Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:9]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Si:15]([O:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: Cc1c(NC[C@@H]2[C@H](O[Si](C)(C)C(C)(C)C)CCCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(NC[C@@H]2NCCC[C@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Yield: 89 %

Procedure:
A solution of 77G (170 mg, 0.34 mmol) in 5% TFA/DCM (5 mL) was stirred at rt for 5 h and LC-MS showed completion. The mixture was concentrated and the residue was dissolved in EtOAc (30 mL), washed with saturated sodium bicarbonate solution (15 mL), brine (10 mL), dried (MgSO4) and evaporated to give desired product 77H (121 m, 89%) as a white solid: Rf (10% MeOH/DCM) 0.39; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 3.2 min (100%); MS (ES) m/z 344.1 [M+H]+; HRMS calcd for C20H33N3OSiCl 394.2081, Found 394.2080.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([NH2:16])[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([CH:14]([NH:16][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][N:26]=2)[CH3:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reactant: N#Cc1ccc(Br)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(Nc1ccc(C#N)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 610 mg (1.8 mmol) 1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethylamine, 1.18 g (2.8 mmol) 2-bromo-5-cyano-pyridine and 0.838 g (2.8 mmol) DIPEA in 3.5 mL DMF was heated to 60° C. for 3 days. The mixture was evaporated, Na2CO3aq. was added and the mixture was extracted with ethyl acetate. The combined organic phases were dried with Na2SO4 and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from DCM, methanol and NH3aq. to yield after evaporation of the product containing fractions 0.526 g (66%) of the title compound as off-white foam. MS (m/e): 431.4 [(M+H)+].
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[H-].[Na+].Cl[NH2:15].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)C.O>[CH2:1]([O:4][C:5]([C:7]1[N:8]([NH2:15])[CH:9]=[CH:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: NCl
Reactant: C=CCOC(=O)c1ccc[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC(=O)c1cccn1N
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a solution of 1H-pyrrole-2-carboxylic acid allyl ester (Example 1a, 0.75 g, 4.96 mmol) in N,N-dimethylformamide (20 mL) at 25° C. was added sodium hydride (0.316 g, 7.29 mmol) and stirred for 1 h. A solution of monochloroamine (36 mL, 7.19 mmol) in diethyl ether (0.2 M) was added and stirred for 1 h and then treated with saturated aqueous sodium bicarbonate solution (50 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (0.90 g) as a yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 4.75 (2H, m), 5.28 (1H, dd, J1=10.0 Hz, J2=1.2 Hz), 5.40 (1H, dd, J1=17.2 Hz, J2=1.6 Hz), 6.03-5.90 (2H, m), 6.87 (1H, dd, J1=4.0 Hz, J2=1.6 Hz), 6.97 (1H, t, J=2.0 Hz).
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N:12]3[C:16](=[O:17])[CH:15]=[CH:14][C:13]3=[O:18])[CH:10]=[CH:11][C:5]=2[N:4]=1.NC1C=CC2N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N(C(OC(C)(C)C)=O)C=2C=1.[CH2:51]([CH:63]1CC(=O)O[C:64]1=O)[CH:52]=[CH:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]CC>>[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N:12]3[C:13](=[O:18])[CH2:14][CH:15]([CH2:64]/[CH:63]=[CH:51]\[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:16]3=[O:17])[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: CCCCCCCCCC=CCC1CC(=O)OC1=O
Reactant: Nc1nc2ccc(N3C(=O)C=CC3=O)cc2[nH]1
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Product: CCCCCCCCC/C=C\CC1CC(=O)N(c2ccc3nc(N)[nH]c3c2)C1=O
Yield: 91 %

