Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(Cl)(Cl)Cl.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-phenylbenzamido)-4-phenylbenzoate (0.11 g) in methanol (4 mL) and chloroform (4 mL), 10% palladium-carbon (40 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 5 hours and 30 minutes and then at 35° C. for 1 hour. To the reaction mixture, 10% palladium-carbon (40 mg) was added, followed by stirring under a hydrogen atmosphere at 35° C. for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid substance was collected by filtration to obtain tert-butyl 2-(2-hydroxy-4-phenylbenzamido)-4-phenylbenzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:27].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:27].[CH3:26][C:2]1([CH3:1])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([O:19][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:31]3[CH2:30][CH2:29][O:28][CH2:33][CH2:32]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(morpholino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine and γ-morpholinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: C(ON=O)CC(C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:23])[C:16]([CH3:22])=[C:17]([C:20]#[N:21])[C:18]=1N)=[O:13])[CH3:10].[I:24]CI.O>C(#N)C>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:23])[C:16]([CH3:22])=[C:17]([C:20]#[N:21])[C:18]=1[I:24])=[O:13])[CH3:10]
Reactant: ICI
Reactant: CCOC(=O)c1c(N)c(C#N)c(C)n1C
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(I)c(C#N)c(C)n1C
Temperature: 55 °C

Procedure:
Add isoamylnitrite (2.5 Eq.) to 3-amino-4-cyano-1,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in preparation 44) and diiodomethane (3.5 eq.) in acetonitrile (10 mL) with stirring at 55° C. under a nitrogen atmosphere. Slowly heat the reaction mixture to 75° C. and heat at this temperature for 3 hours. Cool to room temperature and pour into water, and extract the quenched reaction with ethyl acetate. Wash the organic extracts with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the residue by silica gel chromatography (Prep.2000) eluting with methylene chloride to provide a solid. Recrystallize from ethyl acetate to provide the title compound as crystals. Mass spectrum (m/e): 318.0 M*). (Bruker 300) 1H NMR (CDCl3) 4.31-4.38 (2H, dd), 3.83-3.86 (3H, s), 2.41-2.44 (3H, s), 1.40-1.44 (3H, t).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NC1CCc2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NC1CCc2ccccc2C1=O
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Chloroacetyl chloride (14 g, 124 mmol) was added to a solution of 2-amino-3,4-dihydro-2H-naphthalen-1-one hydrochloride (16 g, 81 mmol) and triethylamine (41 g, 405 mmol) in tetrahydrofuran (600 ml) and the mixture was stirred for one hour. The solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (7.58 g, 31.9 mmol, 39%) as white crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[C:7]([CH:10]=O)=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:23][N:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][CH:18]=2)[C:7](/[CH:10]=[C:30]2/[N:24]([CH3:23])[C:25](=[O:26])[NH:27][C:28]/2=[O:29])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: CN1CC(=O)NC1=O
Product: CCCCc1ncc(/C=C2\C(=O)NC(=O)N2C)n1Cc1ccc(C(=O)O)cc1

Procedure:
This compound is prepared by a procedure similar to Example 1 except that the starting materials are the ester derivative, 2-butyl-1-(4-carbomethoxybenzyl)-5-formylimidazole, and 1-methylhydantoin. The crude mixed isomer products are purified and separated by silica gel column chromatography, eluting with 0.1:1.5:10 glacial acetic acid-methanol-chloroform. The "slow" moving material is the (E) isomer; tlc (0.1:2:10 acetic acid-methanol-chloroform system) 1 spot, Rf 0.5; mp 219°-221° C.; nmr (DMSO-d6), vinyl proton at δ 5.96 ppm; MS (CI) 383 (M39 +1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:9])=[N:7][OH:8])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[C:19][CH2:20][CH2:21][C:22](O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:9]=[C:22]([CH2:21][CH2:20][C:19]#[C:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(F)cc1
Reactant: O=C(O)CCC#Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: Fc1ccc(-c2noc(CCC#Cc3ccccn3)n2)cc1
Temperature: 100 °C
Yield: 25.1 %

Procedure:
A mixture of commercially available 4-fluoro-N′-hydroxybenzamidine (220 mg, 1.4 mmol), 5-(pyridin-2-yl)pent-4-ynoic acid (330 mg, 1.4 mmol), HOBT (210 mg, 1.4 mmol) and EDCI.HCl (400 mg, 2.1 mmol) in dioxane (4.5mL) was stirred at R.T for 7H, The reaction mixture was then heated at 100° C. for 36 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM. The organic layer was washed with water, 1N NaOH and water. The organic layer was dried over Na2SO4, filtred and evaporated. Purification by flash chromatography (prepacked 10 g silicagel column, DCM/MeOH: 99/1 as eluent) to afford 103 mg of 2-(4-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)but-1-ynyl)pyridine (Yield: 25%) as a yellow oil.
Reaction SMILES: N[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:10]([Cl:24])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:25]([NH2:27])=[O:26].Cl.C(=N)(OCC)C.C(O)C>C(OCC)C>[ClH:14].[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:11]2[C:12]([Cl:14])=[CH:13][C:8]([CH2:7][N:6]3[CH:2]=[C:3]([C:25]([NH2:27])=[O:26])[N:4]=[N:5]3)=[CH:9][C:10]=2[Cl:24])=[O:23])=[CH:21][CH:20]=1
Reactant: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Agent: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: NC(=O)c1cn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)nn1

