Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([S:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:16])=[O:15])[CH:10]=[CH:11][C:12]=1[Cl:13].[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[CH3:36][O:35][C:31](=[O:34])[CH2:32][CH:33]1[C:25]2[C:24](=[CH:29][CH:28]=[C:27]([F:30])[CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]1[S:14]([C:9]1[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=1)(=[O:15])=[O:16]
Reactant: O=S(=O)(Nc1ccccc1-c1ccc(F)cc1)c1ccc(Cl)c(Cl)c1
Reactant: C=CC(=O)OC
Agent: [Cu+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
Sodium acetate (370 mg, 4.5 mmol) was dried in a 100 mL two-necked flask at 150° C. in vacuo for 2 hours, then palladium acetate (100.8 mg 0.45 mmol), copper(II) acetate hydrate (90.0 mg, 0.45 mmol), 3,4-dichloro-N-(4′-fluoro-biphenyl-2-yl)-benzenesulfonamide (3.58 g, 9 mmol), methyl acrylate (2.32 g, 27 mmol), 4 Å molecular sieves (3.6 g) and dimethyl formamide (45 mL) were added, and the resulting mixture was stirred at 120° C. for 16 hours. After cooling the reaction mixture was concentrated, then diluted with water (50 mL) and extracted with diethyl ether (2×30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and n-hexane:ethyl-acetate=4:1 as eluent to yield 1.91 g (44%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C@@H:11](O)[CH2:10][C@H:9]2[C:14]([N:16]2[CH2:21][CH2:20][C:19]([CH2:28][N:29]3[C:33]([CH3:35])([CH3:34])[CH2:32][O:31][C:30]3=[O:36])([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])=[CH:4][CH:3]=1.[CH3:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=1[N+:51]([O-:53])=[O:52])(=[O:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@H:9]([C:14]([N:16]3[CH2:17][CH2:18][C:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)([CH2:28][N:29]4[C:33]([CH3:34])([CH3:35])[CH2:32][O:31][C:30]4=[O:36])[CH2:20][CH2:21]3)=[O:15])[CH2:10][C@@H:11]([N:38]([CH3:37])[S:39]([C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][C:43]=3[N+:51]([O-:53])=[O:52])(=[O:41])=[O:40])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@@H]2C[C@H](O)C[C@H]2c2ccc(Cl)cc2)CC1
Reactant: CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CN([C@@H]1C[C@@H](C(=O)N2CCC(CN3C(=O)OCC3(C)C)(C3CCCCC3)CC2)[C@H](c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar was charged with 0.103 g (0.20 mmol) of the product of Step F, 0.073 g (0.28 mmol) of N-methyl-2,4-dinitrobenzenesulfonamide and 0.157 g (0.60 mmol) of triphenylphosphine. The solids were dissolved in 2 mL of benzene, and the atmosphere in the flask was evacuated and purged with nitrogen. The reaction mixture was stirred and cooled to 0° C. with an external ice-water bath and then 95 μL (0.60 mmol) of diethyl azodicarboxylate was added. The reaction mixture was allowed to warm to room temperature and was stirred an additional 1 h at which point TLC analysis (75% ethyl acetate-hexanes) indicated consumption of the starting material. The reaction mixture was then evaporated in vacuo and the residue was purified on a Biotage Flash 40i chromatography apparatus (40 g Flash 40S silica gel cartridge) eluted with 50% ethyl acetate-hexanes. Evaporation of the purified fractions and drying in vacuo afforded the title compound as an amorphous yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[O:17][CH:16]([CH3:19])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[O:17][CH:16]([CH3:19])[CH2:15][NH:14][CH2:13][C:12]=3[S:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2csc3c2OC(C)CN(C(=O)OC(C)(C)C)C3)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc(-c2csc3c2OC(C)CNC3)c1
Yield: 104.5 %

Procedure:
tert-Butyl 8-(3-methoxyphenyl)-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (287 mg) was stirred in 4 N hydrogen chloride-ethyl acetate solution (5 mL) for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 8-(3-methoxyphenyl)-2-methyl-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (220 mg, 92%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][OH:18]>CC#N>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:14][CH2:16][CH2:17][OH:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCBr
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Solvent: CC#N
Product: CC(C)(C)c1ccc(N)cc1OCCO

