Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[NH:14][C@H:13]1[CH2:17][I:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[O:21].B(F)(F)F.CCOCC>O1CCCC1>[O:1]([CH2:8][C:9]([NH:11][C@H:12]1[C:15](=[O:16])[N:14]([CH:20]([OH:21])[C:19]([O:23][CH3:24])=[O:22])[C@H:13]1[CH2:17][I:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CI
Reactant: COC(=O)C=O
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(O)N1C(=O)[C@H](NC(=O)COc2ccccc2)[C@@H]1CI
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of 0.360 g (1.0 mmol) of cis-3-phenoxyacetamido-4-oxo-2-azetidinylmethyl iodide, 0.440 g (5.0 mmol) of methyl glyoxylate, and 246 μl (2.0 mmol) of boron trifluoride etherate in 10 ml of anhydrous tetrahydrofuran is stirred at ambient temperature under an argon atmosphere for 5 hours. At this time 123 μl (1.0 mmol) of boron trifluoride etherate is added and the mixture is stirred for an additional 2 hours. The tetrahydrofuran is removed in vacuo and the residue is taken up in ethyl acetate and extracted with aqueous NaHCO3 and brine. The ethyl acetate solution is dried, filtered and evaporated to give 0.350 g of crude product which is purified by preparative thin-layer chromatography (silica gel GF); 0.174 g of pure product.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccccc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of methyl salicylate (10 g, 66 mmol) and 4-chloromethylpyridine hydrochloride (11 g, 67 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (19 g, 140 mmol) under ice-cooling, and then the mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into an ice water and the aqueous layer was extracted with ethyl acetate (150 mL, twice). The ethyl acetate layer was washed with a saturated brine solution (200 mL), dried over anhydrous sodium sulfate, and concentrated under a reduced pressure to dryness, and the resultant residue was purified with a silica gel column chromatography (hexane/ethyl acetate) and dried to give 12 g (75%) of the titled compound as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O.O>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 80 °C

Procedure:
4.3 Grams of 4-hydroxy-2-fluorobenzoic acid and 8.4 g of acetic anhydride were placed in a two-necked flask and mixed. While the mixture was cooled with water, 5 drops of sulfuric acid were added. After heat generation ended, the mixture was heated at 80° C. for 30 minutes. Thereafter, the reaction mixture was poured into cold water, and a precipitated crystal was recovered by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:36])[CH:28]4[CH2:31][CH:30]([CH2:32][C:33]([OH:35])=O)[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.[C:43]([C:47]1[CH:48]=[C:49]([NH2:54])[C:50]([NH2:53])=[CH:51][CH:52]=1)([CH3:46])([CH3:45])[CH3:44].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:54][C:49]1[CH:48]=[C:47]([C:43]([CH3:45])([CH3:44])[CH3:46])[CH:52]=[CH:51][C:50]=1[NH:53][C:33](=[O:35])[CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[O:17]2)[CH3:36])[CH2:31]1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)C3CC(CC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A solution of 2-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)acetic acid and 4-tert-butylbenzene-1,2-diamine (89.4 mg, 0.545 mmol) in N,N-dimethylformamide (4.5 mL) was treated with N,N-diisopropylethylamine (0.261 mL, 1.50 mmol) dropwise followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (259 mg, 0.681 mmol). The solution was allowed to stir at room temperature for 18 h during which time LCMS indicated the starting material had been consumed. The reaction mixture was concentrated under high vac. The residue was taken up in 30 mL ethyl acetate and 20 mL 1/1 H2O/sat NaHCO3 solution. The mixture was extracted and the aqueous phase was washed with 35 mL ethyl acetate. The combined organic phase was washed with two 20 mL portions of H2O, and 20 mL brine. The organic phase was dried over Na2SO4, filtered and concentrated to yield a tannish brown glass/stiff foam. The crude material was purified by flash chromatography (35 g silica gel; 4% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (272 mg, 82%) as a light tan glass/stiff foam which was a mixture of regioisomeric amides: MS (ESI+) for C41H53N7O6 m/z 728.8 (M+H)+; MS (ESI−) for C41H53N7O6 m/z 726.9 (M−H)−; HPLC purity >95%, (ret. time, 3.14, 3.17 min) two peaks observed due to amide regioisomers.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]1([CH3:33])[CH2:31][NH:30][CH2:29][C@@H:28]1[OH:32]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][C:27]([CH3:33])([CH3:26])[C@@H:28]([OH:32])[CH2:29]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC1(C)CNC[C@@H]1O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@H](O)C(C)(C)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-4,4-dimethylpyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, CD3OD) δ ppm 7.94 (dd, J=7.83, 1.01 Hz, 1 H), 7.83-7.73 (m, 2 H), 7.58 (td, J=7.58, 1.26 Hz, 1 H), 7.47-7.37 (m, 2 H), 7.23 (dd, J=8.59, 1.77 Hz, 1 H), 6.03 (s, 1 H), 5.11 (s, 2 H), 4.02 (dd, J=10.36, 5.31 Hz, 1 H), 3.93 (dd, J=5.05, 3.79 Hz, 1 H), 3.61-3.47 (m, 4 H), 2.37 (s, 3 H), 1.15 (s, 3 H), 1.10-1.05 (m, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21]OS(CC3C=CC(C)=CC=3)(=O)=O)[CH2:16]2)[CH2:11][CH2:10]1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+]>>[N:34]([CH2:21][CH:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH2:14][CH2:13]2)[CH2:16]1)=[N+:35]=[N-:36]
Reactant: Cc1ccc(CS(=O)(=O)OCC2CCCN(C3CCN(c4ccccc4C#N)CC3)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: N#Cc1ccccc1N1CCC(N2CCCC(CN=[N+]=[N-])C2)CC1

