Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:14])[C@H:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH3:5].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=1[F:22])([OH:14])[CH:4]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[CH3:5]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)CCl
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of 0.69 g (3.0 mmol) of (R)-1-chloro-3-(tert-butyldimethylsilyloxy)butan-2-one in 5 mL of toluene was cooled to 0° C., and 5.3 mL (3.3 mmol) of a solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise over a period of 15 minutes. After the completion of the dropwise addition, stirring was continued for another 2 hours, and then 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added thereto, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 3). Thereby, the title compound was obtained in a yield of 94% ((2S,3R): (2R,3R)=90:10).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:25][CH:26]=2)O1>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:25]3[CH:24]=[C:23]([C:27]4[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:22]=[CH:21][CH:26]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: COc1ccn2c(Br)cnc2n1
Product: COc1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Yield: 66 %

Procedure:
3-Bromo-7-methoxyimidazo[1,2-a]pyrimidine (0.48 g, 2.12 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-methoxyimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (458 mg, 66%) as a white powder: δH (400 MHz, CDCl3) 4.08 (3H, s), 6.49 (1H, d, J 7), 7.50 (1H, td, J 8 and 1), 7.51-7.71 (8H, m), 7.81 (1H, dd, J 8 and 1), 8.66 (1H, d, J 7); m/z (ES+) 327 (M++H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=1.B([C:28]1[CH:39]=[CH:38][C:31]([CH2:32][C@@H:33]([C:35]([OH:37])=[O:36])[NH2:34])=[CH:30][CH:29]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:34][CH:33]([CH2:32][C:31]1[CH:38]=[CH:39][C:28]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:22])[F:21])[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:24])[N:3]=2)=[CH:29][CH:30]=1)[C:35]([OH:37])=[O:36]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Nc1nc(Cl)cc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)cc(-c2ccc(CC(N)C(=O)O)cc2)n1
Temperature: 150 °C
Yield: 11.2 %

Procedure:
In a microwave vial, 4-chloro-2-amino-6-[1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. 0.3 ml of 1N aqueous sodium carbonate was added to above solution followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 5.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ 7.96 (m, 3H), 7.80 (d, J=8.06 Hz, 1H), 7.74 (t, J=7.91 Hz 1H), 7.63 (t, J=8.06 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.21 (m, 1H), 6.69 (s, 1H), 3.87 (m, 1H), 3.34 (m, 1H), 3.08 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][N:15]4[C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:20][C:18]1[CH:17]=[CH:16][N:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:2]4([NH2:1])[CH2:3][CH2:4][CH2:5]4)=[CH:11][CH:10]=3)[N:13]=[C:14]2[CH:19]=1
Reactant: NC1(c2ccc(-c3nc4cc(O)ccn4c3-c3ccccc3)cc2)CCC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2c1
Reaction time: 0.13 h
Yield: 34.5 %

Procedure:
To a solution of 2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-ol (75 mg, 0.21 mmol), methyl bromoacetate (0.02 mL, 0.21 mmol, 1.0 equiv) and Cs2CO3 (138 mg, 0.422 mmol, 2 equiv) in DMF (2.5 mL) was stirred at room temperature for 12 h. The resulting mixture added to water (10 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 8 min., gradient to 95% CH2Cl2: 5% MeOH over 5 min.; 95% CH2Cl2: 5% MeOH for 4 min., gradient to 80% CH2Cl2: 20% MeOH over 5 min., 80% CH2Cl2: 20% MeOH for 6.2 min., gradient to 75% CH2Cl2: 25% MeOH over 2.0 min., 75% CH2Cl2: 25% MeOH for 18.2 min.) to give {2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridin-7-yloxy}-acetic acid methyl ester (31 mg, 34%):
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H-].[Na+].[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>C1COCC1>[Cl:12][C:13]1[N:14]=[C:15]([CH2:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH:16]=[N:17][CH:18]=1
Reactant: CNC(=O)OC(C)(C)C
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cncc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl methylcarbamate (prepared following a method substantially similar to the one described in JACS, 2003, 125, 7307-7312)(10.52 g, 80.21 mmol, 1.05 eq.) was dissolved in dry THF (120 mL) and cooled in an ice-bath. NaH (3.51 g, 87.84 mmol, 60%, 1.15 eq.) was added portionwise and the resultant suspension was stirred at RT for 1 hour. The suspension was cooled in an ice-bath and 2,6-dicloropyrazine (11.38 g, 76.39 mmol, 1 eq.) was added portionwise. The reaction mixture was stirred at RT overnight.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH:10]([O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: OC1CN(Cc2ccccc2)CCC1c1ccccc1F
Product: Fc1ccccc1C1CCN(Cc2ccccc2)CC1OCc1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating (3RS,4RS)-1-benzyl-4-(2-fluorophenyl)-piperidin-3-ol with 2-bromomethyinaphthalene there was obtained (3RS,4RS)-1-benzyl-4-(2-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a yellow oil; MS: 284 (M-C11H9)+. By cleavage of the benzyl protecting group with 2,2,2-trichloroethyl chloroformate in an analogous manner to that described in Example 12 (c) there was obtained 2,2,2-trichloroethyl (3RS,4RS)-4-(2-fluorophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a yellow oil; MS: 509 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:23][CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14](F)=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][N:7]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]3[CH2:23][CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][N:7]=1
Reactant: N#Cc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Oc1ccccc1
Temperature: 120 °C
Yield: 29.9 %

