Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][CH2:11][NH:12][NH2:13]>C(O)C>[OH:9][CH2:10][CH2:11][NH:12][N:13]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNCCO
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: OCCNN=Cc1ccccc1
Yield: 97 %

Procedure:
Benzaldehyde (2-hydroxyethyl)hydrazone is prepared by condensation of benzaldehyde with (2-hydroxyethyl)hydrazine according to the following procedure: 10-2 moles of (2-hydroxyethyl)hydrazine are added to a solution containing 10-2 moles of benzaldehyde in 20 ml of ethanol. The reaction is left under reflux for 30 minutes. The mixture is then cooled. The solvents are removed by evaporation. The product obtained is an extremely unstable oil. The crude reaction yield is 97%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](F)[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([F:16])[N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)n1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(F)n1

Procedure:
The title compound, off-white cristalline solid, MS: m/e=312.1, 314.1 (M+H+) was prepared in accordance with the general method of example 1b from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2,6-difluoropyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[C:11](Cl)(=[O:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>>[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N[C@@H]1CCCC[C@H]1N(C)C

Procedure:
This amide was prepared by general procedure A from trans-2-(dimethylamino)cyclohexylamine and acetyl chloride. In the work up the aqueous layer was salted out with solid K2CO3, and extracted well with ether. The resulting oil was recrystallized from ether-petroleum ether (30°-60°) to give colorless rods of the sub-titled amide, 79% yield, m.p. 86°-87.5° raised to 88°-89° on recrystallization. ir NH 3280, 3080; N-alkyl 2770; C=O 1660, 1640; amide II 1565. nmr in CDCl3 and 100 MHz was in accord. Mass spectrum M+ 184.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=O)C.C([C:39]([O:41][CH3:42])=[O:40])#N>C1COCC1>[CH3:42][O:41][C:39]([CH:23]1[CH2:24][CH:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:20][CH2:21][C:22]1=[O:25])=[O:40]
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CC(CCOCc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A solution of LDA (33 ml, 1.5 M in Et2O) in THF (50 mL) at −78° C. was treated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). The mixture was warmed to 0° C. over 30 minutes before re-cooling to −78° C. and adding HMPA (7 mL). Methyl cyanoformate (4.1 mL, 85 mmol) was added, and the mixture stirred for 15 minutes before aqueous quench and work-up. The product was purified by chromatography on SiO2 with 10% EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester was isolated, 5.8 g (49%), and reduced with an equivalent of NaBH4 in MeOH at −10° C. The alcohol (Intermediate R2 above) was purified by chromatography on SiO2 with 30 to 50% EtOAC:Hx. (˜90% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Br)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[S:26]([CH3:29])(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:33]4[CH2:32][CH2:31][CH:30]([N:25]([S:26]([CH3:29])(=[O:27])=[O:28])[CH3:24])[CH2:35][CH2:34]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C1CCNCC1)S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ncc3O2)CC1
Product: CN(C1CCN(c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)CC1)S(C)(=O)=O

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and N-methyl-N-piperidin-4-ylmethanesulfonamide following a procedure analogous to that described in Example 79. LC (method 10): tR=1.35 min; Mass spectrum (ESI+): m/z=495 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:28])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:26](=[O:27])[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1c2c(cc3c1c1c(C(N)=O)cccc1n3Cc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 31.2 %

