Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:1])[CH3:7])(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CC(F)(F)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC(C)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
Treat a solution of 4,4-difluoropentan-1-ol (5 g, 40.3 mmol) and TsCl (8.4 g, 44.3 mmol) in DCM (80 mL) with TEA (6.1 g, 60 mmol) and DMAP (0.5 g, 4 mmol) and stir at RT overnight. Wash the mixture successively with 2M HCl, satd. NaHCO3, then brine, dry over Na2SO4, concentrate and purify by silica gel chromatography (EtOAc/Pet ether) to give the title compound (7.1 g, 63%). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.08 (t, J=5.6 Hz, 2H), 2.47 (s, 3H), 1.94-1.84 (m, 4H), 1.57 (t, J=18.4 Hz, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.Br[C:18](=[CH:20][CH3:21])[CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(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>[CH3:19][C:18]([C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1)=[CH:20][CH3:21]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC=C(C)Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC=C(C)c1ccc(N)nc1
Temperature: 90 °C
Yield: 39.8 %

Procedure:
A reaction flask was charged with 0.5 g (2.27 mmol) of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-pyridin-2-ylamine, 0.31 g (2.50 mmol) of 2-bromo-but-2-ene, 1.48 g (4.54 mmol) of Cs2CO3 and 52 mg (0.045 mmol) of tetrakis(triphenylphosphine)palladium under nitrogen atmosphere. The solids were dissolved in a degassed toluene/ethanol mixture (20 mL, 1/1) and the reaction heated to 90° C. for 7 h. The reaction was quenched with water (5 mL) and TBME (5 mL). The reaction mixture was filtered. The filtrate was extracted with TBME (20 mL). The organic extract was washed with brine and concentrated under reduced pressure. The residue was purified twice by column chromatography (silica, eluent DCM, 0-50% ethyl acetate) to afford 134 mg of 5-(1-methyl-propenyl)-pyridin-2-ylamine. ES−MS: m/z 149 [M+H+];
Reaction SMILES: N#N.[CH:3]([C:5]([CH3:7])=[O:6])=[CH2:4].[N+:8]([CH3:11])([O-:10])=[O:9]>>[N+:8]([CH2:11][CH2:4][CH2:3][C:5](=[O:6])[CH3:7])([O-:10])=[O:9]
Reactant: C=CC(C)=O
Reactant: C[N+](=O)[O-]
Agent: N#N
Product: CC(=O)CCC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of methyl vinyl ketone (2.32 mL, 28.53 mmol) in nitromethane (29.6 mL) was added activated KF/Al2O3 (323 mg, prepared by mixing KF and basic Al2O3 in water followed by concentrating and drying) at 0° C. The reaction mixture was then allowed to warm up to rt and stirred at this temperature for 18 h. The mixture was filtered through neutral Al2O3 and washed with CH2Cl2. The filtrated was concentrated under reduced pressure to give the title compound as a colorless oil.
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:22][C:23]1[CH:32]=[CH:31][C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[CH:24]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Reactant: Nc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1c(Nc2ccc3c(c2)OCCO3)ccc2c1CCCC2
Yield: 98.1 %

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate (3.25 g, 10 mmol) and 6-amino-2,3-dihydrobenzo[1,4]dioxin (1.51 g, 10 mmol) were used in a process similar to Example 1(1) to give the titled compound as red oil (3.20 g, yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:11][C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cc(Cl)cc2c(-c3ccccc3)c[nH]c12
Reactant: O=C1CCCC1
Product: Clc1cc(NC2CCCC2)c2[nH]cc(-c3ccccc3)c2c1

Procedure:
5-Chloro-7-nitro-3-phenyl-1H-indole prepared in Preparation 41 and cyclopentanone were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[CH3:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1.[Pd]>[C:1]([CH:3]([CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CC#N
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)C(C#N)C(C)c1ccccc1

