Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C4CCCCO4)=[CH:19][CH:18]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)[CH2:31][CH3:32]>>[C:34]1([C:30]([CH2:31][CH3:32])=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(c1ccc(CCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(CCCN2CCCC2)cc1)c1ccccc1
Yield: 25.3 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (4-(3-(pyrrolidin-1-yl)propyl)phenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (798 mg, 2 mmol) was reacted with propiophenone (800 mg, 6 mmol) to give 208 mg desired product (25%, Z/E=1/1). m/z=412[M+1]+.
Reaction SMILES: C([NH:8][C@@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][OH:29])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])(OC(C)(C)C)=O.[ClH:36].CCOC(C)=O>CO>[ClH:36].[C:14]([NH:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:24]([NH:26][C@H:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:28][OH:29])=[O:25])[NH2:8])([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(b) above from (R)-N2 -(Boc)-N5 -(Cbz)-(R)-N-(2-hydroxy-1-phenylethyl)ornithine amide (3.8 g; 7.82 mmol; from step (a) above), 50 mL of MeOH and 100 mL of HCl/EtOAc, isolating 2.68 g of the sub-title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Cl:11][C:12]1[C:13]([F:20])=[N:14][C:15](F)=[C:16]([F:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][C:15]2[C:16]([F:18])=[CH:17][C:12]([Cl:11])=[C:13]([F:20])[N:14]=2)[CH:3]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(O)cc(Cl)c1
Reactant: Fc1cc(Cl)c(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(Cl)cc(Oc2nc(F)c(Cl)cc2F)c1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-cyanophenol (1-4; 218 mg; 1.41 mmol) and 3-chloro-2,5,6-trifluoropyridine (1-5; 250 mg; 1.49 mmol) in anhydrous DMF (2 mL) was cooled to −40° C. under a nitrogen atmosphere. The reaction mixture was then treated with 260 mg (1.94 mmol) of anhydrous potassium carbonate added in one portion, and the reaction mixture was vigorously stirred and allowed to warm to room temperature slowly over 90 minutes. The reaction mixture was then stirred for another hour at room temperature. The reaction mixture was diluted with a large excess of water, and a thick precipitate formed. After trituration, the suspension was filtered and the solid dried to give the title compound as an off white amorphous solid. 1H NMR (CDCl3): 7.91 (m, 2H), 7.99 (t, 1H), 8.60 (q, 1H). MS M+1=302.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:9]=1[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[NH:16][S:17]([C:20]([F:23])([F:21])[F:22])(=[O:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2ccccc2)c(NS(=O)(=O)C(F)(F)F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(O)ccc1Oc1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
34.7 g of 4-phenoxy-3-trifluoromethylsulfonylaminoanisole and 31 g of ethanethiol were dissolved in 350 ml of methylene chloride. The resulting solution was then ice-cooled. Thereto was added 27 g of aluminum chloride at the same temperature in 30 minutes. Stirring was conducted for 30 minutes at 5°-10° C. The reaction mixture was poured into 300 ml of ice water and the resulting organic layer was separated. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, dried with anhydrous magnesium sulfate, and subjected to distillation under reduced pressure to remove the solvent. The resulting crystal was recrystallized from toluene to obtain 28.5 g (yield: 85.6%) of 4-phenoxy-3-trifluoromethylsulfonylaminophenol having a melting point of 97°-99° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Li+].CCC[CH2-].[Cl-].[CH3:17][SiH:18]([C:20]1[C:27]2[C:23]([CH:24]=[CH:25][CH:26]=2)=[CH:22][C:21]=1[S:28][CH3:29])[CH3:19]>C1COCC1.CCCCCC>[CH3:19][SiH:18]([C:20]1[C:21]([S:28][CH3:29])=[C:22]([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[C:23]2[C:27]=1[CH:26]=[CH:25][CH:24]=2)[CH3:17]
Reactant: CC1=Cc2ccccc2C1
Reactant: CSC1=C([SiH](C)C)C2=CC=CC2=C1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSC1=C(C2C(C)=Cc3ccccc32)C2=CC=CC2=C1[SiH](C)C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask with sidearm, stirring bar, and 60 mL dropping funnel was added 2-methylindene (13 g, 100 mmol, product made by Boulder) dissolved in THF (20 mL). N-Butyllithium (100 mmol, 40 mL of a 1.6 M solution in hexane) was added dropwise at room temperature. After addition was complete, the flask and contents were stirred an additional 2 h. A solution containing dimethylsilyl(2-methylthiopentalene)chloride in THF (30 mL) was added dropwise at room temperature. Stirring was continued for 1 hour, after which time the reaction was quenched with 30 mL of a 30% water/THF mixture, concentrated on a rotary evaporated, and a sample submitted for analysis.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)/C=C/c1ccc(NC(C)=O)nc1
Reaction time: 3 h