Procedure:
2-(2-tert-Butyl-5-aminophenoxy)ethanol (C-4) was synthesized following the general scheme above starting from 2-tert-butyl-5-nitrophenol (C-1-a) and 2-bromoethanol. HPLC ret. time 2.08 min, 10-99% CH3CN, 5 min run; ESI-MS 210.3 m/z (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12]O.S(Cl)([Cl:19])=O>N1C=CC=CC=1>[Cl:19][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][C:4]1[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1Oc1cccc(F)c1
Solvent: c1ccncc1
Product: Fc1cccc(Oc2ccccc2CCl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-(3-Fluorophenoxy)benzenemethanol (30 g.) was mixed with 13.2 ml. of pyridine. Thionyl chloride (12.4 ml.) was added dropwise at 25°-30°, the mixture stirred 5 hours at room temperature, then partitioned between water and ether. The organic layer was washed with a 10% sodium carbonate solution, then with water, dried over sodium carbonate and evaporated to give the title compound. ##STR12##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:13](Cl)=[O:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([N:6]=[C:13]=[O:14])=[O:5]
Reactant: NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C=NC(=O)c1c(Cl)cccc1Cl
Temperature: 55 °C

Procedure:
A one-liter flask was purged with nitrogen while dry 2,6-dichlorobenzamide (125 grams, 0.64 mole) and dry toluene (300 ml.) were added. The nitrogen purge was continued as oxalyl chloride (100 grams, 0.79 mole) was added over a 15-minute period, with stirring. The reaction mixture was then heated to 55° C. and stirred overnight (about 18 hours) at 55° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)[CH3:5].[OH-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[C:23]1([S:20]([C:4]([CH:6]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([Cl:19])[CH:14]=4)[NH:9][C:8]=3[CH2:7]2)([CH3:5])[C:3]([OH:29])=[O:2])(=[O:22])=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)C(C)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C(=O)O)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To 50 mg (0.115 mmol) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid methyl ester (example 3) in 4 mL of THF/MeOH 1:1, 0.29 mL of 2M NaOH (0.58 mmol, 5 eq) were added. The reaction mixture was stirred at 60° C. for 3 hours, acidified to pH=6 with aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with CH2Cl2/MeOH 3:1 yielded 40 mg (82%) of (RS,SR)-2-benzenesulfonyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-propionic acid as a white solid, MS: 435 (MNH4+).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:23])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([S:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:24]([O:27][NH2:28])[C:25]#[CH:26]>O1CCCC1>[OH:12][C:11]1[CH2:10][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([S:21][CH3:22])=[O:20])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:23])[C:6]=1[C:1](=[N:28][O:27][CH2:24][C:25]#[CH:26])[CH2:2][CH2:3][CH3:4]
Reactant: C#CCON
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(C(=O)SC)cc2)CC1=O
Solvent: C1CCOC1
Product: C#CCON=C(CCC)C1=C(O)CC(c2ccc(C(=O)SC)cc2)CC1=O
Reaction time: 15 h

Procedure:
Into 20 ml of tetrahydrofuran was dissolved 2 g of 2-butyryl-3-hydroxy-5-[4-(methylthio)carbonylphenyl]-2-cyclohexen-1-one and to the solution was added 0.7 g of propargyloxyamine. The mixture was kept for 15 hours at room temperature and the solvent was distilled off from it under reduced pressure. Then, the residue was recrystallized with mixture solvent of benzene-ligroin and 1.6 g of colorless desired crystals having a melting point of 95°-96° C. were obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([CH3:34])[C:25]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][S:30]([C:25]3[C:24]([CH3:34])=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:32])=[O:31])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NS(=O)(=O)c3ccccc3C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Sulfonylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with -toluenesulfonyl chloride (12 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (25 ml) was performed according to the acylation method described in example 6.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.P(=O)(O)(O)O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[C:10]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2cc(-c3ccccc3)n(Cc3ccccc3)c2s1
Reactant: O=C1CCCCC1
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2c(C3=CCCCC3)c(-c3ccccc3)n(Cc3ccccc3)c2s1
Temperature: 80 °C
Yield: 95 %