Procedure:
Following the same procedure to synthesize 1-(2-amino-1H-benzo[d]imidazol-6-yl)-1H-pyrrole-2,5-dione hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.161 g, 0.359 mmol) was reacted with (2-dodecen-1-yl)succinic anhydride (0.096 g, 0.359 mmol) to give the title product (0.142 g, 91% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.46 (d, 1H), 7.28 (s, 1H), 7.19 (d, 1H), δ 5.62 (m, 1H), δ 5.47 (m, 1H), δ 3.19 (t, 1H), δ 2.99 (t, 1H), δ 2.65 (m, 2H), δ 2.06 (m, 2H), δ 1.63 (d, 2H), δ 1.28 (m, 14H), δ 0.89 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 179.8, 176.9, 151.5, 134.9, 133.7, 129.4, 128.3, 124.9, 122.8, 111.4, 110.6, 40.2, 36.1, 34.9, 33.7, 32.5, 31.9, 29.6, 29.4, 29.1, 27.2, 22.6, 13.4 ppm; HRMS (ESI) Calcd for C23H32N4O2 (M+) 396.2525. Found 396.2522.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[C:7]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: Cc1nccn1C(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
8.2 g (0.1 mol) of 2-methylimidazole (a pale yellow solid, 99% pure, m.p. 143°-144° C.) and 50 ml of tetrahydrofuran are placed in a flask. Over a 20 minute period, there is added gradually, with stirring, a solution of 7.0 g (0.05 mol) of benzoyl chloride in 25 ml of tetrahydrofuran. During this period the temperature of the contents of the flask, initially room temperature, rises owing to the exothermic reaction; the temperature of the contents of the flask is maintained at 40° C. by cooling. Stirring is continued, at 40° C., for 10 minutes. Then the mixture is refluxed (at 70° C.) for one hour. An oily layer separates. The mixture is cooled to solidify the oily material and the resulting precipitate is removed by filtration. After removal of tetrahydrofuran by evaporation under vacuum there remains 7.7 g of paste-like crude N-benzoyl 2-methylimidazole.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.I[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[CH:14]=[CH:13][CH:18]=[CH:17][C:16]=2[CH2:19][CH2:20][OH:21])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: OCCc1ccc(I)cc1
Product: Cc1ccc(Nc2ccccc2CCO)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 Example 45 from 4-methyl-2-nitroaniline and 4-iodophenylethyl alcohol.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[C:20]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:13])[CH3:12]>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][CH:21]([N:25]([C:1](=[O:3])[CH3:2])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=2)[C:20]2[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:19]1=2)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Add acetyl chloride (0.3 mmol) followed by pyridine (0.3 mmol) to a solution of 5-(3,5-Bis-trifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.05 g, 0.1 mmol) in dichloromethane (1 mL). After stirring at room temperature for 24 h remove solvent under vacuum. Chromatograph the product over silica gel using ethyl acetate/hexane (10-40%) to elute. This affords the title compound (0.04 g, 71%) as an oil which foams under vacuum: MS (ES+): 563 (M−H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)ccc3F)[C@@H](N)C1)C2
Reaction time: 2 h

Procedure:
Removal of the BOC group in the product from Step A (13.78 g, 27.67 mmol) was accomplished with trifluoroacetic acid (100 ml) in dichloromethane (200 mL) at room temperature. After stirring for 2 h, the reaction was concentrated and neutralized with 25% MeOH and 2.5% ammonium hydroxide in dichloromethane. Solvents were removed under reduced pressure and the resulting crude material was purified on a 65i Biotage™ column eluting with 1.25-5% MeOH and 0.125-0.5% ammonium hydroxide in dichloromethane. The isolated material was further purified by recrystallization from 5:1 EtOAc/CH2Cl2 at 60° C. The crystalline product was washed with cold 2:1EtOAc/hexanes to give the title compound as a light brown solid. 1H NMR (500 MHz, CD3OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88 (s, 1H). LC-MS: 399.04 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1.[CH2:26]=[O:27]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([CH2:26][OH:27])=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nnc(CO)n1Cc1ccc(Cl)cc1
Temperature: 125 °C
Yield: 101.4 %

Procedure:
A mixture of Boc-protected triazole from example 3 (7.7 g, 21.221 mmol) and paraformaldehyde (3.23 g, 5 eq.) in 50 mL of o-xylene was heated at 125° C. for 3 h. After cooling, the mixture was filtered over a Celite-fritted funnel and washed with 10 mL of o-xylene. The filtrate was concentrated in vacuo to provide the desired intermediate as a foam (8.45 g, 100%+)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:19]/[C:20](=[O:21])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)/C=C/c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
In a 250 ml single neck flask was charged 14 g (99.6 mmoles, 1.0 eq) of p-chlorobenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 15.5 g of (E)-4-(4-chlorophenyl)-3-buten-2-one as a faintly yellow oil in 86.2% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][NH2:15]>CN(C)C=O>[NH3:10].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:15][CH2:14][CH2:13][N:12]([CH3:16])[CH3:11])=[O:7]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccnc(Cl)c1
Product: N
Temperature: 70 °C
Reaction time: 8 h
Yield: 11.1 %