Procedure:
To a suspension of (E)-3-(6-acetylaminopyridin-3-yl)acrylic acid (200 mg) in a mixture of dichloromethane (3 ml) and methanol (3 ml) was added a solution of 10% trimethylsilyldiazomethane (3 ml) at ambient temperature and the mixture was stirred for 3 hours. The reaction mixture was evaporated in vacuo, poured into water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3-(6-acetylaminopyridin-3-yl)acrylate (197 mg) as a powder.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([O:12][C@@H:13]1[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]1[O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[N:6][NH:7]2)#[CH:2].I[C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[C:51]([CH3:56])[CH:50]=1>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([C:2]#[C:1][C:3]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:4]=2[C:5]([O:12][C@@H:13]2[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[C@@H:30]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:22]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C@H:14]2[O:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[N:6][NH:7]3)=[CH:50][C:51]=1[CH3:56]
Reactant: C#Cc1cccc2[nH]nc(O[C@@H]3O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]3OC(=O)C(C)(C)C)c12
Reactant: Cc1cc(I)ccc1O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C#Cc2cccc3[nH]nc(O[C@@H]4O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]4OC(=O)C(C)(C)C)c23)ccc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 4-ethynyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indazole (66 mg) in triethylamine (1 mL) were added 4-iodo-2-methylphenol (25 mg), tetrakis(triphenylphosphine)palladium (0) (12 mg) and copper (I) iodide (4 mg), and the mixture was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=3/1-2/1-1/1) to give the title compound (47 mg).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:16])=[O:12])=O)(C)(C)C.[OH:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH:36]=O.[BH3-]C#N.[Na+].CO>C(O)(=O)C>[NH2:8][C:9]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][C@@H:18]1[CH2:22][CH2:21][N:20]([CH2:36][C:35]2[CH:38]=[CH:39][C:40]([O:41][CH3:42])=[C:33]([OH:32])[CH:34]=2)[CH2:19]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: COc1ccc(C=O)cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(OC(F)(F)F)ccc3N)C2)cc1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of (R)-3-[N-{2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl}glycyl]aminopyrrolidine (0.050 mmol), 3-hydroxy-4-methoxybenzaldehyde (0.060 mmol), NaBH3CN (0.15 mmol), and methanol (1.3 mL) was added acetic acid (0.050 mL). The reaction mixture was stirred at 60° C. for 8 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (10 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting material was added 4 N HCl in 1,4-dioxane and the solution was stirred overnight at room temperature. Concentration and preparative TLC gave (R)-3-[{N-(2-amino-5-trifluoromethoxybenzoyl)glycyl}amino]-1-(3-hydroxy-4-methoxybenzyl)pyrrolidine (Compound No. 1896) (9.1 mg, 38%): The purity was determined by RPLC/MS (93%); ESI/MS m/e 483 (M++H, C22H25F3N4O5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CS(=O)(=O)c1cc(Br)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1

Procedure:
A solution of 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202; 200 mg; 0.55 mmol), phenylboronic acid (68 mg; 0.55 mmol;) was placed in a microwave vial and treated with caesium fluoride (252 mg; 1.66 mmol) and bis(triphenylphosphine)palladium(II) chloride (39 mg; 0.06 mmol). The tube was sealed and degased with N2 before adding dioxane (3 ml) and water (1.5 ml). The resulting reaction mixture was irradiated in a microwave reactor at 110° C. for 20 minutes. The reaction mixture was taken up in EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and purified by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc affording the title compound as an orange sticky solid.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])#[N:12]>C(O)C>[O:15]=[C:14]1[C:13]([C:11]#[N:12])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[N:17][NH:16]1
Reactant: O=CC(=O)c1ccccc1
Reactant: N#CCC(=O)NN
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)cn[nH]c1=O

Procedure:
Phenyl glyoxal (1.0 g, 7.46 mmol) and cyanoacetohydrazide (740 mg, 7.46 mmol) were heated to reflux in 10 mL ethanol for 16 hours. After cooling, the solvent was evaporated and the crude brown mixture was purified by silica chromatography (1:9 methanol/dichloromethane). The still impure product was further recrystallized from methanol affording 70 mg pure product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:13])[CH:6]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)c1ccc(O)c(Br)c1
Temperature: -15 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62,4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4 EtO (54% in Et2O, 32.9 mL). The solution was cooled to −15° C. with an ice/methanol bath. N-bromosuccmimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above −10° C. After addition was complete, the cooling bath was removed and the reaction mixture wag allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.39 (t, J=6.7 Hz, 3H, —CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, —CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:31])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>C1COCC1.CCOCC>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:31])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Chenodeoxycholic acid (0.5 g, 1.3 mmol) in THF (10 ml) at 0° C. was treated dropwise with freshly prepared diazomethane in ether (prepared in the usual manner from diazald) until the yellow colour persisted. After 15 minutes at 0° C. the solvent was evaporated to yield a white foam (0.55 g). The compound would not recrystallise, although gas chromatography showed the product to be 97% pure. The product was further purified by preparative silica tlc. (solvent system: EtOAc/CH2Cl2 /AcOH--10:10:1) to afford pure methyl chenodeoxycholate3 (0.42 g, 81%) as a foam: 1H NMR (60 MHz; CDCl3) δ0.65 (3H, s, 18-CH3), 0.91 (3H, s, 19-CH3), 1.85 (2H, s [exchanges on adding D2O], 3α and 7α OH's), 3.1-3.7 (1H, m, 3β-H), 3.64 (3H, s, --OMe), 3.7-3.9 (1H, m, 7β-H); IR (nujol mull) 3384 (OH's), 1740 (C=O) cm-1 ; MS: Found m/z 406.3077; C25H42O4 (M) requires 406.3083.
Reaction SMILES: [C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=O)[CH2:4]1)#[N:2].O=C1CC(C)(C)CC(C)=C1.C#N>CO>[C:1]([C:3]1([CH3:12])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: CC1(C)CC(=O)CC(C)(C#N)C1
Agent: C#N
Solvent: CO
Solvent: CC1=CC(=O)CC(C)(C)C1
Product: CC1(C)CCCC(C)(C#N)C1
Yield: 70 %