Procedure:
A mixture of 5-amino-1-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide (4.3 g), ethyl acetimidate hydrochloride (1.2 g) and absolute ethanol (50 ml) is heated at reflux under nitrogen for 20 hours. The reaction mixture is cooled and diluted with ethyl ether (50 ml). The solid is filtered and dried to give 5-((amino)ethylidine) amino)-1[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide hydrochloride.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16](Cl)=[CH:15][N:14]=1)=[O:12].[C:38]1(B(O)O)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C.Cl[Pd]Cl>[O:7]=[C:8]([N:20]1[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]1)[CH2:9][NH:10][C:11]([C:13]1[CH:18]=[N:17][C:16]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:15][N:14]=1)=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(Cl)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(-c2ccccc2)cn1
Temperature: 90 °C
Yield: 13.2 %

Procedure:
Na2CO3 (140 mg, 1.32 mmol) was added to a stirred solution of 5-chloro-pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (200 mg, 0.44 mmol) in DMF (3 mL). PdCl2 (dppf) (96 mg, 0.13 mmol) and phenyl boronic acid (64 mg, 0.52 mmol) were then added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was filtered, filtrate was then diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated to afford 29 mg (13.3% yield) of 5-phenyl-pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 93.2%. 1H NMR (CDCl3): δ 9.4 (d, 1H), 9.0 (d, 1H), 8.7-8.6 (m, 1H), 8.1-8.0 (m, 2H), 7.8-7.7 (d, 1H), 7.7-7.5 (m, 5H), 7.4-7.3 (d, 1H), 4.46-4.18 (m, 2H), 4.46-4.18 (m, 2H), 4.1-3.86 (m, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[C:23]([CH3:39])=[CH:22][C:18]=1[C:19](Cl)=[O:20].OC1C(C)=CC(C(OC)=O)=C(C)C=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:3][C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([CH3:39])[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)=[CH:25][C:17]=1[CH3:16]
Reactant: Cc1cc(C(=O)Cl)c(C)cc1OC[C@@H]1CN(C)c2ccccc2O1
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(N)c1
Agent: COC(=O)c1cc(C)c(O)cc1C
Product: Cc1cc(C(=O)Nc2cc(C(C)(C)C(=O)O)ccc2Cl)c(C)cc1OC[C@@H]1CN(C)c2ccccc2O1
Yield: 66.1 %

Procedure:
By the same procedures as a series of Example 18 and Example 19 using the compound (139 mg) prepared in Example 16 and 2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride (211 mg) (the compound prepared by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2,5-dimethylbenzoate.), the title compound (211 mg) having the following physical data was obtained.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][C:33](O)=[O:34])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]=[CH:32][C:33]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]([CH3:2])[CH:4]=2)=[O:34])=[CH:36][CH:37]=1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Yield: 95.4 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (2.0 g), triethylamine (1.1 mL), 4-fluorocinnamic acid (1.4 g), WSC.HCl (1.6 g), and methylene chloride (80 mL), to give the captioned compound (2.7 g, 94%) as an oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C=Nc1ccccc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Nc4ccccc4)cc3c2C1
Yield: 7 %

Procedure:
Beginning with 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 10.4 (0.0874 mMol) phenyl isocyanate, 1.0 mg (7%) of the title compound was recovered using the procedure described in detail in Example 12.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)(=[O:11])=[O:10].[CH3:25][O-:26].[Na+].[ClH:28]>CO.O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([O:26][CH3:25])[CH:5]=[CH:4][C:3]=1[S:9]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)(=[O:10])=[O:11].[ClH:28]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(F)cc2F)CC1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)C2CCNCC2)c(F)c1
Temperature: 45 °C
Reaction time: 0.33 h

Procedure:
To a suspension of tert-butyl 4-((2,4-difluorophenyl)sulfonyl)piperidine-1-carboxylate (50 mg, 0.138 mmol) in MeOH (461 μL) was added sodium methoxide (25.6 μL, 0.138 mmol, 5.4 M in MeOH) dropwise. The reaction mixture was allowed to stir at 45° C. for 20 min then concentrated in vacuo. Boc deprotection was carried out by addition of HCl (138 μL, 0.553 mmol, 4 M in dioxane) to the crude reaction mixture in 300 μL dioxane. Stirring at 50° C. for 24 h followed by concentration in vacuo yielded the title compound as its HCl salt (57 mg) as a white solid (10:1 regioisomeric mixture). ESI-MS m/z [M+H]+274.00.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]([O:17]CC)=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl.[CH2:30]([NH:37][NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH2:30]([NH:37][NH:38][C:15]([C:13]1[O:12][N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=2)[N:14]=1)=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: NNCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(NNCc1ccccc1)c1nc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 70 °C
Yield: 40.1 %