Procedure:
40% Methanolic Triton B (0.148 mL, 0.325 mM) was added to a solution of 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid amide, (0.094 g, 0.25 mM) in 5 mL DMF at room temperature. After 2 minutes, methyl bromoacetate (0.049 mL, 0.076 g, 0.5 mM) was added and the resultant mixture stirred at room temperature for 2 h. Cesium carbonate (0.041 g, 0.125 mM) was then added as a solid, and the mixture allowed to stir at room temperature for an additional 2 h. The mixture was diluted with ethyl acetate, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting tan foam was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.035 g (31%) of the title compound (5-benzyl-1-carbamoyl-7,8,9,10-tetrahydro-5H-benzo[b]carbazol-11-yloxy)-acetic acid, methyl ester as a white solid (MP 174–177° C., MW 442.52).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2.S(Cl)([Cl:21])=O>CCOCC>[Cl:21][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: CCOCC
Product: COc1ccc2c(c1)C(Cl)c1ccccc1CO2
Temperature: 5 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
11-Hydroxy-2-methoxy-6,11-dihydrodibenz[b,e]oxepin (13.85 g, 0.057 mole) is dissolved in anhydrous ether (180 ml) and cooled to 5° C. under a dry nitrogen atmosphere. Thionyl chloride (7.37 g; 0.062 mole) in ether (20 ml) is added dropwise while maintaining the temperature below 5° C. (Near the end of the addition a solid precipitates from the solution). The reaction is stirred at ambient temperature for 3 hours and filtered. The filtrate is removed in vacuo to give a solid which is combined with the filtered solid and recrystallized from cyclohexane to provide 10.5 g (70%) of crystals of 11-chloro-2-methoxy-6,11-dihydrodibenz[b,e]oxepin, m.p. 133°-134.5° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH:21]4[CH2:23][CH2:22]4)[CH2:26][CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCN(CC2CC2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-(cyclopropylmethyl)piperazine (57184-25-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=407.6 [MH+].
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[C:7]([C:10]1[O:14][C:13]([CH2:15][CH3:16])=[N:12][C:11]=1[CH3:17])(=[O:9])[CH3:8]>>[CH2:15]([C:13]1[O:14][C:10]([C:7]([C:2]2[CH:6]=[CH:5][O:4][CH:3]=2)([OH:9])[CH3:8])=[C:11]([CH3:17])[N:12]=1)[CH3:16]
Reactant: CCc1nc(C)c(C(C)=O)o1
Reactant: Brc1ccoc1
Product: CCc1nc(C)c(C(C)(O)c2ccoc2)o1

Procedure:
Starting with 3-bromofuran and 5-acetyl-2-ethyl-4-methyloxazole and following the general method of Example 4 the title compound was prepared.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)C.[OH-].[Na+]>CO>[C:4]([CH2:5][C@H:6]([NH:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])=[CH:10][CH:9]=1)([OH:31])=[O:3]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cc(F)ccc2OC)cc1)NC(=O)CCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1-c1ccc(C[C@H](CC(=O)O)NC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
To a solution of (R)-4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylannino)-4-oxobutanoic acid (83 mg, 0.192 mmol) in MeOH (2 mL) is added 1N NaOH (4 mL, 4 mmol) After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-4-(1-carboxy-3-(5′-fluoro-2′-methoxybiphenyl-4-yl)propan-2-ylamino)-4-oxobutanoic acid (58 mg). HPLC retention time=1.46 minutes (condition D); MS (m+1)=404.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.36-2.59 (m, 6 H) 2.84 (dd, J=13.4, 6.3 Hz, 1 H) 2.91 (dd, J=13.4, 6.3 Hz, 1 H) 3.75 (s, 3 H) 4.34-4.56 (m, 1 H) 6.95-7.08 (m, 3 H) 7.26 (d, J=8.1 Hz, 2 H) 7.42 (d, J=8.3 Hz, 2 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.Cl.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH2:48][NH2:49])=[CH:40]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:49][CH2:48][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[NH:39][CH:40]=1)=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1c[nH]c2ccccc12
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2c[nH]c3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1H-indol-3-yl)-methylamine dihydrochloride.
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][CH2:8][CH2:9][N:4]2[C:3](=[O:10])[O:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=2)[CH:15]=[N:14][N:13]=1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:22][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[C:12]([N:7]1[CH2:8][CH2:9][N:4]3[C:3](=[O:10])[O:2][CH2:1][C@H:5]3[CH2:6]1)=[N:13][N:14]=[CH:15]2
Reactant: Clc1ccc2c(Cl)nncc2c1
Reactant: O=C1OC[C@H]2CNCCN12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C1OC[C@H]2CN(c3nncc4cc(Cl)ccc34)CCN12
Temperature: 140 °C

