, 100%) of 18 as a pale yellow syrup. Compound 18 was used without further purification. 1H-NMR (400 MHz, CDCl3, δ ppm) 7.86 (d, J=8 Hz, 2H), 7.57 (t, J=7 Hz, 1H), 7.51 (t, J=8 Hz, 2H), 4.40 (t, J=8 Hz, 1H), 3.68 (s, 3H), 3.63 (m, 1H), 3.69 (q, J=5 Hz, 1H), 3.05 (m, 1H), 2.13 (m, 1H), 1.91 (m, 1H), 1.59 (br s, 2H); 13C-NMR (400 MHz, CDCl3, 6 ppm) 172.79, 138.30, 133.35, 129.44, 127.94, 59.85, 56.26, 52.90, 51.01, 40.02; m/z: 285 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](OC)=O)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:29][C:30]1[NH:20][C:18](=[O:19])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 2.5 g (11.4 mmol) of methyl 3,4-dichlorophenylacetate.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:3]=1.[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>CO>[CH:17](=[N:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)[N:3]=1)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]
Reactant: O=Cc1ccccc1O
Reactant: NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Solvent: CO
Product: Oc1ccccc1C=NC1=NN(c2cccc(C(F)(F)F)c2)CC1
Yield: 51.9 %

Procedure:
A solution of 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (2.29 g) and salicylaldehyde (1.2 g) in methanol (22.9 ml) was heated to reflux for 30 minutes. The resulting semi-solid mass was cooled and then filtered to give an orange-coloured solid which was re-crystallized from ethanol to produce 3-salicylideneamino-1-(3-trifluoromethylphenyl)-2-pyrazoline m.p. 159.1° (yield 1.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[C:6]([C:8]([O:13][CH3:14])([CH:10]([OH:12])[CH3:11])[CH3:9])[CH:7]=1.[CH3:27]I>>[CH3:27][O:12][CH:10]([CH3:11])[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=1)([O:13][CH3:14])[CH3:9]
Reactant: COC(C)(c1cc(F)cc(OCc2ccc3ccccc3c2)c1)C(C)O
Reactant: CI
Product: COC(C)C(C)(OC)c1cc(F)cc(OCc2ccc3ccccc3c2)c1
Yield: 60 %

Procedure:
Using the procedure described in Example 8, (2RS,3SR)-2-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-2-methoxybutan-3-ol was reacted with methyl iodide to give (2RS,3SR)-2-(5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-2-methoxybut-3-yl methyl ether in 60% yield, m.p. 75°-76° C.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[CH2:6]([N:13]([CH2:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.OS(O)(=O)=O.O=S(=O)=O>O>[CH2:20]([N:13]([CH2:6][C:7]1[C:8]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21]
Reactant: O=S(=O)(O)O
Reactant: CCN(Cc1ccccc1)c1ccccc1
Agent: O=S(=O)=O
Solvent: O
Product: CCN(Cc1ccccc1S(=O)(=O)O)c1ccccc1
Temperature: 60 °C

Procedure:
To 30.0 g. of 100% sulfuric acid is added N-benzyl-N-ethylaniline (30.0 g.) dropwise below about 50° C. To this solution is added, at 50°-60° C., 60% oleum (30.0 g.) with good stirring. The mixture is stirred and heated at about 60° C. for three hours and then drowned into 200 ml of water. The free sulfonic acid (Coupler I) which is mostly the meta isomer with a small amount of para, precipitates on standing and is collected by filtration, washed with water, and dried. N-Benzylanilines containing groups such as alkyl, alkoxy, and halogen in the ortho, meta, or para positions of the benzyl group may also be sulfonated by this procedure. The exact location of the sulfonic acid group in these cases is often not known and mixtures usually are produced.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:13][O:14]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:13][OH:14])[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: COC(CO)COCc1ccccc1
Temperature: 25 °C

Procedure:
rac-1-O-Benzyl-2-O-methyl-3-O-tritylglycerol (6.73 g) and 80% HOAc (50 ml) were combined in a 100 ml flask and heated at reflux for three hours. The heat was removed and the reaction mixture was allowed to cool to room temperature. The reaction was neutralized with 10% KOH and extracted with ether. The ether layer was dried (MgSO4) before the solvent was removed in vacuo. Purification of the residue was obtained by column chromatography (150 ml silica gel; hexanes:ethyl acetate, gradient 5:1-0:1). The pure compound 14, rac-1-O-benzyl-2-O-methylglycerol, was obtained as a clear oil (1.84 g, 59.7% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH2:12][OH:13])[N:11]=[C:4]2[N:3]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(CO)nc2n1
Solvent: Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(C=O)nc2n1
Temperature: 25 °C

Procedure:
To a 10 L reactor was sequentially charged CH2Cl2 (5.1 L), (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol (680 g, 3.816 mol), and iodobenzene diacetate (1352 g, 4.197 mol). As the iodobenzene diacetate dissolves, there is a significant endotherm (typically down to 15-16° C.). The jacket was set to 23° C. The mixture was warmed to ambient temperature and Tempo (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical, 43.75 g, 0.28 mol) added in a single charge. The reaction was stirred until 5% of the starting alcohol remained by HPLC. Once the starting material is adjudged to be less than about 5%, the over-oxidized product begins to be observed. Allowing the reaction to run to further completion leads to an overall diminished yield of the desired product. For this reaction, the desired reaction completion was reached in 2.75 h. MTBE (5.1 L) was then slowly charged to the reactor, causing the product to precipitate, and the slurry stirred for an additional 30 mins. The mixture was filtered, washed twice with 1:1 DCM/MTBE (2×1 L), and dried in a vacuum oven overnight at 50° C. to provide 500.3 g (74%) of 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde as an off-white solid. 1H NMR (300 MHz, d6-DMSO): 2.64 (s, 3), 2.78 (d, 3, J=0.8), 7.36 (d, 1, J=0.9), 10.13 (s, 1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C@@H:11]([CH3:21])[N:10]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:9]1=[O:27])(C)(C)C>C(OCC)(=O)C>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C@@H:11]([CH3:21])[N:10]([CH2:22][C:23]([F:24])([F:25])[F:26])[C:9]1=[O:27]
Reactant: Cc1ccccc1[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(F)(F)F)[C@@H]1C
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@@H]1C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]1C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl[(3S,5S,6R)-6-methyl-5-(2-methylphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]carbamate (152 mg, 0.37 mmol) in ethyl acetate (10 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The reaction mixture was allowed to sit for 30 min at 0° C. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=301.3 (M+1).
Reaction SMILES: [OH:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5]OC1.[O:33]1[CH2:38]CC(=O)[CH2:35][CH2:34]1>>[OH:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:18][CH:19]([C:21]4[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=4)[CH2:20]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:35][CH2:34][O:33][CH2:38][CH2:5]1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)COC2)nc1C
Reactant: O=C1CCOCC1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)CCOCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 192, except dihydro-2H-pyran-4(3H)-one was used in place of oxetan-3-one. m/z (ES+) 457 (M+H)+.