Procedure:
Into a round bottom flask was added 5-(8-amino-3-cyclobutylimidazo[1,5-a]pyrazin-1-yl)-2-fluorobenzonitrile (30 mg, 0.0001 mol), phenol (0.023 g, 0.00024 mol), potassium carbonate (0.040 g, 0.00029 mol), DMF (0.8 mL, 0.01 mol) and the reaction mixture was heated at 120° C. for 4 h. Purification by Gilson HPLC afforded 11.4 mg of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=1.98-2.11 (m, 1H), 2.12-2.26 (m, 1H), 2.44-2.55 (m, 2H), 2.55-2.67 (m, 2H), 3.82 (dq, J=8.72, 8.55 Hz, 1H), 5.04 (br. s., 2H), 6.98 (d, J=8.84 Hz, 1H), 7.09 (d, J=5.05 Hz, 1H), 7.12-7.17 (m, 3H), 7.26-7.29 (m, 1H), 7.40-7.48 (m, 2H), 7.79 (dd, J=8.59, 2.27 Hz, 1H), 8.02 (d, J=2.02 Hz, 1H). MS (ES+): m/z 381.94 (100)[MH+]. HPLC: tR=2.53 min (Open Lynx, polar—5 min).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:31]([C:32](=[O:35])[CH2:33]Br)=[C:30]([CH2:36][CH3:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH3:40])=[C:24]([F:43])[CH:23]=1.O>CC(C)=O>[Br:21][C:22]1[CH:42]=[CH:41][C:25]([CH2:26][N:27]2[C:31]([C:32](=[O:35])[CH2:33][O:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:30]([CH2:36][CH3:37])[N:29]=[C:28]2[CH2:38][CH2:39][CH3:40])=[C:24]([F:43])[CH:23]=1
Reactant: CCCc1nc(CC)c(C(=O)CBr)n1Cc1ccc(Br)cc1F
Reactant: Oc1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCc1nc(CC)c(C(=O)COc2ccccc2Oc2ccccc2)n1Cc1ccc(Br)cc1F
Yield: 13 %