Procedure:
The title compound was prepared by a method analogous to that described in Example 8 (Method A). A mixture of (R)-tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (0.800 g, 5.63 mmol), 1,6-dichlorophthalazine (0.516 g, 2.59 mmol) and N,N-diisopropylethylamine(1.40 mL, 8.04 mmol) in 3 mL 1-methyl-2-pyrolidone was heated at 140° C. After 4.5 h the reaction was cooled to RT, quenched with H2O and extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, evaporated onto silica gel and purified by flash chromatography eluting with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:39) to give 1.18 g of a brown liquid. MS m/z: 305.1 [M+1].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH:13]=[CH2:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)[C:12](=[O:15])[CH2:13][CH2:14][C:28]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][N:22]=2)=[O:29])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: O=Cc1cnccn1
Reactant: C=CC(=O)C(CC1CCOC1)c1ccc(S(C)(=O)=O)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCOC2)C(=O)CCC(=O)c2cnccn2)cc1
Temperature: 25 °C
Yield: 14.2 %

Procedure:
To a solution of 4-[4-(methylsulfonyl)phenyl]-5-(tetrahydrofuran-3-yl)pent-1-en-3-one (523 mg) in ethanol (8.5 mL) were added pyrazine-2-carbaldehyde (220 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (50.5 mg) and triethylamine (102 μL), and the mixture was stirred with heating under reflux for 3 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (100 mg, yield 14%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (19:1, volume ratio).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[F:7][C:8]1[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=1)[CH2:11][NH:12][C:13]([NH:15][C:16]1[S:17][CH:18]=[C:19]([CH:21]=O)[N:20]=1)=[O:14].[CH3:26][NH2:27]>CCO>[C:26]([CH:21]([NH:6][CH3:5])[C:19]1[N:20]=[C:16]([NH:15][C:13]([NH:12][CH2:11][C:10]2[CH:23]=[CH:24][CH:25]=[C:8]([F:7])[CH:9]=2)=[O:14])[S:17][CH:18]=1)#[N:27]
Reactant: O=Cc1csc(NC(=O)NCc2cccc(F)c2)n1
Reactant: C[Si](C)(C)C#N
Reactant: CN
Solvent: CCO
Product: CNC(C#N)c1csc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyl cyanide (161 μL) was added to a solution of 1-(3-fluoro-benzyl)-3-(4-formyl-thiazol-2-yl)-urea (409 mg) and MeNH2 (8 M, 0.4 mL) in (EtOH 10 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The additional of 170 μL of trimethylsilyl cyanide was added to convert all starting material into the product. The product was purified by aqueous work-up and chromatography.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12]Br>II>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([F:11])=[C:9]([Br:12])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(F)cc1
Agent: II
Product: CC(C)(C)c1ccc(F)c(Br)c1
Yield: 48.5 %

Procedure:
In this example 5-t-butyl-2-fluorophenol, the starting material for the dealkylation process of this invention, was prepared by first alkylating 480 grams of fluorobenzene with 370 grams of t-butylchloride in the presence of 16.6 grams of aluminum chloride and 33 grams of nitromethane as solvent for the reaction at a temperature ranging from about 0° to 2° C., the t-butylchloride being added incrementally to the mixture of fluorobenzene, aluminum chloride and nitromethane in about 2.5 hours and maintained for about an additional hour at this temperature. The resulting 4-t-butyl-fluorobenzene was recovered by treating the reaction mixture with 150 ml water at 0°-10° C. followed by washing with 5% aqueous NaOH, and the organic layer was then separated, followed by fractionation at about 5 mm reduced pressure and 547 grams of product collected from about 48°-52° C. to yield about a 70% conversion and 86% selectivity to p-t-butylfluorobenzene via gas liquid chromatographic analysis. Following this 304 grams of 4-t-butylfluorobenzene so prepared and a catalyst comprising 12.3 grams of iodine were placed in another reaction apparatus and brominated by incrementally adding about 372 grams of bromine during a period of about 3 hours while maintaining the temperature of the reaction at about 60°-65° C., and then maintaining the reaction mixture for about an additional 9 hours. Upon completion of the bromination the organic layer was washed with saturated sodium thiosulfate solution and then with water, dried and the recovered 312 grams of product was fractionated under a reduced pressure of about 3 mm to isolate about 224 grams of the desired 4-t-butyl-2-bromofluorobenzene distilling at about 40°-77° C. The heart cut of this distillate of about 171 grams analyzed about 90% pure via gas liquid chromatography. To obtain the next product comprising 5-t-butyl-2-fluorophenol the thus formed 4-t-butyl-2-bromo-fluorobenzene (20.0 grams) was hydrolyzed by treatment with 160 ml of water in the presence of 18.6 grams of potassium fluoride and 1.0 grams of cuprous oxide plus 40 grams of sulfolane as a co-solvent, said reaction being effected at an elevated temperature of 250° C. and under a nitrogen atmosphere at a total pressure of about 525 pounds per square inch. At the end of about eight hours of reaction period, the autoclave and contents thereof were allowed to return to room temperature, the excess pressure was discharged, and the product recovered from the mixture by extraction with toluene. Distillation under reduced pressure provided about 11.4 grams of the desired product comprising 5-t-butyl-2-fluorophenol corresponding to a conversion of about 85% and a selectivity of about 70%. N-methylpyrrolidone may also be effectively used as the co-solvent in this hydrolysis.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH3:29])[C:25]=1[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(C=O)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(CN2CCOCC2)c1
Reaction time: 8 h

