Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:37][CH:38]4[CH2:42][CH2:41][O:40][CH2:39]4)=[C:24]([NH:27][C:28](=[O:36])[CH:29]=[C:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:43]#[N:44])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:45](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:37][CH:38]4[CH2:42][CH2:41][O:40][CH2:39]4)=[C:24]([NH:27][C:28](=[O:36])[CH:29]=[C:30]4[CH2:35][CH2:34][N:33]([CH3:45])[CH2:32][CH2:31]4)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:43]#[N:44])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cnc2cc(OC3CCOC3)c(NC(=O)C=C3CCNCC3)cc2c1Nc1ccc(OCc2ccccn2)c(Cl)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(=CC(=O)Nc2cc3c(Nc4ccc(OCc5ccccn5)c(Cl)c4)c(C#N)cnc3cc2OC2CCOC2)CC1
Temperature: 25 °C

Procedure:
To a single-neck reaction flask (50 ml) was added the product of Example 30 (20 mg). The product was dissolved in acetonitrile (10 ml). To the resultant solution were added anhydrous potassium carbonate powders (20 mg) and methyl iodide (5 mg). The resulting mixture was stirred at the room temperature. After the reaction finished, the resultant substance was filtered. The filtrate was rotary-evaporated to dryness to give a crude product. The crude product was purified with thin layer chromatography (developing solvent: chloroform:methanol=92:8).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C@@H:9]([C:23](OCC1C=CC=CC=1)=[O:24])[CH2:10][CH2:11][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[Cl:22])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CO.O.C(Cl)Cl>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH:12]1[CH2:13][NH:14][C:23](=[O:24])[C@H:9]([N:8]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC(CN)c1cccc(Cl)c1Cl)C(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CCC(c2cccc(Cl)c2Cl)CNC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution benzyl N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-D-lysinate (0.45 g, 0.77 mmol) in MeOH (4 mL) and water (2 mL) was added 1N NaOH (3.1 mL, 3.1 mmol). This solution was heated to 40° C. for 6 h, then neutralized with 1N HCl and concentrated. To a solution of this residue in DCM (10 mL) were added EDC (0.19 g, 0.97 mmol) and HOAT (53 mg, 0.39 mmol) followed by triethylamine (0.32 mL, 0.73 mmol). After 2 h, NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated. This residue was purified by silica gel chromatography (0.5%→10% MeOH/DCM) to give di-tert-butyl [(3R)-6-(2,3-dichlorophenyl)-2-oxoazepan-3-yl]imidodicarbonate (300 mg). MS 473 (M+1). Standard deprotection of a portion of this material gave the title product. MS 273 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[CH:16][C:15]2[N:18]=[C:19]([C:21]3[CH:35]=[C:34]([CH3:36])[C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([CH3:37])[CH:22]=3)[O:20][C:14]=2[CH:13]=1>ClCCl>[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[CH:16][C:15]2[N:18]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:37])[C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:34]([CH3:36])[CH:35]=3)[O:20][C:14]=2[CH:13]=1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)cc3o2)cc(C)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.8 ml of trifluoroacetic acid was added to a solution of 90 mg of tert-butyl {4-[6-(2-fluorophenoxy)oxazolo[4,5-c]pyridin-2-yl]-2,6-dimethylphenoxy}acetate in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 2 h. The reaction was then concentrated under reduced pressure and freeze-dried. This gave 101 mg (100%) of the title compound.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=1[CH:30]=[CH:31][N+:32]([O-])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>C1COCC1>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:22]([CH3:23])([CH3:25])[CH3:24])[CH:19]=[C:18]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:17]=1[CH2:30][CH2:31][NH2:32])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)c1cc(OCc2ccccc2)c(C=C[N+](=O)[O-])c(C(C)(C)C)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(OCc2ccccc2)c(CCN)c(C(C)(C)C)c1
Reaction time: 0.03 h