Procedure:
In another example, methyl cyanoacetate can be reacted with acetophenone in the presence of ammonium acetate and acetic acid in refluxing toluene solvent followed by hydrogenation with 5% Pd on C catalyst to yield methyl 2-cyano-3-phenylbutyrate. The latter compound can then be reacted with methyl bromacetate in the presence of potassium carbonate to provide the α-methylbenzyl substituted dimethyl cyanoethane-1,2-dicarboxylate starting 1,2-diester (See Example 8, below): ##STR10## The latter material can then be subjected to the aforesaid 1,2-ester transposition to provide the isomeric terminal diester (See Example 1, below.)
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:35]=[CH:34][C:10]([CH2:11][CH:12]([NH:24][S:25]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:13]3[N:18]=[C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[N:3]1.N1C=C[CH:39]=[CH:38][C:37]=1S(C(NCC1C=CC(C2SC=CN=2)=CC=1)C1N=C(NCC(O)=O)C=CC=1)(=O)=O>C(O)(C)C>[CH:38]([O:22][C:21](=[O:23])[CH2:20][NH:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([N:2]3[CH:6]=[CH:5][CH:4]=[N:3]3)=[CH:35][CH:34]=2)[NH:24][S:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[N:18]=1)([CH3:39])[CH3:37]
Reactant: O=C(O)CNc1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Reactant: O=C(O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OC(=O)CNc1cccc(C(Cc2ccc(-n3cccn3)cc2)NS(=O)(=O)c2cccnc2)n1
Yield: 90 %

Procedure:
Reaction was carried out in the same manner as in Example 29 except for using (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid hydrochloride (25.8 mg, 0.0439 mmol) obtained in Example 7-(b) in place of (6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-ylamino)acetic acid, and using isopropanol (0.20 ml) in place of 1-hexanol. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (20.6 mg) as a colorless oil. (Yield: 90%)
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:12]([CH3:30])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:18][CH:17]=1)=[O:14].[K+].[Br-]>O.CN(C)C=O>[C:1]([S:3][CH:12]([CH3:30])[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]([CH3:29])[CH2:24][C:25](=[O:28])[NH:26][N:27]=2)=[CH:20][CH:21]=1)=[O:14])(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: CC(Br)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
To 20 ml of N,N-dimethylformamide were added 0.54 g of thioacetic acid, 0.98 g of anhydrous potassium carbonate and then 2.0 g of 6-[4-(α-bromopropionylamino)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, and the mixture was reacted for 2 hours at room temperature. The mixture was further reacted for 1 hour after the addition of 2 ml of water. Insoluble matters were removed from the mixture by filtration and the filtrate was concentrated under reduced pressure to obtain a crude end product which was then purified by column chromatography on silica gel (solvent: benzene, acetic acid and methanol in a ratio of 10:3:0.6) whereby 1.8 g of the purified end product was obtained. Amorphous powder. IR-absorption spectra (KBr tablets, cm-1): 3275, 1680, 1540, 1350, 1040 and 840.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([NH2:28])=[N:25][N:24]=2)=[C:19]([Cl:29])[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:29][C:19]1[CH:18]=[C:17]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[S:27][C:26]([NH2:28])=[N:25][N:24]=1
Reactant: Nc1nnc(-c2ccc(Br)cc2Cl)s1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(-c3nnc(N)s3)c(Cl)c2)cn1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
To a stirred solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (197 mg, 0.946 mmol) and 5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (250 mg, 0.860 mmol) in dioxane (8 mL) was added Pd(PPh3)4 (50 mg, 0.043 mmol) followed by a solution of Na2CO3 (274 mg, 2.58 mmol) in water (2 mL). The reaction mixture was purged with nitrogen, sealed, and heated at 80° C. for 1 hour under microwave irradiation, then for an additional 2.5 hours at an increased temperature of 120° C. The reaction mixture was diluted with DCM (40 mL) and washed with saturated NaHCO3(aq) (40 mL). A few mLs of saturated NaCl(aq) were added to clear the resulting slight emulsion and the organic phase separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a yellow solid. The crude material was pre-absorbed onto silica gel and purified by flash chromatography using a 24 g silica cartridge running a MeOH/DCM gradient to afford the title compound as a pale yellow solid (118 mg, 47% yield). LC-MS: Rt 0.83 min; MS m/z 292.0 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1H), 7.97-8.03 (m, 2H), 7.83 (d, J=1.52 Hz, 1H), 7.65 (dd, J=8.34, 1.77 Hz, 1H), 7.41 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[NH2:29][C:30]1[C:31]([C:45](O)=[O:46])=[N:32][C:33]([C:37]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=2[F:44])=[C:34]([F:36])[CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:45]([C:31]3[C:30]([NH2:29])=[CH:35][C:34]([F:36])=[C:33]([C:37]4[C:38]([F:44])=[CH:39][CH:40]=[CH:41][C:42]=4[F:43])[N:32]=3)=[O:46])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1nc(-c3c(F)cccc3F)c(F)cc1N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
3-Amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (6.0 mg, 0.015 mmol), 3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (4.9 mg, 0.018 mmol), HATU (15 mg, 0.038 mmol), DMF (0.036 mL) and DIPEA (6.0 mg, 0.046 mmol) were mixed together and stirred at room temperature for 16 h. The mixture was filtered, concentrated under reduced pressure, and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4 mg, 41%). LCMS calc. for C32H36F3N6O5 (M+H)+: m/z=641.3. Found: 641.0.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C(O)(=[O:26])C>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4=[CH:22][NH:23][C:2](=[O:26])[CH:3]=[C:4]4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(Cl)cc1OCC2
Reactant: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1c[nH]c(=O)cc1OCC2
Temperature: 155 °C
Reaction time: 1 h

