Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:24][C:23]([CH:30]=O)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([N:21]1[C:25]([CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:24][C:23]([CH2:30][NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12]2)=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: CC(C)Cc1cc(CNCCN2CCN(c3cccc(Cl)c3)CC2)nn1C(C)(C)C
Yield: 77.7 %

Procedure:
Compound 77 was prepared using the same method as that of Example 1 except that 4-(3-chlorophenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[C:11]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:18]2)[CH2:13][CH2:12]1.O.CCOC(C)=O>C(Cl)Cl>[F:7][C:11]1([C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:23](=[O:38])[CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3nccs3)CC2)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(F)(c3nccs3)CC2)C1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
DAST (0.2 mL, 1.5 mmol) was added to N-[2-({(3R)-1-[4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexyl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (0.06 g, 0.12 mmol) in CH2Cl2 (5 mL) at −78° C. with stirring under N2. The solution was allowed to warm to 0° C. slowly and stirred for 1 h. Water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and purified by flash chromatography and reverse-phase HPLC to give 0.020 g of the title compound in 31% yield. MS (EI) calcd: (M+H)+=499.2; found: 499.1.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.O>[C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(C(=O)CCc3ccccc3)cc2)S1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 82.4 %

Procedure:
To an ice-cooled solution of the title product of Example 39 (2.0 g, 5.9 mmol) in trifluoroacetic acid (20 ml) was added triethylsilane (0.95 ml, 5.9 mmol). The mixture was stirred for 25 minutes at 0° C., then diluted with water (50 ml) and extracted with ether (2×40 ml). The combined extracts were washed with water (2×40 ml) and 5% sodium bicarbonate (2×40 ml), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with hexane to give present title product as a pale yellow solid (1.65 g, 82%); m.p. 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:9]=[N:10][NH:8][C:7]=12
Reactant: Cc1ccnc(Cl)c1N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Clc1nccc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-chloro-4-methylpyridin-3-amine [133627-45-9] (3.0 g, 21.0 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite (1.45 g, 21.0 mmol) in water (2.5 mL). The reaction mixture was stirred at rt for 15 min then allowed to stand at ambient temperature for 24 h. An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture which was allowed to stand at rt for 3 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The insoluble solid was filtered off (dried under vacuum; batch 1) and the organic filtrate was washed with water and brine, then dried (Phase separator) and concentrated under vacuum (batch 2). The two batches were combined to give 7-chloro-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 153 [M+H]+, tR (HPLC conditions k): 0.9 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=O)[CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2[nH]c(=O)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2nc(Cl)ccc2c1

Procedure:
A solution of 1.7 g of 6-methoxy-2(1H)-quinolone (10 mmoles) in 25 mL POCl3 was refluxed for 2 hours. The reagent was removed under reduced pressure and the resulting gum dissolved in CH2Cl2. The solution was washed with aqueous NaHCO3 to remove remaining acid, dried over MgSO4, and then evaporated to afford 2-chloro-6-methoxy-quinoline as a solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:18]([OH:20])=[O:19].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([CH2:43]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[C:30]([O:34][C:35]([N:37]1[CH2:38][CH2:39][C:40]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)([CH2:43][O:19][C:18](=[O:20])[C:17]2[CH:16]=[C:15]([C:14]([F:28])([F:29])[F:13])[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=2)[CH2:41][CH2:42]1)=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (897 mg) was added to a stirred solution of 3,5-bis(trifluoromethyl) benzoic acid (292 mg) and 4-dimethylaminopyridine (483 mg) in dry dimethylformamide (20 ml). The resulting solution was stirred for 30 minutes then the compound of step (a) above (1.0 g) was added. The resulting solution was stirred at room temperature for 19 hours. At this time the reaction was diluted with water (200 ml) and extracted into ethyl acetate. The organic layers were separated, washed with water, brine, and dried over MgSO4. Filtration and removal of solvent under reduced pressure afforded a yellow oil. Purification by chromatography on silica gel (20% ethyl acetate/n-hexane) afforded the product as a clear oil. 1H NMR (360 MHz, CDCl3) δ 1.4 (9H, s), 1.95 (2H, m), 2.3 (2H, m), 3.03 (2H, m), 3.8 (2H, m), 4.35 (2H, s), 7.0-7.2 (5H, m), 8.01 (1H, s), 8.25 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:32][CH2:31]5)[CH2:26][NH:27][CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:33]=[CH:34][N:35]=[C:10]12.C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[N:17][C:18]([NH:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25]5([CH2:31][CH2:32]5)[CH2:26][N:27]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:28]4)=[CH:23][CH:22]=3)=[N:19][C:12]=2[N:11]2[CH:33]=[CH:34][N:35]=[C:10]12
Reactant: O=c1c2cnc(Nc3ccc4c(c3)CNCC43CC3)nc2n2ccnc2n1-c1c(Cl)cccc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1Cc2cc(Nc3ncc4c(=O)n(-c5c(Cl)cccc5Cl)c5nccn5c4n3)ccc2C2(CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 109B (75 mg, 0.149 mmol) in 2 mL N,N-dimethylformamide was added diisopropylethylamine (0.130 ml, 0.744 mmol) followed by methanesulfonyl chloride (0.017 ml, 0.223 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with ethyl acetate. The organics were washed with saturated aqueous NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated. The crude material was triturated with ethyl acetate, filtered and dried over high vacuum to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.85-1.12 (m, 4H) 1.99 (s, 2H) 2.86-3.02 (m, 3H) 4.55 (s, 2H) 6.90 (d, J=8.33 Hz, 1H) 7.13 (d, J=1.59 Hz, 1H) 7.44-7.94 (m, 6H) 9.16 (s, 1H) 10.84 (s, 1H). MS (ESI+) m/z 582.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[O-])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[C:26]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:25])(=[O:36])=[O:35])=[CH:32][CH:33]=1)#[N:27]
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C#N)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-cyanobenzenesulfonamide. MS (ESI) m/z 500 [M+H]+, 498 [M−H]−, 1H-NMR (DMSO-d6) δ 1.14 (3H, t, J=7.5 Hz), 2.61 (2H, q, J=7.5 Hz), 2.72 (2H, t, J=7.1 Hz), 3.10-3.30 (2H, m), 6.60 (1H, br), 7.19 (1H, t, J=7.1 Hz), 7.28-7.39 (6H, m), 7.70 (1H, s), 7.78 (2H, d, J=7.1 Hz), 8.00-8.08 (4H, m).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19]([CH3:25])([CH3:24])[CH2:18][C:17]3([CH3:27])[CH3:26])=[CH:8][C:7]=1[F:28])C.CO.[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[F:28][C:7]1[CH:8]=[C:9]([C:12]#[C:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][C:19]([CH3:25])([CH3:24])[CH2:18][C:17]3([CH3:26])[CH3:27])[CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)ccc2O1

