Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:20][C:10]1[C:11](=[O:13])[NH:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][C:9]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1
Reactant: O=c1cc(-c2ccncc2)nc(-c2ccccc2)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)nc(-c2ccncc2)c1Br
Temperature: 90 °C
Yield: 92.1 %

Procedure:
2-Phenyl-6-(4-pyridyl)pyrimidin-4-one (0.61 g) obtained in Example 12 was dissolved in 3 ml of acetic acid, and then the mixture was added with 0.48 g of N-bromosuccinimide and heated at 90° C. for 1 hour. Water was added to the reaction mixture, and solid mass was separated by filtration. The solid was washed with water, acetone, and ethyl acetate, and dried to obtain 0.74 g of the desired compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[ClH:3].[C:6]1([C:5]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CO)NC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: CC1(C)COC(c2ccccc2)=N1
Product: Cl
Temperature: 25 °C

Procedure:
To 40 ml of freshly distilled thionyl chloride at 0° was added in portions over 15 minutes with stirring 3.86 g (0.02 mol) 2-benzoylamino-2-methyl-1-propanol. The solution was warmed to room temperature and heated under reflux for 2 hours. The thionyl chloride was removed under reduced pressure to afford a yellow oil which crystallized at 0° following the addition of anhydrous ether. The solid was triturated in anhydrous ether overnight and isolated by filtration under a nitrogen atmosphere. After drying in vacuo over calcium sulfate, 2.00 g (0.009 mol), 45%, 2-phenyl-4,4-dimethyl-1,3-oxazoline hydrochloride was obtained as a white solid, mp 149°-151°; ir (KBr) 1640 (c=N) cm-1, pmr (D2O) δ 1.60 (s, 6H), 4.70 (s, 2H) and 7.3-8.2 (m, 5H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:27])[CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][O:29][C:30](=[O:31])[C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([O:26][C:23]2[CH:22]=[CH:21][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:27])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:25][CH:24]=2)[CH:37]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2)c1

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 346, step 1) was reacted with 3-methoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=516.4 [M+H]+.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26]>>[Br-:20].[CH3:28][O:27][C:25]([C:24]1[CH:23]=[C:22]([CH:31]=[CH:30][CH:29]=1)[CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 80 °C
Reaction time: 10 h
Yield: 100.3 %

Procedure:
Triphenylphosphine (85.8 g) was added to a Tol (400 ml) solution of methyl 3-bromomethylbenzoate (50.0 g), followed by stirring at 80° C. for 10 hours. After this was cooled to room temperature, the crystal precipitated was collected by filtration and washed with Tol. This was dried under reduced pressure to obtain (3-methoxycarbonylbenzyl)(triphenyl)phosphonium bromide (107.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(N(CC)CC)C>N1C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:15]2[C:14](=[O:17])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:28][CH:27]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1n(-c2ccc(Cl)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Yield: 7.6 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (50 mg, 0.14 mmol), prepared as described in Example 1 and 4-chlorophenyboronic acid (44 mg, 0.28 mmol) in pyridine (1.5 mL) was added copper (II) acetate (51 mg, 0.28 mmol) followed by triethylamine (0.04 mL, 0.28 mmol) and 3 Å molecular sieves (100 mg) under argon. The reaction mixture was stirred at reflux for 6 h. After this time, the reaction mixture was cooled to RT and diluted with water (5 mL). The resultant mixture was extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and saturated aqueous NaCl (2×5 mL). The organic layer was dried over MgSO4, filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to give 2,7,8-tris(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (5 mg, 8%) as yellow lyophilate. HPLC: 4.35 min; M+H=467; 1H NMR (CDCl3) δ 8.22 (1H, s), 8.10 (2H, d, J=10.0 Hz), 7.43 (2H, d, J=10.0 Hz), 7.35-7.38 (6H, m), 7.15 (2H, d, J=10.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH:26]1[O:31][C:30](=[O:32])[CH2:29][CH:28]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27]1>>[CH2:34]([O:33][CH:28]1[CH2:27][CH:26]([CH2:25][CH2:24][N:23]2[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:31][C:30](=[O:32])[CH2:29]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: NCCC1CC(OCc2ccccc2)CC(=O)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC1CC(OCc2ccccc2)CC(=O)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 6-(2-aminoethyl)-4-(benzyloxy)tetrahydro-2H-pyran-2-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[N:14][CH:13]=1.C([Si](C(C)C)(C(C)C)[SH:22])(C)C.C(=O)([O-])[O-].[K+].[K+].[C:35]([C:37]1[CH:38]=[C:39]([S:44]([N:47]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=2[O:62][CH3:63])[C:48]2[S:52][N:51]=[CH:50][N:49]=2)(=[O:46])=[O:45])[CH:40]=[CH:41][C:42]=1F)#[N:36]>CN(C)C(=O)C.C(OCC)(=O)C>[C:35]([C:37]1[CH:38]=[C:39]([S:44]([N:47]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][C:55]=2[O:62][CH3:63])[C:48]2[S:52][N:51]=[CH:50][N:49]=2)(=[O:46])=[O:45])[CH:40]=[CH:41][C:42]=1[S:22][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[N:14][CH:13]=1)#[N:36]
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: FC(F)(F)c1ccc(Cl)c(-c2ccnnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Sc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 130 °C
Yield: 73.4 %