Procedure:
A solution of 2.64 g (8.00 mmol) of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine 317 in 250 ml of glacial acetic acid was placed into 350 ml glass pressure vessel. The vessel was closed and the mixture was heated for 64 hours at 155° C. The mixture was cooled down to room temperature. White precipitate appeared. The mixture was concentrated to 50 ml volume in vacuum, the solid material was filtered out, washed with acetic acid, ethyl ether and dried on air. Weight 1.68 g. The above product was stirred with 15 ml of sat NaHCO3 for 1 hour, filtered out, washed with 2×10 ml of water, dissolved in THF/water (10:1) mixture and concentrated. The residue was dried in high vacuum for 18 hours to give 2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9(10H)-one. Yield 1.12 g (45%). M/z 313.1, calc. 312.13. 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 8.41 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 5.84 (s, 1H), 5.78 (dt, J=13.2, 6.6, 1H), 4.57-4.51 (m, 2H), 4.50-4.45 (m, 2H), 1.45 (d, J=6.6, 6H)
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]4=[CH:26][S:27][CH:28]=[C:24]4[N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=O)(C)(C)C.[C:33]1([C:39]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[N:40]2C(C3C=CC=CC=3C3C=CC(CBr)=CC=3)=[N:43][N:42]=[N:41]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:29]([C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]3[N:40]([C:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[N:41]=[N:42][N:43]=3)=[CH:15][CH:16]=2)[C:25]2=[CH:26][S:27][CH:28]=[C:24]2[N:23]=1)[CH2:30][CH2:31][CH3:32]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc2cscc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc2cscc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
This Step A compound can be prepared in a similar fashion to the preparation of 4'-[(2-butyl-1H-thieno[3,4-d]imidazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid t-butyl ester (Example 1, Step B) except that the alkylating agent used can be 2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl methyl bromide in place of t-butyl-4'-bromomethylbiphenyl-2-carboxylate.
Reaction SMILES: [CH3:1][C@@H]([C@@H]1[C@@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](O)C[C@H]4C[C@@H](O)[C@H]3[C@@H]2CC1)CCC(O)=O.[CH3:29][C@@H:30]([C@@H:36]1[C@@:40]2([CH3:57])[C@@H:41]([OH:56])[CH2:42][C@@H:43]3[C@@:48]4([CH3:54])[CH2:49][CH2:50][C@@H:51]([OH:53])[CH2:52][C@H:47]4[CH2:46][C@@H:45]([OH:55])[C@H:44]3[C@@H:39]2[CH2:38][CH2:37]1)[CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[CH3:29][C@@H:30]([C@@H:36]1[C@@:40]2([CH3:57])[C@@H:41]([OH:56])[CH2:42][C@@H:43]3[C@@:48]4([CH3:54])[CH2:49][CH2:50][C@@H:51]([OH:53])[CH2:52][C@H:47]4[CH2:46][C@@H:45]([OH:55])[C@H:44]3[C@@H:39]2[CH2:38][CH2:37]1)[CH2:31][CH2:32][C:33]([O:35][CH3:1])=[O:34]
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[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]3C[C@H](O)[C@]12C
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]3C[C@H](O)[C@]12C

Procedure:
A process for preparing chenodeoxycholic acid from cholic acid comprising the steps of: (1) esterification of the acid group of the cholic acid to produce methyl cholate; (2) selective acetylation of the methyl cholate to produce methyl 3,7-diacetyl cholate; (3) mesylation of the methyl 3,7-diacetyl cholate to produce methyl 3,7-diacetyl-12-mesylcholate; (4) dehydromesylation of the methyl 3,7-diacetyl-12-mesylcholate by hexamethylphosphoric triamide in the presence of a weak base to produce methyl 3,7-diacetylchol-11-enate; (5) hydrogenation of the methyl 3,7-diacetylchol-11-enate to produce methyl diacetyl chenodeoxycholate; and (6) saponification of the methyl diacetyl chenodeoxycholate to produce chenodeoxycholic acid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=2)[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Yield: 63.8 %