Procedure:
To a suspension of 0.0 g (4.59 mmol) of lithium borohydride in 3 mL THF was carefully added 1.3 mL (10.2 mmol) of chlorotrimethylsilane. The reaction mixture was stirred for 2 min and then a solution of 0.367 g (1.0 mmol) of 1-(benzyloxy)-3,5-di-tert-butyl-2-[2-nitrovinyl]benzene from Step B of Example 75 dissolved in 1.5 mL of anhydrous THF was slowly added. The resulting reaction mixture was stirred overnight at room temperature then cooled using an external ice water bath and 15 mL of methanol was slowly added. The resulting mixture was evaporated in vacuo, the residue was the treated with 20 mL of 5 N aqueous sodium hydroxide and then the reaction mixture was extracted with 5 times with 20 mL portions of CH2Cl2. The combined extracts were dried Na2SO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted initially with 5% MeCOH in CH2Cl2 followed by a 95/5/0.5 mixture of CH2Cl2-MeOH-conc. NH4OH. Combination of the purified fractions and evaporation in vacuo afforded the title compound.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li+:13].[Cl-:14].[CH3:15][C:16]1([CH3:24])[O:23][CH2:22][CH:21]2[CH:19]([O:20]2)[CH2:18][O:17]1>C(O)(C)C>[OH:20][CH:21]1[CH2:22][O:23][C:16]([CH3:24])([CH3:15])[O:17][CH2:18][CH:19]1[N:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li+:13].[Cl-:14]
Reactant: CC1(C)OCC2OC2CO1
Reactant: C1CNCCNCCNCCN1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)O
Product: CC1(C)OCC(O)C(N2CCNCCNCCNCC2)CO1
Temperature: 0 °C

Procedure:
10 g (58.08 mmol) of 1,4,7,10-tetraazacyclododecane, 4.85 g (116.16 mmol) of LiCl and 40.0 g (278.4 mmol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane are suspended in 40 ml of isopropanol and refluxed for 60 hours. Then, the reaction mixture is mixed with 30 ml of isopropanol and cooled slowly to 0° C. The crystals that are obtained are suctioned off, washed with 30 ml of methyl-tert-butyl ether and dried in a vacuum. 20.7 g (71% of theory) of 1,7-bis(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1,4,7,10-tetraazacyclododecane LiCl complex is obtained as white crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][CH3:23])[CH2:16][CH2:15]2)[N:7]=1)C.[ClH:25].O1CCOCC1>C(O)C>[ClH:25].[CH3:23][O:22][CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:8]2[N:7]=[C:6]3[CH2:5][C:4](=[O:3])[NH:12][C:11]3=[CH:10][CH:9]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)Cc1nc(OC2CCN(CCOC)CC2)ccc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COCCN1CCC(Oc2ccc3c(n2)CC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 5 (0.483 mmol) in ethanol (5 mL) was added 4M HCl/Dioxane (15 mL). The solution was agitated at room temperature for 18 hours. All components in reaction are extremely polar and elute with solvent front. By LCMS, 6 was the major observed ion. The crude material was concentrated and taken directly on to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:29][NH2:30])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:32](=N)(OC)[CH3:33]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:23][CH2:24]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]3[O:28][C:32]([CH3:33])=[N:30][N:29]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)=N
Reactant: NNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1nnc(C[C@H]2C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N(CC3CC3)C2=O)o1

Procedure:
To a solution of 40 mg (90 μmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide (Example 51) in 0.2 mL of toluene was added methyl acetimidate hydrochloride (13 mg, 116 μmol). The reaction mixture was heated to reflux for 14 h and then the reaction was concentrated under reduced pressure. Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 45 min) provided the title compound as a colorless film.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][NH:7][C:8]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])[CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)=[O:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Br)=[CH:39][CH:38]=1>CS(C)=O>[CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][NH:7][C:8]([C:10]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=3)[CH:18]=[CH:19][CH:20]=2)[NH:12][N:11]=1)=[O:9]
Reactant: Fc1ccc(CBr)cc1
Reactant: C[Si](C)(C)CCOCNC(=O)c1n[nH]c(-c2cccc(-c3ccccc3O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCNC(=O)c1n[nH]c(-c2cccc(-c3ccccc3OCc3ccc(F)cc3)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.05 g (0.122 mmol) of 2-trimethylsilylethoxymethyl-5-[2′-(hydroxy)biphenyl-3-yl]-1,2,4-triazole-3-carboxamide (prepared according to procedures described in Example 53) in 4 mL of DMSO was added 0.16 g (0.488 mmol) of cesium carbonate and the reaction mixture was stirred at rt for 20 min. To the reaction mixture was added 0.025 mL (0.244 mmol) of 4-fluorobenzylbromide and the reaction mixture was heated at 80° C. for 18 hr. The reaction mixture was partitioned between water and EtOAc. The organic fraction was washed with water and brine, dried (MgSO4) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica, EtOAc: hexanes, 3:10) to give the title compound.
Reaction SMILES: [OH-].[K+].CC(C)(C)C([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH3:23])[C:9]=1[CH3:24])=O>O.CO.C1(C)C=CC=CC=1>[CH3:24][C:9]1[C:10]([CH3:23])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH3:14])=[CH:13][C:8]=1[OH:7]
Reactant: Cc1cc(OC(=O)C(C)(C)C)c(C)c(C)c1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1cc(O)c(C)c(C)c1OCc1ccccc1
Yield: 71.3 %