Procedure:
4-[2-Chloro-5-(trifluoromethyl)phenyl]pyridazine (Preparation 21, 0.050 g, 0.193 mmol), triisopropylsilanethiol (0.090 g, 472 mmol) and potassium carbonate (0.055 g, 0.398 mmol) were dissolved in N,N-dimethylacetamide (2 mL) in a Reactivial®. The reaction mixture was heated to 130° C. for 1 hour and 15 minutes. Then, the reaction was cooled to room temperature and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 1, 0.085 g, 1.96 mmol) was added. The mixture was stirred at room temperature for thirty minutes. The reaction mixture was diluted in ethyl acetate (15 mL) and washed twice with a solution of saturated aqueous brine (15 mL). The aqueous layer was extracted with ethyl acetate (5 mL). The organic phases were combined and dried over sodium sulphate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ISCO™, 0-50% ethyl acetate in heptane gradient elution, 12 g SiO2) to give title compound as a yellow foam (0.095 g, 73%).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[S:7])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[OH:20][CH:21]1[CH2:24][O:23][CH2:22]1.N1C=CC=CC=1>O>[O:23]1[CH2:24][CH:21]([O:20][C:6](=[S:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:1]([CH3:3])[CH3:2])[CH2:22]1
Reactant: OC1COC1
Reactant: CC(C)c1ccccc1C(=S)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)c1ccccc1C(=S)OC1COC1
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of 12.9 g of 2-isopropylthiobenzoic acid chloride and 20 ml of absolute toluene is added dropwise at a temperature of from 15° to 20° C. to a mixture of 4.44 g of 3-hydroxy-oxetane, 6.64 g of pyridine and 60 ml of absolute toluene. The resulting suspension is stirred for 2 hours at a temperature of from 20° to 25° C. and for a further 3 hours at a temperature of from 40° to 45° C. Water is added to the reaction mixture and the organic phase is washed with water, dried and concentrated by evaporation to yield 12.6 g of 2-isopropylthiobenzoic acid oxetan-3-yl ester in the form of a pale yellow oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:16])=[CH:15][CH:14]=2)=[O:13])[CH2:29][CH2:30]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 88.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (384 mg) was obtained. Using the obtained [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (303 mg) and by the reaction and treatment in the same manner as in Example 123, the title compound (264 mg) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:22]C(/N=N/C(OCC)=O)=O.C([O:34][C:35](=[O:52])[C@@H:36]([O:50][CH3:51])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]#[C:45][CH2:46][CH2:47][CH2:48][OH:49])=[CH:40][CH:39]=1)C.[C:53]1([C:59]2[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C1COCC1>[C:59]1([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:60]=[CH:61][C:62]([O:49][CH2:48][CH2:47][CH2:46][CH2:45][C:44]([C:41]2[CH:40]=[CH:39][C:38]([CH2:37][C@H:36]([O:50][CH3:51])[C:35]([OH:34])=[O:52])=[CH:43][CH:42]=2)=[O:22])=[CH:63][CH:64]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCCO)cc1)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(C(=O)CCCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (0.24 g, 0.915 mmol) in 5 mL of dry THF was treated at 0° C. with diethylazodicarboxylate (0.159 g, 0.915 mmol) and stirred for 20 min. A solution of (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 21, Step A) (0.18 g, 0.61 mmol) and 4-phenylphenol (0.156 g, 0.915 mmol) in 2 mL of dry THF was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 10:1 to 3:1). Fractions with Rfs 0.48 and 0.45 (hexanes/ethyl acetate 2:1) corresponding to the coupled compound and starting phenol, respectively, were combined and concentrated. The mixture was dissolved in 5 mL of methanol and was treated with a mixture of 75 mg of mercury (II) oxide and 4% sulfuric acid in water. The solution was stirred at 55° C. for 3 h, cooled to room temperature, diluted with saturated aqueous NaHCO3 (20 mL), and extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH and stirred for 2 hours. The methanol was evaporated under vacuum, and the aqueous solution was diluted with brine (6 mL) and washed with diethyl ether (3×15 mL). The aqueous layer was acidified with 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL). The combined extracts were dried (MgSO4) and concentrated to a white solid (19%). 1H-NMR (200.15 MHz, CDCl3): δ 7.89 (d, 2H, J=8.4), 7.55–7.23 (m, 9H), 6.93 (d, 2H, J=8.8), 4.06–3.99 (m, 3H), 3.38 (s, 3H), 3.18 (dd, 1H, J=4.3, 4.4), 3.03 (t+m, 3 H, J=6.9), 1.96–1.86 (m, 4H).
Reaction SMILES: C([Mg]Br)C.[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)#[CH:6].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]=[O:34]>C(OCC)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[O:24][N:23]=[C:22]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[C:21]=1[CH:33]([OH:34])[C:6]#[C:5][C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: C#Cc1cncnc1
Reactant: O=Cc1c(COC2CCCCO2)noc1-c1ccccc1Cl
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(C#Cc1cncnc1)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Yield: 40.1 %