Procedure:
To a solution of 0.63 g (3.36 mmol) of 2-phenoxyphenol and 0.62 g (4.48 mmol) of K2CO3 in 75 mL acetone at ambient temperature was added 1.00 g (2.24 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-bromoacetyl-1H-imidazole obtained from Part B of Example 11 in 25 mL acetone. After stirring at reflux overnight, the reaction mixture was poured into water and extracted with 3×100 mL ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and the solvents evaporated under reduced pressure. The crude product was purified by flash column chromatography using 10-40% ethyl acetate in hexane, which provided 0.16 g (6.3%) of a clear oil after evaporation of solvents under reduced pressure. 1H NMR (300 MHz, CDCl3): δ 0.95 (t, 3H, J=7.3 Hz); 1.29 (t, 3H, J =7.3 Hz); 1.66 (m, 2H); 2.60 (m, 2H); 2.81 (q, 2H, J=7.3 Hz); 5.00 (s, 2H); 6.38 (t, 1H, J=7.8 Hz); 6.89-7.29 (m, 10H). ##STR106##
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1)[C:14]#[N:15]
Reactant: O=Cc1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cn2)c(Br)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Combine 6-chloro-pyridine-3-carbaldehyde (1.00 g, 7.09 mmol), 3-bromo-4-hydroxy-benzonitrile (1.48 g, 7.80 mmol) in dimethylacetamide (40 mL). Add potassium carbonate (1.47 g, 10.64 mmol) and stir and heat the reaction at 130° C. for 2 h. Let cool down the reaction to room temperature and poured into water. Filter the precipitate formed, washing with water, to give the title compound (1.55 g, 72%)
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([OH:31])=O)[CH:17]=2.C(=O)=O.[CH3:35][N:36]([CH3:41])[S:37]([NH2:40])(=[O:39])=[O:38].C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:13][C:14]1[NH:15][C:16]2[C:21]([C:22]=1[CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:20][CH:19]=[C:18]([C:29]([NH:40][S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])=[O:31])[CH:17]=2
Reactant: CN(C)S(N)(=O)=O
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1,1′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added to a stirred solution of 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (2.03 g, 6.3 mmol) in THF (6 mL) at 22° C. The evolution of CO2 was instantaneous and when it slowed the solution was heated at 50° C. for 1 hr and then cooled to 22° C. N,N-Dimethylsulfamide (0.94 g, 7.56 mmol) was added followed by the dropwise addition of a solution of DBU (1.34 g, 8.8 mmol) in THF (4 mL). Stirring was continued for 24 hr. The mixture was partitioned between ethyl acetate and dilute HCl. The ethyl acetate layer washed with water followed by brine and dried over Na2SO4. The extract was concentrated to dryness to leave the title product as a pale yellow friable foam, (2.0 g, 74%, >90% purity, estimated from NMR). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.28-1.49 (m, 3H) 1.59-2.04 (m, 7H) 2.74-2.82 (m, 1H) 2.88 (s, 6H) 7.57 (dd, J=8.42, 1.46 Hz, 1H) 7.74 (d, J=8.78 Hz, 1H) 7.91 (s, 1H) 11.71 (s, 1H) 12.08 (s, 1H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1([CH:16]=[C:17]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C([O-])(=O)CCCCCCCCCCC.C([Sn+](CCCC)CCCC)CCC.CCOCC>[CH:10]1([CH:16]=[C:17]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:18]([O:23][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Reactant: O=C=Nc1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)(C)C(OC(=O)Nc1ccccc1)C(=CC1CCCCC1)n1cncn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 25.1 %

Procedure:
6.5 g (0.055 mol) of phenyl isocyanate and three drops of tributyl-tin laurate, as the catalyst, were added to a solution of 13.15 g (0.05 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol (Example 2) in 100 ml of ether. The mixture was stirred at room temperature for 5 days. After distilling off the solvent in vacuo, the residue was recrystallised from ethyl acetate/ligroin. 4.8 g (25.1% of theory) of 1-cyclohexyl-4,4-dimethyl-3-phenylcarbamoyloxy-2-(1,2,4-triazol-1-yl)-pent-1-ene of melting point 156° C. were obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([NH2:17])=[C:9]([Cl:18])[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:19][CH2:20]O>Cl>[NH2:1][C@H:2]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[C:10]([NH2:17])=[C:9]([Cl:18])[CH:8]=1)[C:3]([O:5][CH2:19][CH3:20])=[O:4]
Reactant: CCO
Reactant: Nc1c(Cl)cc(C[C@@H](N)C(=O)O)cc1C(F)(F)F
Agent: Cl
Product: CCOC(=O)[C@H](N)Cc1cc(Cl)c(N)c(C(F)(F)F)c1

Procedure:
A solution of 3.5 g (10.97 mmol) (R)-2-amino-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-propionic acid in 100 mL EtOH and 70 mL ethanolic HCl (11.5 M) was stirred overnight at RT. The mixture was evaporated down i.vac., the residue was taken up in 150 mL water, combined with 30 mL of 15% K2CO3 solution, extracted with 150 mL EtOAc, the organic phase was separated off and dried over Na2SO4. After removal of the desiccant and solvent the desired product was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:12])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)s1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)s1
Yield: 79.2 %