Procedure:
Following general procedure L and using [2-fluoro-4-(2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl]acetic acid ethyl ester (Compound 31, 0.21 g, 0.58 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by flash column chromatography over silica gel (230-400 mesh) using 50% ethyl acetate in hexane, the title compound was obtained as a solid (0.184 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:22])[C@@H:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42])[CH3:37]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:22])[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:42][CH2:41][CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:43])=[O:18])=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)[C@@H](O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product of Step C (5.00 g, 15.7 mmol) in THF (100 mL) was added CDI (3.05 g, 18.82 mmol). After stirring at room temperature for one hour, β-alanine ethyl ester hydrochloride (3.61 mg, 23.53 mmol) was added, then the mixture was stirred at room temperature for two days. The mixture was diluted with EtOAc then washed with 1N NaOH, then water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated to provide the title compound which was used without further purification. 1H NMR (499 MHz, CDCl3): δ 7.74 (d, J=7.9 Hz, 2H); 7.32 (d, =8.2 Hz, 2H); 7.28 (t, J=4.0 Hz, 2H); 7.25-7.15 (m, 2H); 6.88 (brs, 1H); 4.77 (d, 0.1=7.7 Hz, 1H); 4.20 (q, J=7.1 Hz, 2H); 3.75 (q, J=5.9 Hz, 2H); 2.89 (ddd, J=11.1, 7.7, 4.1 Hz, 1H); 2.66 (1, J=5.8 Hz, 2H); 1.47-1.37 (m, 2H); 1.30 (t, J=7.1 Hz, 3H); 1.11 (m, 2H); 0.76 (t, J=7.3 Hz, 3H). LC-MS: LC1 1.14 min. (M+H)+ 418.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:11]([OH:30])[CH2:12][N:13]1[C@H:22]([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14]1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:38](O)(=[O:49])[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:26]([NH:25][C:23]([C@@H:22]1[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][N:13]1[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:9][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:6])[NH2:5])[NH:1][C:38]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1)=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 64 h
Yield: 25 %

Procedure:
A solution of 154 mg of 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg of quinaldic acid in 6 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 41 mg of hydroxybenzotriazole, 35 mg of N-ethylmorpholine and 68 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 50 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 671 [M+H]+, NMR: δ (d4CH3OH, 400 MHz):
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:22]([N-]CC)C.[Li+].C([Li])[CH2:29][CH2:30][CH3:31].C[Si](CCl)(C)C.CC(C)=O>O1CCCC1.O>[CH3:22][C:30]([CH3:29])=[CH:31][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: [Li]CCCC
Reactant: CC[N-]CC
Agent: C[Si](C)(C)CCl
Agent: [Li+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 0.25 h