Procedure:
Add 3M ethylmagnesium bromide (36 mL, 109 mmol) in diethyl ether to a 0° C. solution of 5-ethynyl-pyrimidine (8.1 g, 77 mmol) in THF (75 mL). Add 5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazole-4-carbaldehyde (10 g, 31 mmol) in THF (75 mL) and stir 15 h at RT. Quench the reaction with 1N HCl and extract with diethyl ether (2×150 mL). Wash the organic phase with brine (150 mL), dry over sodium sulfate, filter and concentrate under reduced pressure. Purification by flash chromatography (silica gel, 1:1 to 3:7 hexanes/EtOAc) gives the title compound (5.3 g, 40%): 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.35 (s, 2H), 7.44–7.62 (m, 4H), 5.65 (t, J=14 Hz, 1H), 5.08–5.28 (m, 1H), 4.80–4.95 (m, 2H), 4.42–4.60 (m, 1H), 3.80–4.01 (m, 1H), 3.51–3.68 (m, 1H), 1.54–1.90 (m, 6H); TLC Rf=0.20 (3:7 Hexanes:EtOAc).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].[Br:13][C:14]([F:18])=[C:15]([F:17])[F:16]>CN(C)C=O>[Br:13][CH:14]([F:18])[C:15]([F:17])([F:16])[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: FC(F)=C(F)Br
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC(F)(F)C(F)Br)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
278 g of 4-nitrophenol and 56 g of potassium hydroxide were dissolved in 800 ml of dimethylformamide, 179 g of bromotrifluoroethylene were fed in, a little at a time, at 40° C., and stirring was then continued for 2 hours at 60° C. The solvent was removed under reduced pressure in a rotary evaporator, the residue was poured into ice-water and extracted with 3×500 ml of methylene chloride, the extract was washed with dilute sodium hydroxide solution and water and dried over Na2SO4, and the solvent was removed. When the residue was distilled, 279.5 g of pure product passed over at 114° C./1.3 mbar.
Reaction SMILES: [C:1]([C:6]1([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([O:3]CC)=[O:2].[OH-].[Na+].C(O)C.O.[OH-].[Li+]>O.O1CCCC1>[C:1]([C:6]1([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1(SCc2ccc(OC)cc2)CCCCC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1ccc(CSC2(C(=O)O)CCCCC2)cc1
Temperature: 60 °C
Yield: 91.8 %