Procedure:
Benzyl bromide (1.42 mL, 11.6 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (2.0 g, 11.6 mmol) in acetonitrile (30 mL) with triethylamine (2.68 mL, 19.32 mmol) and refluxed for 12 h. The mixture was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1-benzyl-4-(4-nitrophenyl)piperazine (2.2 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8](=O)[C:9]2[C:10](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)=[CH:4][CH:3]=1.C1COCC1>CO>[C:9]1([CH2:8][NH:7][CH2:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccccc1C(=O)NCc1ccc(F)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(CNCc2ccccc2CNCc2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 81.9 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with condenser and nitrogen tube, was added N1,N2-bis(4-fluorobenzyl)phthalamide (2 g, 5.2 mmol, 1 eq) and THF (HPLC grade 100 mL). The clear solution was cooled to 0° C., before borondimethylsulphide (12 g, 15 mL, 164 mmol, 30 eq) was added slowly. The reaction mixture refluxed for 36 h, cooled to −10° C. to −15° C. and treated with methanol slowly through a dropping funnel until frothing stopped (50 mL). The reaction mixture concentrated to dryness and once again cooled to 0° C., before methanol (100 mL) was added slowly, The reaction mixture was refluxed for 40 h and concentrated under vacuum to dryness to give the crude product (1.5 g, 85%) as a solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.28 (m 6H), 7.22-7.19 (m, 2H), 7.10-7.05 (m, 4H), 3.72-3.64 (m, 8H). MS (ESI): 353.2 (M+H)+.
Reaction SMILES: [Mg].[CH3:2][C:3]([N:23]1[CH2:28][CH2:27][N:26](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1)([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH3:4]>CO>[CH3:4][C:3]([N:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]1)([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C(C)(C)c3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)CC2)cc1
Agent: [Mg]
Solvent: CO
Product: CC(C)(c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1)N1CCNCC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Magnesium (1.83 g, 75.0 mmol) was added to a methanol solution (50 ml) of 1-{1-methyl-1-[4-(4-trifluoromethylbenzyloxy)phenyl]ethyl}-4-(toluene-4-sulfonyl]piperazine (2.67 g, 5.0 mmol) and stirred at 60° C. After hours, magnesium (0.61 g, 25.1 mmol) was added thereto and further stirred. After 1 hour, heating was stopped and the solvent was distilled off. Ice and 10% hydrochloric acid (100 ml) were added to the residue and stirred. Ethyl acetate was added and further stirred. The mixture was separated into layers, and the water layer was made basic using a 25% sodium hydroxide aqueous solution. Ethyl acetate was added to the mixture, followed by stirring. The mixture was filtered through Celite to remove the insoluble matter. The filtrate was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate. After removing the desiccant by filtration, the solvent was distilled off to afford the title compound as a slightly yellow oil (1.05 g, 55%).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([NH:25][NH2:26])[CH2:23][CH3:24]>CO>[C:1]1([C:7]2[N:25]([CH2:22][CH2:23][CH3:24])[N:26]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][O:10][CH2:9][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccccc2)COCC1=Cc1ccccc1
Solvent: CO
Product: CCCn1nc2c(c1-c1ccccc1)COCC2=Cc1ccccc1

Procedure:
A mixture of tetrahydro-3,5-bis-(phenylmethylene)-4H-pyran-4-one (3.6 g, 13 mmole) and propylhydrazine (1.1 g, 14 mmole) in methanol (250 ml) is heated at reflux temperature for 3-4 hours. MeOH is then removed in vacuo. The residue is dissolved in CHCl3 and washed with dilute HCl and water, then dried (anhydrous MgSO4) and concentrated in vacuo to give a yellow oil. When this crude oil is triturated with a small amount of acetonitrile the major product of this reaction precipitates out. The filtrate is concentrated and the residue is applied to a dry-packed Al2O3 (Activity I, neutral) column. The fractions eluted with ether are combined and recrystallized first from ether/hexane, then from cyclohexane until a constant m.p. (126.5°-128.5° C.) is reached, giving the product in crystalline form (99% pure).