Procedure:
To a suspension of ethyl 3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxylate (Intermediate A) (1.0 g, 3.3 mmol) and K2CO3 (1.1 g, 13 mmol) in THF (17 mL) was added benzylhydrazine dihydrochloride (780 mg, 5.0 mmol). The mixture was heated to 70° C. for 3 h. The mixture was cooled to RT, filtered (Celite), and concentrated under reduced pressure. The crude oil was purified by Biotage (5% EtOAc/Hexane—60% EtOAc) to provide a white solid (500 mg, 40%): MS (ES+) C17H13F3N4O3 requires: 378. found: 379 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.O=[CH:26][CH2:27][CH2:28][NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH2:32]([O:31][C:30]([NH:29][CH2:28][CH2:27][CH2:26][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]1)=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2N)CC1
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccccc2NCCCNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
The compound prepared in Example 302 (0.455 g) was suspended in 1,2-dichloroethane (10 mL). Benzyl 3-oxopropylcarbamate (0.425 g) and beaded molecular sieves were added and the reaction mixture stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.870 g) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 20-30% ethyl acetate/hexane) to furnish the title compound (0.629 g) with the following physical properties.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8](Cl)[N:7]=1>C(Cl)Cl>[Cl:5][C:6]1[N:7]=[C:8]([N:3]([CH3:4])[CH3:2])[CH:9]=[C:10]([Cl:12])[N:11]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)c1cc(Cl)nc(Cl)n1
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Dimethylamine hydrochloride (35.6 g, 0.44 mol) was added to a vigorous stirring solution of 2,4,6-trichloropyrimidine (80.0g, 0.44 mol) in CH2Cl2 (1.5 L) at −78° C. Triethylehtylmine (88.2 g, 0.87 mol) was added dropwise to the above mixture and stirred for 3 hours at −78° C. The resulting mixture was brought to 0° C. over a period of 3 hours and the reaction was then quenched with water (250 mL). The organic layer was separated, washed with aqueous citric acid (2×100 mL), brine (2×200 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography [eluent: EtOAc/hexanes (1:9)], giving the desired product (59.9 g, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:19][C:20]1[C:25]([CH2:26][C:27](O)=[O:28])=[CH:24][CH:23]=[C:22]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=2)[N:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:17][C:27](=[O:28])[CH2:26][C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=3)=[CH:23][CH:24]=2)=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNC(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 84A]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[4-(2-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:6]1[C:5]2[CH:31]=[C:32]([F:33])[C:2]([F:1])=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]([C:18]1[N:19]=[C:20]([CH3:30])[S:21][C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:17]
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Reactant: CN(C)CCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3n2CCN(C)C)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared from (RS)-1-[2-(5,6-difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (300 mg) and (2-chloro-ethyl)-dimethyl-amine, according to a procedure similar to that described for Example 71 as a white solid (88 mg, 26%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.S(=O)(=O)(O)O.C(O)(=O)C>[Cl-].[Zn+2].[Cl-].O>[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[CH:13][C:14]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To neat 4-fluorobenzoyl chloride (50.00 g, 315 mmol) in a flask at 130° C. was added 4-bromoaniline (17.00 g, 100 mmol) in several portions. After it was stirred at 130° C. for 1 hour and the temperature was raised to 190° C., to the reaction mixture was added zinc chloride (11.00 g, 80.7 mmol) in several portions, then it was heated at 220° C. for 22 hours. Once cooled to 180° C., to the mixture was carefully added concentrated sulfuric acid (50 mL), acetic acid (70 mL), water (70 mL), and another portion of sulfuric acid (50 mL). The mixture was heated at 120° C. overnight. It was poured into water (500 mL) and a white solid was precipitated. It was collected by filtration and was dissolved in ethyl acetate and washed with 5% sodium carbonate until pH of the aqueous phase reached 8. The filtrate was basified with sodium carbonate and extracted with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–20% ethyl acetate/hexane) to provide the title compound (13.64 g, 46% yield). 1H NMR (CDCl3) δ 7.67 (m, 2H), 7.51 (d, 1H), 7.37 (dd, 1H), 7.14–7.20 (m, 2H), 6.65 (d, 1H), 6.02 (br s, 2H); ES-MS (m/z) 296 [M+3]+, 294 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)c(O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(O)c1

Procedure:
4-Bromo-3-hydroxybenzoic acid (100 mg) was dissolved in absolute ethanol (10 ml) and concentrated sulfuric acid (60 μl) added. The reaction was heated at reflux under nitrogen for 22 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate/chloroform (1:1) and water. The organic layers were combined, dried using a hydrophobic filter and the solvent evaporated leaving ethyl 4-bromo-3-hydroxybenzoate as a white solid (109 mg).