Procedure:
Dissolve 1-(carboethoxy)-1-(4-methoxybenzylthio)cyclohexane (1.45 g, 4.7mmol) in water (2.5 mL) and tetrahydrofuran (10 mL). Treat with 2.5N sodium hydroxide (4 mL, 10mmol. Heat at 60° C. for 2 hours, add 95% ethanol (10 mL) and lithium hydroxide monohydrate (0.42 g, 10 mmol) Heat to a gentle reflux for 20 hours, cool and evaporate the solvent in vacuo. Partition between water (50 mL) and ether (50 mL). Separate the aqueous phase and acidify to pH 1. Extract with methylene chloride (50 mL), dry (Na2SO4) and evaporate the solvent in vacuo to give 1-(carboxy)-1-(4-methoxybenzylthio)cyclohexane as a white solid (1.21 g, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]([CH2:43][CH2:44][O:45][CH3:46])[CH3:42])=O>>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]([CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[C:10]([NH:9][CH2:8][CH2:6][C:5]2[CH:35]=[CH:36][C:2]([O:1][CH2:38][CH2:39][N:41]([CH2:43][CH2:44][O:45][CH3:46])[CH3:42])=[CH:3][CH:4]=2)[CH:15]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: COCCN(C)C(=O)CCl
Product: COCCN(C)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 50.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22].[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30](C(O)=O)=[C:29]([O:37][CH3:38])[CH:28]=1>>[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:6]([NH:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25])[CH2:11]2)=[O:7])=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCN(CCCCN)C1
Reactant: CCCN=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CCCNC(=O)NCCCCN1CC[C@@H](CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-((3S)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.50 g) as starting compound was reacted and treated in the same manner as in Example 34 using n-propyl isocyanate (0.57 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (1.11 g) to give 4-amino-5-chloro-2-methoxy-N-((3S)-1-(4-(3-n-propylureido)butyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:28]1[CH:32]([C:33]([F:36])([F:35])[F:34])[N:31]([CH3:37])[C:30]([C:38](=[NH:40])[NH2:39])=[N:29]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:40]=[C:38]([C:30]4[N:31]([CH3:37])[C:32]([C:33]([F:36])([F:35])[F:34])=[N:28][N:29]=4)[N:39]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CN1C(C(=N)N)=NN(O)C1C(F)(F)F
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4nnc(C(F)(F)F)n4C)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 70 mg (0.33 mmol) of 1-hydroxy-4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazole-3-carboximidamide were reacted according to the General Method 2. Yield: 37 mg (30% of theory)
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:22]2[CH2:27][CH2:26][N:25](CCOC)[CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][CH2:20][CH3:21])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].NC1C=C([C@H](N2CCN([CH2:62][CH2:63][CH2:64][O:65][CH3:66])CC2)C2C=CC(C(N(CC)CC)=O)=CC=2)C=CC=1.C(=O)CC.[B][B][B][B][B][B][B][B][B][B].C(O)(C(F)(F)F)=O>>[CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:22]2[CH2:27][CH2:26][N:25]([CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][CH2:20][CH3:21])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCCNc1cccc([C@@H](c2ccc(C(=O)N(CC)CC)cc2)N2CCN(CCOC)CC2)c1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(N)c2)N2CCN(CCCOC)CC2)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CCC=O
Solvent: O=C(O)C(F)(F)F
Product: CCCNc1cccc([C@@H](c2ccc(C(=O)N(CC)CC)cc2)N2CCN(CCCOC)CC2)c1
Yield: 55 %

Procedure:
Using the same method as for COMPOUND 61 and using COMPOUND 60 (86.0 mg, 0.20 mmol), propionaldehyde (0.014 mL, 0.19 mmol) and decaborane (7.2 mg, 0.059 mmol) afforded COMPOUND 62 (89 mg, 55% yield) as its TFA salt. This material was lyophilized from CH3CN/H2O to produce a hygroscopic, slightly yellow solid. Purity (HPLC): >97%; Optical purity (Chiral HPLC): >93%; 1H NMR (400 MHz, CD3OD) δ 1.01 (t, J=7.4 Hz, 3H), 1.09 (br t, J=6.6 Hz, 3H), 1.22 (br t, J=6.6 Hz, 3H), 1.70 (sextet, J=7.6 Hz, 2H), 1.95-2.04 (m, 2H), 2.39 (br s, 2H), 3.01 (br s, 2H), 3.15-3.28 (m, 8H), 3.33 (s, 3H), 3.45-3.61 (m, 6H), 4.55 (s, 1H), 7.10-7.16 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.37-7.44 (m, 3H), 7.57 (d, J=8.0 Hz, 2H). Found: C, 53.22; H, 6.76; N, 7.48. C29H44N4O2×2.0 H2O×2.0 CF3COOH has C, 53.22; H, 6.77; N, 7.52%. [α]D17=−1.5 deg [c 0.779, MeOH].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[C:34]1([C:40]2([OH:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:43]2[CH2:44][CH2:45][C:40]([OH:46])([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:41][CH2:42]2)=[O:18])[N:8]([C:6](=[O:7])[C:28]2[CH:27]=[CH:26][C:25]([C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)=[CH:33][CH:32]=2)[CH2:12]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N2CCC(O)(c3ccccc3)CC2)N(C(=O)c2ccc(-c3ccncc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and 4-phenyl-4-piperidinol, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=499.