Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(C)=O.[Br-].[C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[C:36]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1([C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(O)CCCCCC=C(c1ccccc1)c1ccccc1
Yield: 70.5 %

Procedure:
The reaction was carried out as in Example 87 using the following reagents: sodium hydride (56% dispersion in oil; 8.36 g); dimethylsulfoxide (100 mL), (6-carboxyhexyl)triphenylphosphonium bromide (37.7 g), benzophenone (17.5 g); and tetrahydrofuran (100 mL). The crude product, isolated in the usual way, was recrystallized from hexane (200 mL) to yield 16.6 g of 8,8-diphenyl-7-octenoic acid, mp 88°-89° C. Anal. Calculated for C20H22O2 : C, 81.60; H, 7.53. Found: C, 81.34; H, 7.25.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[CH:17]([S:20](Cl)(=[O:22])=[O:21])([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([S:20]([NH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:22])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)C(C)(C)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)CNS(=O)(=O)C(C)C
Reaction time: 24 h
Yield: 21.2 %

Procedure:
To a solution of methyl 3-amino-2,2-dimethylpropanoate (200 mg, 1.53 mmol) and Et3N (0.64 mL, 4.59 mmol) in 2 mL CH2Cl2 was added isopropylsulfonyl chloride (0.34 mL, 3.05 mmol). The reaction was stirred for 24 h, quenched by the addition of saturated aqueous NaHCO3, extracted with CHCl3, and chromatographed (1:1 hex:EtOAc) to provide methyl 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoate (77 mg, 21%) as a solid. 1H NMR (400 MHz, CDCl3), 4.78 (t, 1H, J=6.6 Hz), 3.68 (s, 3H), 3.20-3.11 (m, 3H), 1.36 (d, 6H, J=6.9 Hz), 1.23 (s, 6H). Methyl 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoate was hydrolyzed using aqueous NaOH to provide 3-[(isopropylsulfonyl)amino]-2,2-dimethylpropanoic acid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]#[N:23])=[N:4][C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl.[OH2:25].[OH-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:22]([NH2:23])=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: COc1ccc(-c2nc(C#N)c(N)nc2-c2ccccc2)cn1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (500 mg) was dissolved in dioxane (10 ml) and conc. HCl (5 ml). The solution was stirred at 80° C. for 5 hours. The reaction mixture was cooled to 25-30° C. and concentrated in vacuo to give a residue. To the residue was added water and 1N NaOH to adjust the pH of the aqueous mixture to 6-7. The precipitated crystals were collected by filtration dried in vacuo to give 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (390 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[NH:14])[C:6]1=[O:28].CCN(C(C)C)C(C)C.[C:39]1([CH2:45][S:46](Cl)(=[O:48])=[O:47])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([S:46]([CH2:45][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:48])=[O:47])[C@@H:7]([CH2:11][CH2:12][C:13]([NH:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[NH:14])[C:6]1=[O:28]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)CN1CCN[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCN(S(=O)(=O)Cc2ccccc2)[C@@H](CCC(=N)NCNS(=O)(=O)c2ccc(C)cc2)C1=O
Temperature: -78 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of the compound of Example 16 (0.48 mmol) and DIEA in CH2Cl2 (2 mL) at −78° C., was added α-toluenesulfonyl chloride (110 mg, 0.57 mmol). The mixture was stirred at −78° C. for three hours and evaporated in vacuo. The residue was dissolved in CH2Cl2 and H2O. The organic layer was washed with sat. NaHCO3, sat. NaCl, dried over Na2SO4 and evaporated to give the title compound as a solid (50% yield).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:39][C:40]1[CH:44]=[CH:43][NH:42][N:41]=1.CO>CN1CCCC1=O.[Cu]>[F:32][C:5]1[CH:4]=[N:3][C:2]([N:42]2[CH:43]=[CH:44][C:40]([CH3:39])=[N:41]2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])[C:6]=12
Reactant: Cc1cc[nH]n1
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
A mixture of 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (50 mg, 0.1 mmol), potassium carbonate (13 mg, 0.1 mmol), copper (6.0 mg, 0.1 mmol) and 3-methylpyrazole (32 uL, 0.4 mmol) in N-methylpyrrolidinone (0.5 mL) was heated at 160° C. for 6 h. MeOH (3 mL) was added and the solution was filtered through Celite. Solvent was removed in vacuum and residue was dissolved in DMF and purified using reverse phase prep HPLC to afford 1-(4-fluoro-7-(3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (6.9 mg) as a white solid; 1HNMR (500 MHz, CDCl3) δ 8.46 (d, J=2 Hz, 1H), 8.19 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 7.55-7.50 (m, 5H), 6.25 (d, J=2.0 Hz, 1H), 3.78 (m, 2H), 3.56 (m, 2H), 3.35 (m, 2H), 3.25 (m, 2H), 2.36 (s, 3H). LCMS: m/e 501 (M+H)+, ret time 2.34 min (method 2) and 1-(4-fluoro-7-(5-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (13.7 mg); 1HNMR (500 MHz, CDCl3) δ 8.25 (m, 1H), 8.08 (bs, 1H), 7.65 (m, 1H), 7.60 (m, 5H), 6.27 (m, 1H), 3.87 (m, 2H), 3.66 (m, 2H), 3.46 (m, 2H), 3.36 (m, 2H), 2.83 (s, 3H). LCMS: m/e 501 (M+H)+, ret time 2.34 min (method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19](N)=[C:18]([CH3:23])[CH:17]=2)=[C:12]([CH:24]([CH3:26])[CH3:25])[CH:11]=[N:10]1.ClC1C=CC=C(Cl)C=1N1C(CO)=C(C(C)C)C=N1.[Br:45]C1C=CC(O)=CC=1C>>[Br:45][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[N:10]=[CH:11][C:12]=2[CH:24]([CH3:26])[CH3:25])=[CH:17][C:18]=1[CH3:23]
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1N
Reactant: Cc1cc(O)ccc1Br
Agent: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br