Procedure:
A solution (0.2 M) of methyl 6-benzyl-5-phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate in acetic acid was treated with acetic anhydride (10 eq.), cyclohexanone (10 eq.) and 85% phosphoric acid (2.3 eq.). The mixture was heated at 80° C. for 3 h, then was poured into ice cold ammonium hydroxide. The product was extracted with AcOEt and the combined organic phase was washed sequentially with aqueous HCl (1 N), aqueous NaHCO3 (saturated solution) and brine then dried and concentrated. The crude was purified by flash chromatography on silica gel (1:30 acetone/toluene) affording the title compound (95%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:12][C@@H:11]([CH3:13])[NH:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[NH4+].[Cl-]>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][N:10]1[C@H:11]([CH3:13])[CH2:12][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:15])[C:9]1=[O:14])[CH3:32]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 13-7 (1.83 g, 8.4 mmol) in THF (22 mL) at -78° C. was added sodium bis(trimethylsilyl)amide (9.4 mL, 9.4 mmol; 1M/THF) dropwise. After an additional 20 min, ethyl bromoacetate (1.13 mL, 10.3 mmol) was added dropwise. After an additional 20 minutes, the mixture was allowed to warm to 0° C., and 20 mL sat. aqueous NH4Cl was added. The layers were separated, the aqueous layer washed with EtOAc, and the combined organic extracts were dried over K2CO3. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40% ethyl acetate/hexanes) to give 13-8 as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][SH:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.F[C:18]1[N:32]=[C:31]([F:33])[CH:30]=[CH:29][C:19]=1[C:20]([NH:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[O:21].CCCCCC.CC(=O)OCC>CN(C=O)C>[F:33][C:31]1[N:32]=[C:18]([S:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:19]([C:20]([NH:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[O:21])=[CH:29][CH:30]=1
Reactant: O=C(NCc1cccs1)c1ccc(F)nc1F
Reactant: SCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(NCc1cccs1)c1ccc(F)nc1SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
919 mg (6.0 mmol) of K2CO3 and 305 mg (2.0 mmol) of 3-phenylpropane-1-thiol were added to a solution of 509 mg (2.0 mmol) of 2,6-difluoro-N-(thiophen-2-ylmethyl)-nicotinamide in DMF (10 ml), and the mixture was stirred for 1 h at RT. Dilution with water and extraction with EA were then carried out. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 4:1) of the residue yielded 336 mg (0.9 mmol, 43%) of 6-fluoro-2-(3-phenylpropylthio)-N-(thiophen-2-ylmethyl)pyridine-3-carboxylic acid amide. MS: m/z 387.1 [M+H]+.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=3)=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:13]([NH:15][C@@H:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:17])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C>C1COCC1.[Pd].CCO>[NH2:11][C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:37]=[CH:36][C:35]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:40][CH:39]=3)=[CH:34][N:33]=2)=[CH:28][CH:27]=1)[C:13]([NH:15][C@@H:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH3:17])=[O:14]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)OCc4ccccc4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Yield: 81.4 %

Procedure:
Prepared using General Procedure 18: To a stirred solution of tert-butyl ((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (860 mg, 1.238 mmol) in THF (30 mL) was added palladium on carbon (10 wt %) as a slurry in EtOH (4 mL). To this mixture was added acetic acid (1 mL) and the reaction mixture was hydrogenated at 4 bar pressure at room temperature. The reaction mixture was diluted with THF (50 mL) and filtered through Celite. The crude product was loaded onto a column in 5% AcOH in MeOH/THF. The column was washed with MeOH/THF/DCM and then the product was eluted with 0.7 M ammonia in MeOH/THF/DCM. The resultant mixture was concentrated in vacuo to afford 565 mg (77%) of tert-butyl ((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate INT-24 as a yellow solid. LCMS-ESI (m/z) calculated for C33H44N4O4: 560.3; no m/z observed, tR=2.61 min (Method 11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][CH:14]([O:23][CH2:24][CH3:25])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[CH:21]=O)[CH3:12]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:21]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:15]=3[CH:14]([O:23][CH2:24][CH3:25])[O:13][CH2:11][CH3:12])[N:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CCOC(OCC)c1ccncc1C=O
Reactant: CNc1cc(Cl)ccc1N
Solvent: C1COCCO1
Product: CCOC(OCC)c1ccncc1-c1nc2ccc(Cl)cc2n1C
Temperature: 25 °C

Procedure:
A solution of 5-chloro-N1-methylbenzene-1,2-diamine (383 mg, 2.446 mmol) and 4-diethoxymethyl-pyridine-3-carbaldehyde (512 mg, 2.446 mmol) in 1,4-dioxane (20 mL) was heated to 75° C. overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel flash chromatography employing heptane-ethyl acetate (1:1) to give of 6-chloro-2-(4-diethoxymethyl-pyridin-3-yl)-1-methyl-1H-benzoimidazole.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:12](#[N:15])[CH:13]=[CH2:14].C1(CNCC2CCCCC2)CCCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:12](/[CH:13]=[CH:14]/[C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:15]
Reactant: C=CC#N
Reactant: COC(=O)c1ncccc1Br
Agent: [Pd]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ncccc1/C=C/C#N
Temperature: 80 °C

