Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2C=[CH:16][C:15](O[Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CC=C(O[S:52](C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2[S:52][C:15]([CH3:16])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)s2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 170.0 mg (0.366 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 202.0 mg (1.48 mmol) of zinc chloride, 24 mg (0.022 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 ml of THF, and 5-methyl-2-lithiothiophene (prepared by adding 58.6 mg (0.36 ml, 0.915 mmol) of n-butyllithium (2.5 M solution in hexanes) to a cold solution (−78° C.) of 89.8 mg (0.915 mmol) of 2-methylthiophene in 2.0 ml of THF). 1H NMR (CDCl3): δ 8.00 (2H, d, J=8.3 Hz), 7.59 (1H, d, J=1.7 Hz), 7.55 (2H, d, J=8.2 Hz), 7.43 (1H, dd, J=1.7, 8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 6.87 (1H, d, J=3.5 Hz), 6.74 (1H, d, J=2.8 Hz), 6.15 (1H, t, J=4.8 Hz), 4.38 (2H, q, J=7.1 Hz), 2.52 (3H, s), 2.32 (2H, d, J=4.8 Hz). 1.40 (3H, t, 7.1 Hz), 1.32 (6H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>>[CH3:13][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1nnc(-c2ccc(Br)cc2)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)o1

Procedure:
The title compound was prepared from a stirred solution of 2-(4-bromophenyl)-5-methyl-1,3,4-oxadiazole (D110) and 4-boronobenzoic acid using a similar procedure to Description 11, as a white crystalline solid (68%).
Reaction SMILES: O=[C:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O.O.[NH2:26][NH2:27]>CCO>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:2]1[CH:3]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[NH:27][N:26]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)c2ccccn2)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccn3)n[nH]2)CC1
Temperature: 80 °C

Procedure:
Unpurified tert-butyl 4-(3-oxo-3-pyridin-2-ylpropanoyl)piperidine-1-carboxylate (2.00 g, 6.02 mmol) was dissolved in 20 ml of EtOH and hydrazine hydrate (0.321 ml, 6.62 mmol) was added and the reaction was warmed to 80° C. After 15 h the reaction was concentrated in vacuo and the residue was purified by flash column chromatography (dissolve in DCM, elute with 98:2 to 95:5 DCM/MeOH). tert-Butyl 4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidine-1-carboxylate was obtained as a yellow oil. 1H NMR (CDCl3): δ 8.60 (m, 1H), 7.73 (dt, J=1.7, 7.6 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.22 (m, 1H), 6.57 (s, 1H), 4.18 (bs, 2H), 2.89 (m, 4H), 2.00 (d, J=12.5 Hz, 2H), 1.67 (m, 2H), 1.48 (s, 9H). m/z (m+1): 329.2
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1.OS(O)(=O)=O>>[F:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of HNO3 (0.55 mL) was added a mixture of (3-fluorophenyl)acetic acid (2 g, 13 mmol) and H2SO4 (4 mL) at 0° C. dropwise. After 2 hours, the mixture was diluted with ice-water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give (3-fluoro-4-nitrophenyl)acetic acid. 1H-NMR (400 MHz, MeOD) δ ppm 8.2˜8.24 (m, 1H), 7.26˜7.3 (m, 2H), 4.06 (s, 2H).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:37][CH3:38])[CH2:5][CH2:6][N:7]([S:33]([CH3:36])(=[O:35])=[O:34])[C:8]1[CH:13]=[CH:12][C:11]([C:14](O)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:16][CH3:17])=[CH:10][CH:9]=1)[CH3:3].Cl>C(O)C>[CH2:37]([N:4]([CH2:2][CH3:3])[CH2:5][CH2:6][N:7]([S:33]([CH3:36])(=[O:35])=[O:34])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:16][CH3:17])=[CH:12][CH:13]=1)[CH3:38]
Reactant: CCC(c1ccc(OC)cc1)C(O)(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: CCC(=C(c1ccccc1)c1ccc(N(CCN(CC)CC)S(C)(=O)=O)cc1)c1ccc(OC)cc1
Yield: 75 %

Procedure:
N-(2-Diethylaminoethyl)-4'-[1-hydroxy-2-(p-methoxyphenyl)-1-phenylbut-1-yl]methanesulfonanilide hydrochloride (34.5 g., 0.0616 mole) is dissolved in 200 ml. of concentrated hydrochloric acid and 200 ml. ethanol and the solution is refluxed for 1 hr. The ethanol is distilled under reduced pressure and the aqueous residue is basified with 50% aqueous NaOH to pH 11.0. The dehydration product is extracted with ethyl ether and the ether solution is washed with water, saturated sodium chloride, and dried (MgSO4). Distillation of the solvent yields 30.5 g. of an oil which is crystallized by dissolving in hot isopropanol and cooling the solution; 23.2 g., (75% yield with both Z and E isomers present in equal amounts), m.p. 120°-130°C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([CH:25]([F:27])[F:26])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(difluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=383.1, tR (minutes, Method F)=3.02
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Ic1cccs1
Product: Fc1ccc(-c2cccs2)cc1