Procedure:
The title compound is prepared essentially according to the preparation of 4-[2-(2,6-Dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenylamine using [2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-methanol and 4-bromo-3-methyl-phenol. ES/MS m/e 454.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 82 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 82%). 1H NMR (200 MHz, CDCl3): δ 3.30 (s, 4H), 3.91 (s, 4H), 4.15 (s, 3H), 6.79-6.91 (m, 3H), 7.17-7.42 (m, 4H), 7.79 (m, 1H).
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][C:10]2[C:11]3[C:12](=O)[CH2:13][CH2:14][C:15]=3[C:16]([I:18])=[CH:17][C:9]=2[CH2:8][CH2:7]1)=O)C.[CH2:22]([Mg]Br)[CH3:23].C(OC(N1CCC2C3C(C4CC4)(O)CCC=3C=CC=2CC1)=O)C>>[CH2:22]([CH:12]1[C:11]2[C:10]3[CH2:20][CH2:21][NH:6][CH2:7][CH2:8][C:9]=3[CH:17]=[C:16]([I:18])[C:15]=2[CH2:14][CH2:13]1)[CH3:23]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(=O)CC3
Agent: CCOC(=O)N1CCc2ccc3c(c2CC1)C(O)(C1CC1)CC3
Product: CCC1CCc2c(I)cc3c(c21)CCNCC3