Procedure:
A solution of 20.8 g (2.1×177 mmol) of potassium hydroxide in 100 mL of water is added to a solution of 57.8 g (177 mmol) of 2,2-dimethylpropanoic acid, 2,3,5-trimethyl-4-(phenylmethoxy)phenyl ester (Example B) in 300 mL of methanol. The solution is stirred at reflux for 6 hours, then permitted to stir at ambient temperature for another 8 hours. The solvent is removed on a rotary evaporator and the residual aqueous solution (dark brown) is diluted with 100 mL of water and acidified with excess 6N hydrochloric acid solution (40 mL). The product is isolated with diethyl ether and the diethyl ether solution is washed with 2×100 mL saturated (10%) sodium bicarbonate solution, brine, dried (magnesium sulfate) and evaporated leaving 48.4 g of crude product as a light brown solid. Chromatography on a 6.5 cm column containing 350 g of silica gel prepared in toluene and elution with 95% toluene:5% ethyl acetate affords 30.6 g of the title compound; mp 101°-103° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([OH:4])(=[O:6])=[O:3].[OH:6][CH2:7][C:8]#[C:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: CS(=O)(=O)Cl
Agent: O=C(c1ccccc1F)c1cc(Cl)ccc1C#CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 0 °C

Procedure:
Dropwise 13 ml (0.17 mole) of methanesulfonyl chloride was added to a solution of 28.9 g (0.1 mole) of 3-hydroxy-1-[4-chloro-2-(2-fluorobenzoyl)phenyl]propyne and 24.4 ml (0.175 mole) of triethylamine in 300 ml of methylene chloride which was cooled to 0° C. The mixture was washed with ice water, cold 1 N hydrochloric acid, cold saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Concentration of the methylene chloride solution gave a brown oil which was crystallized from ether to give a yellow solid. Recrystallization from a mixture of ether and petroleum ether gave off-white prisms, mp 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][C@H:5]([CH3:9])[C:6](Cl)=[O:7].[NH2:15][C:16]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:17]#[N:18].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[C:17]([C:16]([NH:15][C:6](=[O:7])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:2]=1[Cl:1])[CH3:9])([CH3:22])[CH:19]([CH3:21])[CH3:20])#[N:18]
Reactant: C[C@@H](Oc1ccc(Cl)cc1Cl)C(=O)Cl
Reactant: CC(C)C(C)(N)C#N
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Cl)cc1Cl)C(=O)NC(C)(C#N)C(C)C
Temperature: -5 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A stirred solution of (R)-2-(2,4-dichlorophenoxy)propionyl chloride (380.25 g, 1.5 mol) in toluene is cooled to -10° C. and treated simultaneously, with cooling, with 2-amino-2,3-dimethylbutyronitrile (168.3 g, 1.5 mol) and triethylamine (181.8 g, 1.8 mol) so as to maintain a reaction temperature range of -5° C. to -10° C. When the simultaneous addition of amines is complete, the reaction mixture is stirred at -5° C. for 2 hours, allowed to warm to room temperature in the absence of external heating, and treated with water. The phases are separated. The organic phase is cooled to 0° C., treated with 10% NaOH, and stirred for 1 hour at 0° C. The phases are separated. The organic phase is again washed with fresh 10% NaOH for 1 hour at 0° C., separated and washed a third time at 0° C. for 1 hour with fresh 10% NaOH. The organic phase is then washed sequentially with water, brine and water, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is crystallized in petroleum ether to give the title product as a white solid, 435 g (88% yield) identified by NMR analysis.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:13][CH2:12]1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:16][CH2:15]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Reaction time: 3 h