Procedure:
3-[5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-3-methyl-isoxazol-4-yl]-benzaldehyde (25 mg, 0.05 mmol) and morpholine (0.3 ml) were mixed with DCE (0.5 ml) in an microwave tube. Sodium triacetoxyborohydride (15 mg, 1.4 equiv) was added, the tube sealed, and nitrogen atmosphere introduced. After 1 hr more sodium triacetoxyborohydride (15 mg) was added and the reaction left stirring overnight. TLC analysis showed that the reaction had not gone to completion so a drop of acetic acid was added and the reaction again left stirring overnight after which the reaction was quenched with 1M NaHCO3 solution (7 ml) and extracted into EtOAc (5 ml). This was dried over MgSO4 and the solvent removed in vacuo to provide 13 mg of the crude product as an off white powder which was taken over to the deprotection step.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[N:15][CH:16]=2)[O:8][N:7]=1.[C:20](OCC)(=O)C.O>CO>[CH3:5][C:6]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[N:15][CH:16]=2)[O:8][N:7]=1
Reactant: Cc1noc(-c2cncc(C(=O)O)c2)n1
Reactant: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1cncc(-c2nc(C)no2)c1
Temperature: 25 °C

Procedure:
Thionyl chloride (2.5 ml) was added dropwise in methanol (25 ml) under cooling at 7°-9° C. After the mixture was stirred for 30 minutes at the same temperature, 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylic acid (2.5 g) was added thereto and the mixture was refluxed for 3 hours. After being cooled to room temperature, the mixture was poured into a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer was successively washed with 10% potassium carbonate aqueous solution and brine, and then dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from diethyl ether to afford methyl 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-pyridinecarboxylate (2.12 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:35][CH2:36]SC)[C:13]([NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][C@H:17]1[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>IC.CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:35][CH2:36][N:15]([C@H:16]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:18][C@H:17]2[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@H]1CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38 %

Procedure:
tert-Butyl (1R,3R,4S)-4-((S)-2-benzyloxycarbonylamino-4-(methylthio)butanamido)-3-(methylsulfonylmethyl)cyclohexylcarbamate (6.9 g) was dissolved in iodomethane (100 mL), and the resulting solution was stirred at rt for 72 h before being concentrated in vacuo. The residue was dissolved in methylene chloride, and the resulting solution was concentrated; this was repeated to afford the salt. MS found: (M+H)+=586.5. This material was dissolved in DMF (20 mL) and the solution was charged with Cs2CO3 (12.0 g). After 12 h, the reaction was partitioned between EtOAc and brine. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(methylsulfonylmethyl)cyclohexylcarbamate (2.4 g). MS found: (M+H)+=524.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]3[CH:28]=[CH:27][C:21]4[CH2:22][CH2:23][CH2:24][NH:25][CH2:26][C:20]=4[CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[ClH:1].[C:29]([N:25]1[CH2:24][CH2:23][CH2:22][C:21]2[CH:27]=[CH:28][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)=[CH:19][C:20]=2[CH2:26]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc(C2CCN(CCCOc3ccc4c(c3)CNCCC4)CC2)cc1
Product: CC(=O)N1CCCc2ccc(OCCCN3CCC(c4ccc(Cl)cc4)CC3)cc2C1
Product: Cl

Procedure:
Using 8-[3-[4-(4-chlorophenyl)-1-piperidinyl]propoxy]-2,3,4,5-tetrahydro-1H-2-benzazepine obtained in Example 207 and acetic anhydride, the title compound was obtained as colorless amorphous powder by the same procedure as in Example 17.