Procedure:
West German Patent No. 1,240,854 discloses a method for synthesizing 3-cyano-3,5,5-trimethyl cyclohexanone by causing isophorone to react with hydrogen cyanide in the presence of an alkali metal salt as a catalyst with methanol used as a dispersant for the catalyst. When this method was replicated, however, it was found that the reaction produced 3-cyano-3,5,5-trimethyl cyclohexane only in a low yield of about 70% and entailed by-production of a large amount of polymer of hydrogen cyanide. Thus, this method is problematic as a commercial process.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2C(S(C2C=CC(F)=CC=2)(=O)=O)N)=CC=CC=1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][S:33]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: NC(c1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)S(=O)(=O)c1ccc(F)cc1
Product: O=C(NCCc1ccccn1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1ccc(F)cc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and 4-fluorophenylsulfonyl chloride, according to the general working procedure 106 mg of 2′-(4-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained; m.p. 130° C. MS (ES+): m/e=490 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14]([OH:16])=O)=[N:7]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH2:46][CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1>C(N(CC)CC)C>[NH:50]1[CH:49]=[C:48]([CH2:47][CH2:46][NH:45][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[C:9]([OH:13])[C:10]([Cl:12])=[CH:11][C:2]=3[Cl:1])[N:7]=2)=[O:16])[N:52]=[CH:51]1
Reactant: NCCc1c[nH]cn1
Reactant: O=C(O)c1ccc2c(Cl)cc(Cl)c(O)c2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCc1c[nH]cn1)c1ccc2c(Cl)cc(Cl)c(O)c2n1

Procedure:
According to the procedure described in Example 1,5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid 19 (597 mg, 2.31 mmol), dicyclohexylcarbodiimide (483 mg, 2.31 mmol), 1-hydroxybenzotriazole hydrate (316 mg, 2.31 mmol), histamine dihydrochloride (425 mg, 2.31 mmol) and triethylamine (0.5 mL) gave, after column purification (silica gel, ethyl acetate/isopropanol/water (12:4:1)), 5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid [2-(1H-imidazol-4-yl)-ethyl]-amide (PBT 1038) as a pale straw-coloured solid (276 mg, 34%). 1H NMR (DMSO-d6, 400 MHz): δ 11.40 (br, 2 H), 9.74 (m, 1 H), 8.64 (d, J=8.6, 1 H), 8.28 (d, J=8.6, 1 H), 7.92 (s, 1 H), 7.53 (s, 1 H), 6.83 (s, 1 H), 3.59 (m, 2 H), 2.81 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO.S(=O)(=O)(O)O.[C:21](=O)([O-])O.[Na+]>ClCCCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:21])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 68 %

Procedure:
To a solution of 4-hydroxy-3-nitrobenzoic acid (15.8 g, 86.3 mmol) in 1,2-dichloroethane (150 mL) were added methanol (14 mL) and conc. sulfuric acid (0.5 mL) and the mixture was heated to 80° C. and stirred. Methanol (9 mL) was added on the way and the mixture was stirred for 21 hours. The reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution (400 mL) and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give methyl 4-hydroxy-3-nitrobenzoate as a yellow solid (11.5 g, 68%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: ClCc1coc(/C=C/c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (130 mg) in DMF (4 ml), 60% oily sodium hydride (22 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(4-chlorophenyl)ethenyl]oxazole (140 mg) was added under ice cooling. After stirring at 0° C. for 1 hour, then at room temperature overnight, water was added under ice cooling. The precipitate was collected by filtration, washed with water, and dissolved in a mixture of THF-ethyl acetate. This solution was dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate-diethyl ether to yield the titled compound (168 mg) as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:3][CH:2]=1.Br[CH2:15][C:16]#[N:17]>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1
Reactant: N#CCBr
Reactant: c1cc(CN2CCNCC2)ccn1
Product: N#CCN1CCN(Cc2ccncc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-4-ylmethyl-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=217.2: 1HNMR(CDCl3) 8.55 (d, 2H), 7.25 (d, 2H), 3.50 (s, 4H), 2.70-2.40 (m, 8H).