Procedure:
Combine trans-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-carbamic acid benzyl ester (23.0 g, 0.06 mol), palladium, 10% wt. on activated carbon (0.5 g), in EtOAc (100 mL) and charge the flask with hydrogen (50 psi). After 3 hours, filter the reaction mixture through a pad of Celite® and evaporate the solvent to obtain trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine as a dark oil (14.4 g, 99%): MS (EI) m/z=229 (M+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.Br[CH2:34][CH:35]([F:37])[F:36].C(N(CC)CC)C>CN(C)C=O.CO>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][N:29]([CH2:34][CH:35]([F:37])[F:36])[CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:14])[F:15])[C:5]=12
Reactant: FC(F)CBr
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(CC(F)F)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (21 mg, 0.043 mmol, racemic intermediate from Example 129, Step 2), 2-bromo-1,1-difluoroethane (3.8 μL, 0.048 mmol), and triethylamine (18 μL, 0.13 mmol) in N,N-dimethylformamide (0.3 mL) was stirred overnight at 70° C. The mixture was diluted with methanol (MeOH) and purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.3 mg (16%) of the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H24F4N7O (M+H)+: m/z=478.2; Found: 478.1.
Reaction SMILES: [Si](OCCC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)(C(C)(C)C)(C)C.BrC[C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][C:38]=1[Cl:45].CO.N(CC)CC>CC#N>[Cl:45][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:37]=1)[C:41]#[N:42]
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Solvent: CO
Solvent: CCNCC
Product: N#Cc1cccc(Cl)c1
Temperature: 80 °C

Procedure:
4-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (3.98 g, 8.5 mmol) and 4-bromomethyl-3-chlorobenzonitrile (2.93 g, 12.7 mmol) are dissolved in MeCN (40 mL) and heated at 80° C. for 5 h. After cooling to room temperature MeOH (40 mL) and Et2NH (7 mL) are then added and the solution is warmed 70° C. for 1 h. The solution is evaporated to dryness and the residue purified via flash column chromatography (acetone/CH2Cl2 1:3→MeOH/CH2Cl2 5:95) to give 4-{5-[2-tert-butyl-dimethylsilanyloxy)ethyl]-imidazol-1-ylmethyl}-3-chlorobenzonitrile as an oil. MS (ESI) m/z 376.3, 378.3 (M+H).
Reaction SMILES: [CH2:1]([C:13]1[O:17][C:16]([CH3:18])=[C:15]([C:19]([O:21]CC)=[O:20])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[OH-].[Na+].C(O)C>[CH2:1]([C:13]1[O:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc(C(=O)OCC)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCc1cc(C(=O)O)c(C)o1