Procedure:
A solution of 5-bromothiophene-2-carboxylic acid (5.0 g, 24 mmol), methyl iodide (5.1 g, 30 mmol), and potassium carbonate (6.7 g, 48 mmol) in DMF (50 mL) was stirred at room temperature for 64 h. The reaction was quenched with water and the aqueous layer was extracted multiple times with ethyl acetate. The combined organic layers were washed with aqueous lithium chloride and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to afford the desired product (4.2 g, 79%): 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J=4.0 Hz, 1H), 7.07 (d, J=4.0 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12]OS(C)(=O)=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[C-:18]#[N:19].[Na+]>CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH2:12][C:18]#[N:19])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1(c2ccccn2)CCCC1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1(c2ccccn2)CCCC1
Temperature: 140 °C
Yield: 82.1 %

Procedure:
To a stirred solution of methanesulfonic acid 1-pyridin-2-yl-cyclopentylmethyl ester (433) (2 g, 7.843 mmol) in dimethyl sulfoxide (15 mL), KI (0.13 g, 0.784 mmol), NaCN (0.769 g, 15.686 mmol) were added and the reaction was subjected to heating at 140° C. for 5 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with ethyl acetate (2×70 mL). The combined extracts were washed with brine, dried and concentrated. The resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 15% ethyl acetate in hexane as eluent to get (1-pyridin-2-yl-cyclopentyl)-acetonitrile (434) (1.2 g, 82%) as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=[CH:14][N:13]=3)[NH:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]2[N:7]=[C:8]([S:10]([CH2:11][C:12]3[C:17]([O:18][CH3:19])=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=[CH:14][N:13]=3)=[O:36])[NH:9][C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2nc(SCc3nccc(OCC(F)(F)F)c3OC)[nH]c2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(S(=O)Cc3nccc(OCC(F)(F)F)c3OC)[nH]c2c1
Yield: 69.2 %

Procedure:
5-Methoxy-2-[[3-methoxy-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (989 mg) was dissolved in chloroform (30 ml), to which a solution of m-chloroperbenzoic acid (503 mg) in chloroform (8 ml) was added dropwise under ice-cooling over 5 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then a saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography, to give 5-methoxy-2-[[3-methoxy-4-(2,2,2-trifluoroethoxy)pyrid-2-yl)methylsulfinyl]benzimidazole (712 mg) as a light brownish yellow powder. m.p. 36°-46° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To the suspension of 4-(4-fluoro-phenyl)-1H-indole (2.28 g, 10.79 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (147 mL) was added pyridinium tribromide (90% purity from Aldrich, 11.51 g, 32.38 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (108 mL). Zinc dust (10.52 g, 162 mmol) was added to the reaction mixture portionwise, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated and the syrupy residue was suspended in water for 4 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (2.40 g, 98%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([OH:46])=O)[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH:60]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:66][S:63]([CH:60]4[CH2:62][CH2:61]4)(=[O:65])=[O:64])=[O:46])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)O)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 2d (200 mg, 0.305 mmol) was dissolved in DCM (10 ml). EDAC (70 mg, 0.366 mmol) was added and the reaction mixture was stirred at RT for 30 min. Cyclopropanesulfonic amide (41 mg, 0.336 mmol) and DBU (96 μl, 0.641 mmol) were added and the reaction was stirred at RT for 72 h. 5% Citric acid was added and the organic layer was separated and washed with brine, dried, filtered and evaporated. This material was used directly in the following step without further purification.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1.F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].Cl>CS(C)=O.O>[C:16]([C:15]1[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=1[NH:7][N:8]1[CH:12]=[N:11][N:10]=[CH:9]1)#[N:17]
Reactant: N#Cc1ccccc1F
Reactant: Nn1cnnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Nn1cnnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
6.67 Grams of potassium tert-butoxide was dissolved in 36 ml of anhydrous dimethylsulfoxide, and 5.00 g of 4-amino-4H-1,2,4-triazole was added thereto and the mixture was stirred for 15 minutes at room temperature. Subsequently, 9 ml of an anhydrous dimethylsulfoxide solution containing 3.23 g of 2-fluorobenzonitrile was added dropwise to the solution over a period of 10 minutes, and the mixture was stirred for further 15 minutes. The reaction mixture was poured into 90 ml of water and 90 g of ice, and the solution was then adjusted to have pH of 5.7 with 1N hydrochloric acid. The crystals precipitated out were collected by filtration and dried to give 2.64 g of 4-[(2-cyanophenyl)amino]-4H-1,2,4-triazole.