Procedure:
The title compound was prepared from 23 (1.37 g, 3.0 mmol) and sodium azide (0.4 g, 6.0 mmol) according to the procedure described in 12 to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([O:21][CH3:22])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl.O=S(Cl)Cl.[CH3:31]O>>[ClH:19].[CH2:1]([O:2][C:3](=[O:23])[C@H:4]([O:21][CH3:22])[CH:5]([NH2:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:11][CH:12]=1)[CH3:31]
Reactant: CO
Reactant: COC(=O)[C@H](OC)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](OC)C(N)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-3-amino-4-(3′-chloro-biphenyl-4-yl)-2-methoxy-butyric acid methyl ester (500 mg, 1.15 mmol) in MeOH (5 mL) is added 2M NaOH aqueous solution (5 mL). After being stirred at room temperature for 2 h, the reaction mixture is acidified with 2M HCl and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in EtOH (5 mL) and treated with SOCl2 (0.252 mL, 3.26 mmol). After being stirred at 55° C., the reaction mixture was concentrated. The residue is used for a next step without further purification. HPLC retention time=1.49 minutes (condition A): MS (m+1)=348.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][C:14]([CH2:24][NH:25][CH3:26])=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(C)c(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of tert-butyl ({1-[(3-fluoro-4-methylphenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (287 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 125 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:28]2[CH2:33][CH2:32][CH:31]([C:34]([F:37])([F:36])[F:35])[CH2:30][CH:29]=2)[C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:8][C:7]=2[CH:27]=1.[H][H]>C(O)C.[Pd]>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([CH:28]2[CH2:29][CH2:30][CH:31]([C:34]([F:35])([F:36])[F:37])[CH2:32][CH2:33]2)[C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:8][C:7]=2[CH:27]=1
Reactant: FC(F)(F)c1cc(C2=CCC(C(F)(F)F)CC2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: FC(F)(F)c1cc(C2CCC(C(F)(F)F)CC2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
6-Trifluoromethyl-4-(4-trifluoromethyl-cyclohex-1-enyl)-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (10 mg, Example 139b) was subjected to catalytic hydrogenation in ethanol (1 mL) using 10% Pd/C (10 mg, Aldrich) as catalyst. The reaction was conducted at room temperature under 1 atmosphere hydrogen for 2 days. The catalyst was filtered through a Celite® pad, the filter cake was washed with methanol and the filtrate was evaporated in vacuo to give the title compound as a film. MS (ESI, pos. ion) m/z: 565(M+1).
Reaction SMILES: [NH4+].[Cl-].[Cl:3][C:4]1[C:5]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([N:20]([CH3:29])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:13][C:12]=2[O:30][CH3:31])=[N:8][CH:9]=1>O.C(O)C.[Fe]>[Cl:3][C:4]1[C:5]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:6][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([N:20]([CH3:29])[CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:13][C:12]=2[O:30][CH3:31])=[N:8][CH:9]=1
Reactant: COc1cc(N(C)CCN2CCOCC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N(C)CCN2CCOCC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 79.6 %

Procedure:
A solution of NH4Cl (28.1 mg, 0.53 mmol) in water (13.00 mL) was added in one portion to a stirred mixture of N-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-2-methoxy-N′-methyl-N′-(2-morpholin-4-ylethyl)-5-nitrobenzene-1,4-diamine (Intermediate 106, 426 mg, 0.75 mmol) and iron (251 mg, 4.50 mmol) in ethanol (39 mL). The resulting mixture was stirred at reflux for 2 h. Further iron (251 mg, 4.50 mmol) and NH4Cl (28.1 mg, 0.53 mmol) was added and the mixture was stirred at reflux for a further 0.5 h. The mixture was concentrated in vacuo and the residue was mixed with DMF (5 mL) and then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia in CH2Cl2 and appropriate fractions were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 2M methanolic ammonia in CH2Cl2 gave the title compound (304 mg, 80%) as a yellow foam; 1H NMR: 2.43 (4H, m), 2.45 (2H, t), 2.68 (3H, s), 2.93 (2H, t), 3.51-3.61 (4H, m), 3.66 (3H, s), 4.73 (2H, s), 6.77 (1H, s), 6.90 (1H, s), 7.12 (1H, m), 7.34 (1H, m), 8.37 (1H, s), 8.43 (1H, d), 8.49 (1H, s), 8.84 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 509.
Reaction SMILES: [CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:1][C:2]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH2:26][CH2:27]3)=[CH:16][CH:15]=2)[C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([CH3:10])=[C:4]2[N:3]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCNCC4)cc3)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1cc(C)c2nc(C)n(Cc3ccc(NCC4CCN(C5CCOCC5)CC4)cc3)c2n1
Reaction time: 0.25 h
Yield: 53.6 %