Procedure:
Example 7 was prepared in a similar fashion to Example 4, except Intermediate 1 was used as the starting material and ethylmagnesium bromide (3M in diethyl ether) was used for instead of cyclopropylmagnesium bromide (Example 4, step (a)). 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 1H); 3.28-3.21 (m, 1H); 2.97-2.73 (8H); 2.62-2.60 (br s, 1H); 2.22-1.90 (m, 3H); 1.45-1.30 (m, 2H); 0.95 (t, J=7.2 Hz, 3H); MS: ESI (positive): 342, (M+1).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:34](N(C(C)C)CC)(C)[CH3:35].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[CH2:24]([O:23][C:20]1[N:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:5])[CH:34]=[CH2:35])[CH2:9][CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1)[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(OCCc3ccccc3)nc2)CC1
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(OCCc3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
[1-(6-Phenethyloxy-pyridine-3-sulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.18 g, 0.39 mmol) was suspended in a 4M solution of HCl in Dioxane (10 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.34 ml, 1.99 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 50% DCM, 50% EtOAc) to give the title compound (0.032 g, 19% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:24][CH2:25][CH2:26][CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:8](=[O:16])[C:7](=[CH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:5]2.[H][H]>[Pd].CO>[CH3:1][C:2]1[C:3]([O:24][CH2:25][CH2:26][CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH3:15])[C:8](=[O:16])[CH:7]([CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:5]2
Reactant: CCCOc1cc2c(c(OCCC)c1C)CCC(=Cc1cccnc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCOc1cc2c(c(OCCC)c1C)CCC(Cc1cccnc1)C2=O
Yield: 68.5 %

Procedure:
A mixture of Compound 25 (3.96 g, 10.8 mmol) and 10% palladium on carbon (600 mg) in abs. methanol (100 mL) was hydrogenated at 1 atm for 12 hr. The hydrogen was replaced with nitrogen, the reaction was filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 20% ethyl acetate:hexanes) provided 2.72 g of Compound 26.
Reaction SMILES: [Cl:1][C:2]1[S:18][C:5]2[NH:6][C:7](=S)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.O.[NH2:20][NH2:21]>CO>[Cl:1][C:2]1[S:18][C:5]2[N:6]=[C:7]([NH:20][NH2:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)sc2N1
Solvent: CO
Solvent: O
Product: NNC1=Nc2sc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
1.1 g (0.00376 mol) of 7-chloro-1,3-dihydro-5-phenyl-2H-thieno[2,3-e]-1,4-diazepine-2-thione are dissolved in 400 ml of absolute methanol with warming and 1 ml of 100% hydrazine hydrate is added. The solution is concentrated to 50 ml and left to crystallize in a refrigerator. After filtration under vacuum and drying, there is obtained 7-chloro-2-hydrazino-5-phenyl-3H-thieno[2,3-e]-1,4-diazepine as colorless crystals, melting at 204°-207° C. (decomposition from 185° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24](Br)[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[CH:25]=[C:24]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[CH:23]=[CH:22][N:21]4[C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(Br)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C#C[Si](C)(C)C)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 90 °C
Reaction time: 0.02 h
Yield: 82.5 %

Procedure:
To a mixture of {1-[4-(7-bromo-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol), [1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) CH2Cl2 complex (7.9 mg, 0.01 mmol, 5 mol %) and copper(I) iodide (3.7 mg, 0.019 mmol, 10 mol %) in DMF (2 mL) under an argon atmosphere was added trimethylsilylacetylene (0.08 mL, 0.58 mmol, 3.0 equiv) and triethylamine (0.13 mL, 0.96 mmol, 5.0 equiv). The resulting mixture was heated at 90° C. for 1 h in a microwave apparatus, then concentrated under reduced pressure. The remaining material was separated between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phases were washed with water (25 mL), dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material (112 mg) was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 99% CH2Cl2/1% MeOH for 1 min., gradient to 90% CH2Cl2/10% MeOH over 10 min.; 90% CH2Cl2/10% MeOH for 5.2 min.) to give {1-[4-(3-phenyl-7-trimethylsilanylethynyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (84 mg, 82%):
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([CH2:24][C:25](O)=[O:26])=[O:23])=[CH:18][CH:19]=2)[C:14]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:28])[CH2:13][C:12]1([CH3:36])[CH3:35])(=[O:10])[CH3:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22]([CH2:24][C:25]([O:7][CH2:1][C:2]3[O:6][CH:5]=[CH:4][CH:3]=3)=[O:26])=[O:23])=[CH:18][CH:19]=2)[C:14]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:28])[CH2:13][C:12]1([CH3:36])[CH3:35])(=[O:10])[CH3:9]
Reactant: OCc1ccco1
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CC(=O)OCc3ccco3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Condensation of furfuryl alcohol (17 μl) and 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (15 mg) under the agency of HATU (29 mg) and N,N-diisopropylethylamine (33 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.O>CCO.[Pd]>[CH3:9][C:7]1[C:5]2[NH:6][C:14](=[O:16])[NH:10][C:4]=2[CH:3]=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2[nH]c(=O)[nH]c2c1
Reaction time: 3 h