Procedure:
Saponification of 0.5 g of the ester was accomplished by refluxing 12 hours in 10 ml of 25% aqueous sodium hydroxide and 5 ml of ethanol. Acidification of the mixture precipitated the crude acid, which was purified by sublimation to give 5-dodecyl-2-methyl-3-furoic acid, mp 70°-73° C.
Reaction SMILES: CN(/[CH:4]=[N:5]/[C:6](=O)[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([O:16][CH3:17])=[C:9]([O:18][CH3:19])[CH:8]=1)C.[F:21][C:22]([F:33])([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](=[NH:27])[NH2:26]>>[CH3:19][O:18][C:9]1[CH:8]=[C:7]([C:6]2[N:26]=[C:25]([C:24]3[C:23]([C:22]([F:32])([F:21])[F:33])=[N:31][CH:30]=[CH:29][CH:28]=3)[N:27]=[CH:4][N:5]=2)[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]=1[O:16][CH3:17]
Reactant: N=C(N)c1cccnc1C(F)(F)F
Reactant: COc1cc(C(=O)/N=C/N(C)C)cc([N+](=O)[O-])c1OC
Product: COc1cc(-c2ncnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of (E)-N-((dimethylamino)methylene)-3,4-dimethoxy-5-nitrobenzamide (1.12 g, 4 mmol) ethanol (30 mL) was added 2-(trifluoromethyl)nicotinimidamide (0.756 g, 4 mmol). The reaction mixture was heated to reflux for 5 hours. It was cooled to room temperature and the solvent was removed by evaporation. The residue was then dissolved in a dichloromethane/isopropanol mixture (50 mL, 70:30) and the organic phase was washed with water, dried over anhydrous magnesium sulphate, filtered and evaporated. The crude product was recrystallized from ethanol to give 2-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine, 1.221 g (75%).
Reaction SMILES: P([O-])([O-])(O)=O.[K+].[K+].S([O-])([O-])(=O)=O.[Mg+2].[CH3:14][C@@H:15]([C@@H:21]1[C@@:25]2([CH3:42])[C@@H:26]([OH:41])[CH2:27][C@@H:28]3[C@@:33]4([CH3:39])[CH2:34][CH2:35][C@@H:36]([OH:38])[CH2:37][C@H:32]4[CH2:31][C@@H:30]([OH:40])[C@H:29]3[C@@H:24]2[CH2:23][CH2:22]1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:14][C@@H:15]([C@@H:21]1[C@@:25]2([CH3:42])[C:26]([CH2:27][CH:28]3[C@@:33]4([CH3:39])[CH2:34][CH2:35][C@@H:36]([OH:38])[CH2:37][C@H:32]4[CH2:31][C@@H:30]([OH:40])[C@H:29]3[C@@H:24]2[CH2:23][CH2:22]1)=[O:41])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
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
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@H]3C(CC(=O)[C@]12C)[C@@]1(C)CC[C@@H](O)C[C@H]1C[C@H]3O
Reaction time: 0.25 h

Procedure:
10 g of soybean protein (ESUSAN-MEAT; trade name; AJINOMOTO Inc. ), 1 g of dipotassium hydrogen phosphate and 0.2 g of magnesium sulfate 7hydrates were dissolved in 500 ml of refined water, and 50 g of cholic acid, 5 g of sodium hydroxide and 2 g of sodium carbonate were dissolved in 500 ml of refined water, then both solutions were sterilized at the temperature of 121° C. for 15 minutes. After cooling, two solutions were mixed and the mixture was used for a culture medium (pH10.2). Thereafter, the same procedure as Example 1 was proceeded and 12-keto-cholic acid was obtained. The ratio in the product was cholic acid 0.5% and 12-keto-cholic acid 99.5%.
Reaction SMILES: [Na].C(O)C.[C:5]([O:13]CC)(=[O:12])[CH2:6][C:7]([O:9]CC)=[O:8].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[CH2:28]Br>CCOCC>[F:25][C:24]([F:26])([F:27])[C:21]1[CH:20]=[C:19]2[C:18](=[CH:23][CH:22]=1)[CH2:17][C:6]([C:7]([OH:9])=[O:8])([C:5]([OH:13])=[O:12])[CH2:28]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: FC(F)(F)c1ccc(CBr)c(CBr)c1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)C1(C(=O)O)Cc2ccc(C(F)(F)F)cc2C1

Procedure:
Sodium (1.12 g, 48.6 mmol) was added to ethanol (16 mL). The solution was heated to reflux until all sodium was dissolved. To this solution was added diethyl malonate (3.71 g, 23.19 mmol) in ether (45 mL) and the above 1,2-bis-bromomethyl-4-trifluoromethylbenzene (7.7 g, 23.19 mmol) in ether (45 mL). The mixture was refluxed for 16 hrs and the precipitate was filtered out. The filtrate was evaporated and the residue was treated with water (35 mL) and potassium hydroxide (5.30 g). The mixture was stirred and refluxed for 5 hrs and treated with water (20 mL). The resulting mixture was extracted with ether (50 mL). The aqueous phase was acidified with concentrated hydrochloric acid and cooled in an ice bath. Solids were filtered and washed with water. After air drying, 5-trifluoromethyl-indan-2,2-dicarboxylic acid was obtained (3.08 g). LC-MS showed a single peak, C12H19F3O4 (m/e) calcd 274.0453, obsd 273.0 (M−H).