Procedure:
A solution of 5 g (17 mmoles) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]-imidazole in dry tetrahydrofuran is treated at -20° C. with a solution of 17 mmoles of lithium diethylamide from 6.8 ml of 2.5 M n butyl lithium. After warming, a solution of 1.57 g (17 mmoles) of trimethylsilylmethylchloride in tetrahydrofuran is added dropwise. When the reaction is complete, the mixture is immersed in an ice bath and a second solution (17 mmoles) of lithium diethylamide is added. After stirring for 15 minutes, a solution of 0.99 g (17 mmoles) of acetone in tetrahydrofuran is added, and the mixture is stirred 15 minutes at 0° and 15 minutes at 25° C. The mixture is poured into water, extracted with methylene chloride, and the organic layer dried, and chromatographed on silica to afford the desired titled compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CCOC(C)=O>[Br:1][CH2:2][CH2:3][CH2:4][O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1
Reactant: C1=COCCC1
Reactant: OCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: BrCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromopropan-1-ol (1.25 g, 9.0 mmol) and 3,4-dihydro-2H-pyran (2.04 ml, 22.5 mmol) in dichloromethane (50 ml) at 0° C. was added p-toluenesulfonic acid monohydrate (85 mg, 0.45 mmol). The reaction mixture was stirred at 0° C. for 15 min then warmed to room temperature and stirred for 2 h. The reaction was diluted with EtOAc and washed with water, sat NaHCO3, and brine then dried over MgSO4 and concentrated to afford 2-(3-bromopropoxy)-tetrahydro-2H-pyran as a light brown oil which was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[Cl:27])=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccc1Cl
Temperature: 25 °C
Yield: 39.8 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.2 g, 0.025 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.024 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hrs, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of 2-chloroaniline (3.2 g, 0.25 mole) and triethylamine (2.5 g, 0.025 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into water (350 ml). The mixture was allowed to precipitate and filtered. The filter cake was twice suspended in water (250 ml) and filtered. The filter cake was air dried and twice recrystallized from tetrahydrofuran to give 4.22 g (40%) of a white solid, mp. 230.5°-232° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(CC2CCCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.61 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.71 g, 46%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:3][CH:2]=1.C(O)CO.[CH3:25][NH:26][CH3:27]>O>[NH3:26].[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:26]([CH3:27])[CH3:25])=[CH:3][CH:2]=1
Reactant: ClCCCCCCOc1ccc(-c2ccccc2)cc1
Reactant: CNC
Solvent: O
Solvent: OCCO
Product: CN(C)CCCCCCOc1ccc(-c2ccccc2)cc1
Product: N

Procedure:
1-(4-biphenyloxy)-6-chlorohexane (5.0 g) and ethylene glycol saturated with dimethylamine (60 ml), were heated at reflux for 3 hours using a dry ice condenser. The solution was added to water. The resulting mixture was extracted with ethyl acetate, dried with sodium sulfate and evaporated. The crude product was chromatographed on silica gel, eluting with a solution of dichloromethane:methanolic ammonia (95:5), to yield 6-(4-biphenyloxy)-1-dimethylaminohexane, which was converted to the hydrochloride salt, m.p. 163°-165° C.
Reaction SMILES: N1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=C2)=[S:7])C=CN=C1.N1C=CN=C1.[CH3:18][O:19][C:20]1[C:21]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)=[N:24][CH:25]=1.[C:39]1(N)[C:40](N)=CC=[CH:43][CH:44]=1>C(Cl)Cl.CC#N>[NH2:10][C:11]1[CH:43]=[CH:44][CH:39]=[CH:40][C:12]=1[NH:8][C:6]([NH:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[N:22]=[C:21]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:20]([O:19][CH3:18])=[CH:25][N:24]=2)=[CH:27][CH:28]=1)=[S:7]
Reactant: Nc1ccccc1N
Reactant: COc1cnc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CC#N
Product: COc1cnc(-c2ccc(NC(=S)Nc3ccccc3N)cc2)nc1N1CCOCC1
Yield: 69.5 %

Procedure:
A mixture of di-imidazol-1-yl-methanethione (0.5 g, 1.50 eq.), imidazole (0.03 g, 0.3 eq.) and CH3CN (7 ml) was added dropwise to 4-(5-methoxy-4-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (0.5 g, 1.0 eq.) in CH2Cl2 (5 ml) at 0° C. When S.M. is disappear in TLC, dropping benzene-1,2-diamine (0.37 g, 3.0 eq) to the solution for 3 hrs at 50° C. The solvent was removed in vacuo. The resulting solution was crystallized in a EA solution, and filtered to given a light yellow solid, which was then dried in vacuo to give of a product (0.53 g, 70.18%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:7][N:6]=[C:5]1[SH:16].[H][H].F[C:20]1[CH:21]=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH3:26])[CH:25]=1>CN(C=O)C>[CH3:3][N:4]1[C:8]([C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[N:7][N:6]=[C:5]1[S:16][C:20]1[CH:21]=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH3:26])[CH:25]=1
Reactant: [H][H]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Cn1c(S)nnc1C(F)(F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Sc2nnc(C(F)(F)C(F)(F)F)n2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Sodium hydride (0.10 g) was added to a DMF solution (12 ml) of 4-methyl-5-pentafluoroethyl-4H-[1,2,4]triazol-3-thiol (0.70 g), and the mixture was stirred at room temperature until the generation of hydrogen gas stopped. Continuously, 5-fluoro-2-nitrotoluene (0.47 g) was added thereto and the mixture was further stirred at room temperature for 1 hour. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and then dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography (mixed solvent of n-hexane and ethyl acetate) to obtain the aimed 4-methyl-3-(3-methyl-4-nitrophenyl sulfanyl)-5-pentafluoroethyl-4H-(1,2,4)-triazole (0.55 g).