Procedure:
A mixture of 4,6-dimethyl-2-nitroaniline (10.0 g, 60.2 mmol) and 10% Pd/C (1.0 g) in EtOH (300 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm) for 3 h, then filtered through a celite pad and concentrated in vacuo. The crude solid was dissolved in CH3CN (200 mL) and triphosgene (15.0 g, 50.5 mmol) was added. The mixture was stirred for 1 h, then H2O (200 mL) was added slowly and stirring was continued for 1 h. The precipitate was isolated by filtration and dried to give the title compound. MS: m/z=163 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)#[CH:11]>>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([C:10]#[C:11][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:13]=[N:14][CH:15]=1
Reactant: N#Cc1cccc(I)c1
Reactant: C#Cc1cncc(OC)c1
Product: COc1cncc(C#Cc2cccc(C#N)c2)c1
Yield: 68 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 3-iodobenzonitrile (681 mg, 3.0 mmol) and 3-ethynyl-5-methoxypyridine from PREPARATION 10 (415 mg, 3.1 mmol) at room temperature for 16 h to give the title compound (564 mg, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([C:14]([OH:16])=[O:15])[CH2:10]2)=[O:5])[CH3:2].[CH:17]1(O)[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH:7]12[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([CH2:12][CH2:13]1)[CH2:10][CH:9]([C:14]([O:16][CH:22]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)=[O:15])[CH2:8]2
Reactant: OC1C=CCCC1
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)N1C2CCC1CC(C(=O)OC1C=CCCC1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-4) (1.88 g, 8.27 mmol) in dichloromethane (30.0 mL) was added 2-cyclohexen-1-ol (0.812 g, 8.27 mmol, Aldrich), EDC (2.38 g, 12.4 mmol), and DMAP (0.100 g). The mixture was stirred at room temperature overnight and quenched with EtOAc (200 mL). The organic solution was washed with a 5% aqueous HCl solution (100 mL), saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL), and dried over anhydrous MgSO4, and concentrated. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-5) as colorless oil.
Reaction SMILES: CC1C=C(SC[C:11](O)=[O:12])C=C(C)C=1.N1C=CC(SCC(O)=O)=CC=1.[C:25]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=[CH:29][C:28]([S:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=1>>[CH3:11][O:12][C:39]1[CH:38]=[CH:37][C:36]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=2)=[CH:41][CH:40]=1
Reactant: O=C(O)CSc1ccc(-c2ccccc2)cc1
Reactant: Cc1cc(C)cc(SCC(=O)O)c1
Agent: O=C(O)CSc1ccncc1
Product: COc1ccc(-c2ccc(SCC(=O)O)cc2)cc1