Procedure:
A microwave vial were charged with methyl 3-bromopicolinate (2.84 g, 13.15 mmol), acrylonitrile (0.907 g, 17.09 mmol), N,N-dicyclohexylmethylamine (3.08 g, 15.78 mmol), tri-tert-butylphosphine (0.789 mL, 0.789 mmol, 1 M in toluene), tris(dibenzylideneacetone)dipalladium (0) (0.361 g, 0.394 mmol) and 10 mL of 1,4-dioxane under nitrogen. The reaction mixture was capped and heated to 80° C. in an oil bath for 20 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated, and the residue was triturated with ethyl acetate to give the title compound as a solid as the first batch. 1H NMR analysis showed only the trans isomer. The mother liquor was concentrated, and the residue was purified by silica gel flash column chromatography eluting with 20-50% ethyl acetate in hexane to give a second batch of the title compound. 1H NMR analysis showed indicated only trans product. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.70 (dd, J=4.6, 1.6, 1H), 8.27 (dd, J=8.1, 1.6, 1H), 8.04-7.94 (m, 1H), 7.71 (dd, J=8.1, 4.6, 1H), 6.53 (d, J=16.5, 1H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]=1)=[O:4]>C(O)C.[Pt]=O>[F:1][C:2]([F:24])([F:25])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:9]=1)=[O:4]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N=Cc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1NCc1ccccc1
Reaction time: 18 h
Yield: 51 %

Procedure:
The product from step (a) (11.9 g) and platinum oxide (0.2 g) in ethanol (150 ml) was hydrogenated at room temperature and 3 atmospheres pressure for 18 hrs. The catalyst was filtered and the ethanol evaporated to afford the crude product as a red oil (12 g). This was purified by flash chromatography on silica using petroleum ether/ethyl acetate (3.1) as eluant. Evaporation of the major fraction eluted afforded sub-title compound as white crystals (6.1 g) mp 80°-82°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](OC)[C:3]=1[C:11]1[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.COC1C=CC=CC=1C1OCC(C)(C)N=1.COC1C=CC=CC=1[Mg]Br>>[Cl:1][C:2]1[C:3]([C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)=[C:4]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1cc(Cl)cc(Cl)c1C1=NC(C)(C)CO1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: COc1ccccc1C1=NC(C)(C)CO1
Agent: COc1ccccc1[Mg]Br
Product: CC1(C)COC(c2c(Cl)cc(Cl)cc2-c2ccc(F)cc2)=N1

Procedure:
By substituting equimolar amounts of 2-(2,4-dichloro-6-methoxyphenyl)-4,4-dimethyl-2-oxazoline and 4-fluorophenylmagnesium bromide for 2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline and 2-methoxyphenylmagnesium bromide, the title compound was prepared following the procedure of Example 17, Step A, (85%), mp 93°-95° C.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([C:34]([F:37])([F:36])[F:35])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:33][C:30]([F:31])([F:32])[O:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[N:19]=[C:18]([C:34]([F:35])([F:36])[F:37])[C:17]([CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:38])=[O:3])=[CH:10][CH:11]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4ccc(OC(F)(F)F)cc4)nc3C(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3ccc(-c4ccc(OC(F)(F)F)cc4)nc3C(F)(F)F)cc21

Procedure:
In analogy to the procedure described in example 5 g], {6-[6-(4-trifluoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as colorless solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[CH:22]=[N:21][N:20]=[C:19]2[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])=[O:9].[Br:37]N1C(=O)CCC1=O>>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([N:18]2[C:19]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]4[C:25]3=[O:34])=[N:20][N:21]=[C:22]2[Br:37])=[C:7]([CH:17]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccccc1Br)c1cc(C(F)(F)F)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1Br)c1cc(C(F)(F)F)ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 5-trifluoromethyl-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]-2'-bromobenzophenone is reacted with N-bromosuccinimide to form 5-trifluoromethyl-2-[3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]-2'-bromobenzophenone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-])=O>O1CCOCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2nc3cc(-c4cc5ccccc5o4)ccc3o2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(-c2nc3cc(-c4cc5ccccc5o4)ccc3o2)cc1N
Temperature: 25 °C
Reaction time: 36 h
Yield: 86.3 %

Procedure:
A suspension of 2-(3-nitro-4-methoxyphenyl)-5-(benzofuran-2-yl)benzoxazole (50 mg, 0.13 mmol) in dioxane (10 ml) was placed under an atmosphere of argon. Palladium on carbon (10%) (10 mg) was added and the reaction purged with hydrogen and stirred at room temperature for 36 h. The reaction was filtered through a bed of celite and the filtrate concentrated to give the subtitle compound (40 mg, 86%). MS m/z 357.1 (M+H)+.