Procedure:
2-Iodothiophene and 4-fluorophenylboronic acid were treated in a manner similar to Reference Example 26-(2) to give 2-(4-fluorophenyl)thiophene as colorless powder.
Reaction SMILES: N.[Na].Br[C:4](Br)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][N:13]=2)=[CH:8][CH:7]=1>C(OCC)C.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[C:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:16][N:17]=2)=[CH:10][CH:11]=1)#[CH:4]
Reactant: CCCCCc1cnc(-c2ccc(C=C(Br)Br)cc2)nc1
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Product: C#Cc1ccc(-c2ncc(CCCCC)cn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
About 100 ml of ammonia were condensed at -78° C. under argon gasification in a sulphonation flask equipped with a gas inlet tube, dry-ice condenser and mechanical stirrer and treated with sodium metal until the blue colouration persisted. A spatula tip of iron (III) nitrate was subsequently added, the now greyish mixture was treated portionwise with 820 mg of sodium metal and the resulting mixture was stirred at -78° C. for a further 30 minutes. A solution of 1.02 g of 2-[p-(2,2-dibromovinyl)phenyl]-5-pentylpyrimidine in 10 ml of diethyl ether was added dropwise within 5 minutes, then the green-yellow mixture was stirred at -78° C. for a further 45 minutes, the ammonia was evaporated and the mixture was subsequently treated with 30 ml of saturated ammonium chloride solution and extracted three times with 50 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time and once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the resulting orange oil on silica gel with 10% ethyl acetate/petroleum ether gave 447 mg (71%) of 2-(p-ethynylphenyl)-5-pentylpyrimidine as colourless crystals; m.p. 72.3° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]1[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26]>CO.Cl[Pd]Cl>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:22]=[CH:23][C:24]=1[C:25]([F:26])([F:27])[F:28]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)c(F)c2)c1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
Methyl 2-chloroisonicotinate (2.86 g, 16.67 mmol), PdCl2 (dppf) (0.278 g, 0.38 mmol) and potassium carbonate (1.161 mL, 19.24 mmol) were distributed equally over 3 microwave reaction vials. 2-(3-Fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane (3.72 g, 12.82 mmol) dissolved in methanol (45 mL) was split into 3 equal portions and added to the vials. The vials were capped and heated in a single node microwave reactor at 100° C. for 10 min each. The contents of the vials was combined and the solvent evaporated. The residue was dissolved in DCM and washed with water. The organic phase was filtered through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. 7:1 of heptane:EtOAc over 10 CV was used as mobile phase. Crude methyl 2-(3-fluoro-4-(trifluoromethyl)phenyl)isonicotinate (2.92 g, 76%) was isolated. MS m/z 300 (M+H)+
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li]CCCC.[CH2:9]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16](OCC)=[O:17])[CH2:12][CH2:11]1>C1COCC1>[CH2:9]=[C:10]1[CH2:15][CH2:14][CH:13]([C:16](=[O:17])[CH2:1][C:2]#[N:3])[CH2:12][CH2:11]1
Reactant: C=C1CCC(C(=O)OCC)CC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C1CCC(C(=O)CC#N)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
CH3CN (2.55 mL, 48.8 mmol. 2.2 eq) was added dropwise to a solution of nBuLi (48.8 mmol) in 180 mL of THF at −78° C. After stirring for 1 h at −78° C., a solution of ethyl 4-methylenecyclohexanecarboxylate (3.73 g, 22.2 mmol) in 20 mL of THF was added dropwise and the resulting reaction mixture (turned into nearly clear solution after addition) was stirred at −78° C. for 1 h, then slowly warmed to 0° C. before being quenched with sat. NH4Cl. THF was removed and the residue was diluted with EtOAc. The organic layer was separated and washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-30% EtOAc/Hexanes, Rf=0.2 in 20% EtOAc) to afford 3-(4-methylenecyclohexyl)-3-oxopropanenitrile as a colorless oil (3.25 g).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[S:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=3)[C:17](O)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:35]=1)([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[P:58]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([O:60][CH2:61][C:62]([NH2:65])([CH3:64])[CH3:63])=[O:59].C(N(CC)C(C)C)(C)C>CS(C)=O>[C:72]([O:71][P:58]([O:60][CH2:61][C:62]([NH:65][C:17]([C:16]1[CH:20]=[CH:21][C:22]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:32])[O:33][CH3:34])=[CH:28][CH:29]=2)=[C:14]([NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:35][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:15]=1)=[O:18])([CH3:64])[CH3:63])([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:59])([CH3:75])([CH3:74])[CH3:73]
Reactant: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Yield: 79.4 %