Procedure:
 was acylated with (3,5-dimethyl-phenylsulfanyl)acetic acid, with pyridin-4-ylsulfanyl-acetic acid, with 2-(biphenyl-4-ylsulfanyl)-acetic acid, and with 2-(4′-methoxy-biphenyl-4-ylsulfanyl)-acetic acid, respectively, to give the following compounds as pale-yellow solids:
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[I:12]N1C(=O)CCC1=O>CC#N>[Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][C:9]([I:12])=[C:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2cc(Cl)oc12
Solvent: CC#N
Product: Nc1ncc(I)c2cc(Cl)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 2-chlorofuro[2,3-c]pyridin-7-amine (9.0 g, 53.8 mmol) in MeCN (250 mL) was treated with N-iodosuccinimide (18.2 g, 80.8 mmol) added portionwise over a 5-10 min period. The mixture was stirred at RT for 16 h. The reaction was then quenched with 20% aqueous Na2S2O3 and stirred for 10 min. EtOAc (200 mL) was added and the phases separated. The organic phase was washed with 20% aqueous Na2S2O3 (50 mL), then water (2×100 mL) and finally with brine. After drying over Na2SO4, the organic extracts were filtered and concentrated in vacuo. The material was purified using flash chromatography (25% EtOAc:hexane) to afford 12.6 g (80%) of the title compound. 1H NMR (300 MHz CDCl3): δ 4.76 (br. s, 2H), 6.49 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.BrC1CCCC=C1>>[C:1]1([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8]
Reactant: Cc1ccc(C)c([Mg]Br)c1
Reactant: O=C1CCCCC1
Agent: BrC1C=CCCC1
Product: Cc1ccc(C)c(C2=CCCCC2)c1

Procedure:
Phenylterephthalic acid is valuable as an interemediate in the preparation of liquid crystalline polyesters. For example, U.S. Pat. No. 4,391,966 describes the use of phenylterephthalic acid in preparing melt-spinnable, anisotropic melt forming aromatic polyesters. Further, E. K. Weisburger and J. H. Weisburger describe the reaction of 2,5-xylylmagnesium bromide with either cyclohexanone or 3-bromocyclohexene to provide 1-(2,5-xylyl)cyclohexene, which is then dehydrogenated using sulfur to provide 2,5-dimethylbiphenyl, which is oxidized by KMnO4 to provide phenylterephthalic acid in 74% yield. The permangenate process provides an isolation and purification problem, since a relatively large amount of manganese waste is produced.
Reaction SMILES: ClC1C=CC(C2C(COC3C=CC(Cl)=CN=3)CCN(C(C3C=CC(C4ON=C(C)N=4)=CC=3)=O)C2)=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[C@@H:49]([CH:50]([NH:52][C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][N:54]=3)[CH3:51])[CH2:48][CH2:47][NH:46][CH2:45]2)=[CH:40][CH:39]=1.[C:61]([C:63]1[CH:64]=[CH:65][C:66]([N:69]2[CH2:74][CH2:73][CH:72]([C:75](O)=[O:76])[CH2:71][CH2:70]2)=[N:67][CH:68]=1)#[N:62]>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[C@@H:49]([CH:50]([NH:52][C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][N:54]=3)[CH3:51])[CH2:48][CH2:47][N:46]([C:75]([CH:72]3[CH2:71][CH2:70][N:69]([C:66]4[CH:65]=[CH:64][C:63]([C:61]#[N:62])=[CH:68][N:67]=4)[CH2:74][CH2:73]3)=[O:76])[CH2:45]2)=[CH:40][CH:39]=1
Reactant: CC(Nc1ccc(C#N)cn1)[C@H]1CCNC[C@@H]1c1ccc(Cl)cc1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Agent: Cc1noc(-c2ccc(C(=O)N3CCC(COc4ccc(Cl)cn4)C(c4ccc(Cl)cc4)C3)cc2)n1
Product: CC(Nc1ccc(C#N)cn1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of [(3RS, 4RS)-3-(4-chloro-phenyl)-4-(5-chloro-pyridin-2-yloxymethyl)-piperidin-1-yl]-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone (example 1, step i) the title compounds were prepared from 6-{1-[(3S,4S)-3-(4-Chloro-phenyl)-piperidin-4-yl]-ethylamino}-nicotinonitrile and 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) with subsequent separation via preparative HPLC on chiral pak AD eluting with heptane/ethanol to yield 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(SR)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile as off-white solid. MS (m/e): 554.4 [(M+H)+] and 4-{(3S,45)-3-(4-Chloro-phenyl)-4-[(RS)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile as off-white solid. MS (m/e): 554.4 [(M+H)+]