Procedure:
To a solution of 2-chloroisonicotinic acid (0.50 g, 3.17 mmol) in N,N-dimethylformamide (20 mL) was added 1,1′-carbonyldiimtidazole (0.565 g, 3.49 mmol). The solution was heated at 70° C. for 30 min. The reaction mixture was cooled to room temperature and N,N-dimethylethane-1,2-diamine (0.31 g, 3.49 mmol) was added. The solution was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue was purified on a silica gel column using chloroform/methanol/conc. NH3(aq), (90:10:1), as the eluent to afford 40 mg (5,7% yield) of the title compound as a colorless oil: 1H NMR (CDCl3, 400 MHz) 8.51 (d, J=5 Hz, 1 H), 7.68 (s, 1 H), 7.56 (dd, J=5, 1 Hz, 1 H), 6.92-7.08 (br s, 1 H), 3.58-3.48 (m, 2 H), 2.59-2.52 (m, 2 H), 2.28 (s, 6 H); MS (TSP) m/z 228 (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCCO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCO)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-aminopropan-1-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (quin, J=6.69 Hz, 2 H) 2.44 (s, 3 H) 3.32-3.39 (m, 2 H) 3.49 (br. s., 2 H) 4.51 (br. s., 1 H) 7.66 (dd, J=7.83, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.78 (d, J=6.82 Hz, 1 H) 8.17 (br. s., 1 H) 8.41 (d, J=6.32 Hz, 2 H) 8.69 (t, J=5.43 Hz, 1 H) 8.88-8.95 (m, 1 H) 12.93-13.41 (m, 1 H). MS m/z [M+H]+ 378.1.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[CH:18]=[N:17]1)[CH3:15]>>[CH2:14]([N:16]1[CH:20]=[C:19]([CH2:21][N:22]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH:18]=[N:17]1)[CH3:15]
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CCn1cc(CN(C(=O)C2CCCc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 12.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.57 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.12 g) was obtained. melting point: 75-76° C.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][Si](C)(C)C)=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)(C)C.C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][CH:11]=2)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Product: C#Cc1ccc(Cc2ccc(C#C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In Step III of FIG. 1, a suspension of 1.00 g (2.78 mmoles) of bis(4-trimethylsilylethynylphenyl)methane [Compound (4)] in 50 ml anhydrous deaerated methanol was treated with enough anhydrous ethyl ether to dissolve all solid particles at 25° C. Anhydrous potassium carbonate (300 mg) was added and the mixture was stirred at 25° C. under argon for 16 hours. The solvent was removed and the solid residue was dissolved in 50 ml dichloromethane, treated with 5 g of silica gel and evaporated to dryness. The powder was placed on top of a 40 cm (I.D. 30 mm) column of silica gel (EM Labs, 70-230 mesh) and the column was developed with passage of hexane. A crystalline white solid [Compound (6)] was recovered from the eluate: 0.60 gm (2.78 mmoles, 100%); mp 63°-64° C. After drying at 56° C./0.01 mm Hg inside an Abderhalden apparatus for 2 hours, the mp increased to 65.5°-66.5° C. IR(KBr) 3280 (very strong, sharp, --C≡C--H), 2100 (weak, sharp, --C≡C--) and 1500 cm-1 (medium, sharp, C=C); MS (70 eV) m/e 216 (molecular ion); NMR(CDCl3) δ 3.03 (s, 2H, C≡C--H), 3.95(s, 2H, CH2), 7.10 and 7.43 ppm (q, 8H, JAB =8.0 Hz, aromatic).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C1OC1.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CCCN)CC.CC([OH:31])C>>[CH:9]1[CH:8]=[C:7]([CH2:18][C:12]2[C:17]([OH:31])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]([OH:5])=[CH:11][CH:10]=1
Reactant: Cc1ccccc1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CC(C)O
Agent: CCN(CC)CCCN
Product: Oc1ccccc1Cc1ccccc1O
Reaction time: 4 h