Procedure:
To a suspension of the product from Example 441D (200 mg, 0.41 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (187 mg, 0.57 mmol) in DMSO (2 mL) was added the product of Example 438C (178 mg, 0.57 mmol) then N,N-diisopropylethylamine (0.220 mL, 1.10 mmol) dropwise at room temperature under N2. After 2 hours the reaction was quenche with water (20 mL) and extracted with ethyl acetate (75 mL). The organic layer was washed sequentially with water (3×) and saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate to give the title compound as a pale yellow amorphous solid (245 mg., 79%).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:12][C@H:11]([OH:21])[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[S:1]1[C:5]([C@H:6]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH2:12][C:11](=[O:21])[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:38]=[CH:39][CH:40]=[CH:41][C:2]1=2
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](OC2CCCCO2)c2cc3ccccc3s2)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](OC2CCCCO2)[C@@H]1/C=C/[C@@H](OC1CCCCO1)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.2 %

Procedure:
To a solution consisting of (Z)-7-((1R,2R,3R,5S)-2-((3R,E)-3-(benzo[b]thiophen-2-yl)-3-(tetrahydro-2H-pyran-2-yloxy)prop-1-enyl)-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid (intermediate 32, 0.191 g, 0.327 mmol) in anhydrous DCM (3 mL) was added Dess-Martin periodinane (0.153, 0.360 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified on an 8-g Analogix flash silica cartridge. Elution with 200:1 DCM-methanol with 0.5% acetic acid (300 mL) afforded the title intermediate 33 (208 mg); MS (+cAPCI) m/z 605 (m+Na+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(F)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(4-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:10]=[C:9]1[CH3:19])(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[CH3:19][C:9]1[N:8]([NH2:7])[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:10]=1
Reactant: Cc1nc(-c2cnn(C)c2)cn1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cnn(C)c2)cn1N
Reaction time: 18 h

Procedure:
A solution of tert-butyl[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]carbamate (8.0 g, 29 mmol) in methylene chloride (200 mL) and trifluoroacetic acid (40 mL) was stirred at room temperature for 2.5 hours. After removal of solvents in vacuo, the residue was stirred in 1:1 ethyl acetate/heptane for 18 hours. The resulting solid was isolated by filtration to provide the product as a white solid. Yield: 5.3 g, 18 mmol, 62%. The mother liquor was concentrated in vacuo, and the residue was stirred for 30 minutes in a 1:1:1 mixture of ethyl acetate/heptane/diethyl ether (50 mL); filtration provided additional product as a white solid. Combined yield: 7.8 g, 26.8 mmol, 92%. 1H NMR (400 MHz, DMSO-d6) δ 2.54 (s, 3H), 3.89 (s, 3H), 6.55 (br s, 2H), 7.65 (s, 1H), 7.85 (d, J=0.7 Hz, 1H), 8.11 (br s, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([S:11][CH2:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])(=[O:10])[CH3:9]>>[C:8]([S:11][CH2:12][CH:13]([CH3:17])[C:14]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:15])(=[O:10])[CH3:9]
Reactant: N[C@@H](CO)C(=O)O
Reactant: CC(=O)SCC(C)C(=O)Cl
Product: CC(=O)SCC(C)C(=O)N[C@@H](CO)C(=O)O

Procedure:
Following the procedure of Example 16, L-serine is reacted with 3-acetylthio-2-methyl-propanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl -1-oxopropyl]-L-serine.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:21])[N:6]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 16 %

Procedure:
6-Amino-9-benzyl-2-ethylthiopurine (214 mg, 0.75 mmol) and bromine (0.5 ml) were dissolved in 100 ml of methylene chloride and the solution was stirred at room temperature for 7 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (43 mg, yield 16%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:41](Cl)=[O:42].C(N(CC)CC)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:41]([N:40]([CH3:39])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:42])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)N(C)c2ccccc2)C2CC2)C(C)C)ccc1OC
Temperature: 60 °C

Procedure:
A mixture of (3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (216 mg, 0.41 mmol), N-methyl-N-phenyl carbamoylchloride (274 mg, 1.62 mmol), triethylamine (0.45 mL, 3.24 mmol) and DMAP (1 mg, 0.008 mmol) in THF (15 mL) is heated at 60° C. for 4 h. After cooling to RT 1N HCl is added and the mixture is extracted with ethyl acetate, the combined organic extracts are dried (Na2SO4), filtered and the solvent is evaporated. Purification by flash chromatography on silica gel (eluent gradient: CH2Cl2 100% CH2Cl2/MeOH 9:1) affords the title compound. MS (LC-MS): 667.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 6.02 min.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41](=[O:49])[C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)[C:25]3[N:29]=[C:28]([O:30]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1.Cl>C(OCC)C.C(O)C>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)([OH:49])[C:2]3[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=3[F:10])[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: CCOc1nc2c(C(=O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCOCC
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccc(F)cn2)c2c(F)cc(F)cc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To 1-bromo-2,4,6-trifluorobenzene (0.02 ml, 0.16 mmol) in diethyl ether (0.52 mL) at −78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 60 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3.5 mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:51][CH2:52][CH:53]([CH3:55])[CH3:54])[CH:48]([CH3:50])[CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:51]([CH2:52][CH:53]([CH3:55])[CH3:54])[CH2:47][CH:48]([CH3:50])[CH3:49])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CNCC(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CC(C)C)CC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with diisobutylamine (Alfa) to give the title product. LC-MS (ES+) 776 [(M+H)+].