Procedure:
A solution of Compound 157 (0.250 g, 0.69 mmol) in 1,2-dichloroethane was added with tetrahydro-4-pyranone (0.096 mL, 1.04 mmol) followed by stirring for 15 minutes. The mixture was added with sodium triacetoxyborohydride (0.439 g, 2.07 mmol) followed by stirring at room temperature for 5 hours. The reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:2 mol/L ammonia-methanol solution=19:1). The obtained crystals were recrystallized from ethanol-diisopropyl ether to obtain Compound 158 (0.166 g, 0.37 mmol, 54%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (374 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an orange oil (450 mg, 74%).
Reaction SMILES: [CH2:1](NC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.[BH3-]C#N.[Na+].[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>CO>[CH2:1]([NH:27][C:26]1[CH:28]=[CH:29][C:30]([F:31])=[C:24]([Cl:23])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(NCc2ccccc2)cc1Cl
Temperature: 23 °C
Reaction time: 18 h

Procedure:
Benzylaniline (3.69 g, 34.8 mmol), AcOH (1.11 mL), and NaBH3CN were added to a solution of 3-chloro-4-fluoroaniline (5.07 g, 34.8 mmol) in MeOH (200 mL) containing molecular sieves. The resulting mixture was stirred at 23° C. for 18 h. Sieves were removed by filtration and the filtrate was concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and CH2Cl2 (50 mL, 2×20 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (SiO2, 0-12% EtOAc/hexanes gradient) to give N-benzyl-3-chloro 4-fluoroaniline (7-1) 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 6.93 (dd, J=8.8, 5.8 Hz, 1H), 6.62 (dd, J=6.1, 3.1 Hz, 1H), 6.44 (ddd, J=8.9, 3.7, 3.1 Hz, 1H), 4.27 (s, 2H), 3.98 (brs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>>[C:27]([C:26]1[CH:30]=[CH:31][C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:23]=2)=[CH:33][C:25]=1[Cl:24])(=[O:28])[NH2:29]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(Cl)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(Cl)c4)ccc3o2)CC1
Yield: 13.7 %

Procedure:
Following the General Procedure-2, the titled compound (25 mg) was prepared from Intermediate 7 (150 mg, 0.4 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (110 mg, 0.4 mmol) as a brown solid. M.P.: 169-171° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.03 (s, 1H), 7.87 (bs, 1H), 7.82-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.59 (bs, 1H), 7.52 (d, J 7.9, 1H), 3.94 (d, J 12.9, 2H), 3.30-3.22 (m, 1H), 3.08-2.92 (m, 2H), 2.09 (d, J 10.6, 2H), 1.75-1.63 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)([CH3:28])[CH3:27])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:22]([O:24][C:25](=[O:37])[C:26]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:2][C:3]2[C:4]([CH:19]3[CH2:21][CH2:20]3)=[N:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)=[N:7][CH:8]=2)=[CH:34][CH:35]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 418 mg (1.34 mmol) 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine and 300 mg (1.34 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] in 5 ml DMF was treated with 523 mg (1.61 mmol) cesium carbonate. The reaction mixture was stirred 4 h at RT and then it was taken up in ether and washed with 1N HCl and water. The ether layers were concentrated under reduced pressure and the crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 giving 550 mg of pure 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:20])[CH:17]([CH3:19])[CH3:18]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and isobutyryl chloride
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][C:19]=1[F:22]
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccc(F)c(F)c2n1
Product: Fc1ccc2nn(CCC#Cc3ccccn3)nc2c1F
Yield: 58.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (42 mg, 0.26 mmol) and 2-(but-3-ynyl)-4,5-difluoro-2H-benzo[d][1,2,3]triazole (50 mg, 0.24 mmol); Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 41 mg (0.14 mmol, 60%) of 4,5-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:19]([O:23][C:24]([N:26]([CH2:28][C:29](O)=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]([CH2:28][C:29]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:30])[CH3:27])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CN(CC(=O)Nc1ncn(CCCc2ccccc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 94 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.00 g (8.19 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 114 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 3.20 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(3-phenylpropyl)-5-imidazolecarboxamide (yield 94%).