Procedure:
252 g of Adeka Resin EP-4100, 16 g of PGE (phenyl glycidyl ether), 70 g of toluene and 70 g of IPA were added to 132 g of DEAPA and the addition reaction was carried out at 80° to 90° C. for 4 h while the solvent was refluxed. Then, toluene and IPA were distilled out. After thorough distillation of the solvent, a reaction product (A-2) was obtained. This reaction product was mixed with the phenoic novolac (B-1) obtained in Example 1 or bisphenol F in a ratio shown in the following table and a melt masking reaction was carried out at 150° C. for 3 h.
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(C2N=CC=CN=2)=CC=CN=1)=O.[CH3:33][C@:34]1([NH:40][C:41]2[CH:46]=[N:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=2)[CH2:38][CH2:37][CH2:36][C@@H:35]1[NH2:39].[CH3:51][C:52]1[N:56]=[C:55]([C:57]2[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=2[C:59](O)=[O:60])[O:54][N:53]=1>>[CH3:51][C:52]1[N:56]=[C:55]([C:57]2[CH:65]=[CH:64][CH:63]=[CH:62][C:58]=2[C:59]([NH:39][C@H:35]2[CH2:36][CH2:37][CH2:38][C@:34]2([CH3:33])[NH:40][C:41]2[CH:46]=[N:45][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:43][N:42]=2)=[O:60])[O:54][N:53]=1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1
Product: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@]2(C)Nc2cnc(C(F)(F)F)cn2)n1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 144) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 190 mg, 0.73 mmol) and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 179 mg, 0.88 mmol). After work-up, the crude material was loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. This was then recrystallised from MTBE to afford the title compound.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[NH:8][NH2:9].N1CCCN[C:11]1=[S:16].CCl>C(O)(C)C>[ClH:1].[CH3:11][S:16][C:3]1[NH:2][CH2:7][CH2:6][CH2:5][N:4]=1.[NH2:8][NH2:9]
Reactant: NNC1=NCCCN1
Reactant: S=C1NCCCN1
Agent: CCl
Agent: Cl
Solvent: CC(C)O
Product: CSC1=NCCCN1
Product: NN
Temperature: 4 °C

Procedure:
The preparation of the starting material, 1,4,5,6-tetrahydropyrimidin-2-ylhydrazine hydrochloride, is carried out as follows: 1,4,5,6-tetrahydropyrimidin-2-thione and methyl chloride (excess) are added to isopropanol and the mixture heated in an autoclave at 170°-180° C. for hours. Cooling to 4° C. yields a precipitate of 2-methylthio-1,4,5,6-tetrahydropyrimidine hydrochloride, which upon treatment with hydrazine in boiling ethanol yields the desired intermediate melting at 191°-192° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][C:24](=[O:26])[N:23]([CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[S:22]2(=[O:34])=[O:33])=[C:17]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:16]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[S:22](=[O:34])(=[O:33])[N:23]([CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:24](=[O:26])[CH2:25]2)=[C:17]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3N)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of ((1R*,2S*)-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-cyclohexyl)-carbamic acid tert-butyl ester (Example 66, step C) (150 mg, 0.238 mmol) in 2 mL of TFA/methylene chloride (1:1) is stirred at RT for 15 min. The solvent is removed under reduced pressure to give the title compound which is used directly in the next step.
Reaction SMILES: [CH3:1]I.[Mg].FC1C=CC(C(C2C=CC(F)=CC=2)OCC[N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])[CH2:17][CH2:16]2)=CC=1.[Cl-:38].[NH4+].[Cl-].[Na+]>C(OCC)C.O1CCCC1>[ClH:38].[ClH:38].[C:25]1([C:23]([CH3:1])([OH:24])[CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CI
Reactant: [Cl-]
Reactant: O=C(CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1)c1ccccc1
Agent: [Mg]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(CCN1CCNCC1)c1ccccc1
Product: Cl

Procedure:
A Grignard solution was prepared by adding 11.4 g (0.08 mol) methyl iodide in 100 ml of anhydrous diethyl ether under a nitrogen atmosphere to 2 g (0.08 at) of magnesium, after which the reaction mixture was refluxed for one hour. At the reflux temperature 100 ml of anhydrous tetrahydrofuran and a solution of 4.5 g (0,01 mol) of 3-[4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-piperazinyl]-1-phenyl-1-propanone in 100 ml of anhydrous tetrahydrofuran were successively added dropwise. After two hours refluxing, the reaction mixture was poured out into a mixture of an ammonium chloride solution and ice, after which the mixture was saturated with sodium chloride. The organic layer was separated off, washed with salt solution and the liquid was evaporated. The residue was taken up in diethyl ether, and the solution was carefully acidified with an ethereal solution of hydrogen chloride to pH=3. The precipitate obtained of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl)]-α-phenyl-α-methyl-1-piperazinepropanol dihydrochloride was filtered off, dried and crystalized once from a mixture of methanol and diethyl ether.