Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:32][CH3:33])=[CH:5][C:6]2[C:15]3[C:14](=O)[NH:13][C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[C:10]=3[N:9]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:8](=[O:30])[C:7]=2[CH:31]=1.O=P(Cl)(Cl)[Cl:36].P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:36][C:14]1[N:13]=[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]2=[C:10]2[C:15]=1[C:6]1[CH:5]=[C:4]([O:32][CH3:33])[C:3]([O:2][CH3:1])=[CH:31][C:7]=1[C:8](=[O:30])[N:9]2[CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c4ccccc4[nH]c(=O)c3c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c4ccccc4nc(Cl)c3c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Precursor 29 (22.5 mg, 0.05 mmol) was mixed with POCl3 (3 mL) and phosphorus pentachloride (100 mg, 10 equiv) was added slowly at room temperature. Starting material dissolved upon PCl5 addition, forming a clear yellow solution. The reaction mixture was stirred for 1 h and then heated at reflux for 1.5 h. After disappearance of starting material, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The brown oily residue was dissolved completely in ice-cold water (3 mL) and concentrated ammonium hydroxide solution was added dropwise to neutral pH. The cloudy aqueous solution was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with concentrated ammonium hydrochloride solution, dried with sodium sulfate and evaporated to dryness under reduced pressure to yield 32 as an amorphous solid (15 mg, 66%): mp 185-190° C. (dec.), IR (KBr) 1651, 1606 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1 H), 8.17 (d, J=8.5 Hz, 1 H), 7.95 (d, J=7.6 Hz, 1 H), 7.82 (t, J=7.6 Hz, 1 H), 7.77 (s, 1 H), 7.71 (t, J=7.4 Hz, 1 H), 4.56-4.28 (m, 2 H), 3.97 (s, 3 H), 3.96-3.88 (m, 5 H), 3.76 (t, J=12.0 Hz, 2 H), 3.42 (d, J=11.9 Hz, 2 H), 3.18 (s, 2 H), 3.05 (d, J=11.1 Hz, 2 H), 2.42 (s, 2 H); 13C NMR (126 MHz, CDCl3) δ 161.90, 152.44, 149.88, 145.75, 144.76, 144.57, 130.45, 127.92, 126.50, 125.47, 124.66, 119.34, 117.80, 110.25, 108.06, 107.89, 63.23, 55.91, 55.78, 53.12, 50.89, 48.68, 22.93; positive ESIMS m/z (rel intensity) 468/470 (MH+, 100/32), 381/383 (97/30). Anal. Calcd for C25H28Cl3N3O4.1.2H2O: C, 53.38; H, 5.45; N, 7.47. Found: C, 53.36; H, 5.45; N, 7.10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH3:36])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:17])[CH2:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH3:36])=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: Cc1cc(O)ccc1SCC(=O)OC(C)(C)C
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1SCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 20A], (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid tert-butyl ester (example 20C]), was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give {2-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenylsulfanyl}-acetic acid tert-butyl ester, which was subsequently saponified in analogy to the procedure described in example 20B] to yield the title compound as white solid of mp. 168–169° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:23]
Reactant: O=C=Nc1ccccc1Cl
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(Nc1ccccc1Cl)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 4-benzylpiperidine and 2-chlorophenyl isocyanate. 1H NMR (400 MHz, CDCl3): 8.19 (dd, J=8.3, 1.5 Hz, 1H), 7.33-7.12 (m, 7H), 7.03 (brs, 1H), 6.96-6.90 (m, 1H), 4.12-4.05 (m, 2H), 2.85 (td, J=13, 2.3 Hz, 2H), 2.57 (d, J=6.8 Hz, 2H), 1.82-1.69 (m, 3H), 1.34-1.20 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
2-Chloro-4-fluorophenol (5.64 g, 38.5 mmol) was added to a solution of acetic acid (16.5 mL), nitric acid (8.66 mL) and water (7.5 mL) at 0° C. The reaction mixture was stirred vigorously for 5 hours at 0° C. The resulting precipitate was filtered, washed with water and dried under vacuum to yield 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol, 83%) as a yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=2)[CH2:19][CH2:18]1)C(=O)OC(C)(C)C>ClCCl>[CH3:8][NH:9][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=2)[CH2:19][CH2:18]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nccn2C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CCN(c2nccn2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 ml) was added at 0° C. to a solution of tert-butyl methyl(1-(1-methyl-1H-imidazol-2-yl)piperidin-4-yl)carbamate (241 mg, 0.82 mmol, 1 eq) in dichloromethane (5 ml), and the reaction mixture was stirred for 1 h at room temperature. Concentration under reduced pressure was then carried out. The crude product so obtained was used in the next stage without being purified further.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([NH2:18])[CH:12]=1.CCN(CC)CC>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([NH:18][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH:12]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cl)c(NC(=O)CCCCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
4-Chlorobutyryl chloride (2.82 g, 20 mmol, 2.0 equiv) in CH2Cl2 (5 ml) was added over 2 min to a stirred solution of 3-amino-4-chloro-benzoic acid methyl ester (D27c) (1.66 g, 10 mmol, 1 equiv) and NEt3 (2.22 g, 22 mmol, 2.2 equiv) in CH2Cl2 (40 ml). The resulting mixture was stirred for 1 h at room temperature then washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. The residue was triturated with CH2Cl2 to give 4-chloro-3-(4-chloro-butanoylamino)-benzoic acid methyl ester (D28c) (1.81 g, 48%) as a pale pink solid.
Reaction SMILES: Cl.C(O[CH:5]=[CH:6][C:7](=[NH:11])OCC)C.Br.[CH2:13]([O:15][C:16]([C:18]([NH2:20])=[NH:19])=[O:17])C.[Na]>CO>[NH2:11][C:7]1[CH:6]=[CH:5][N:20]=[C:18]([C:16]([O:15][CH3:13])=[O:17])[N:19]=1
Reactant: CCOC(=O)C(=N)N
Reactant: CCOC=CC(=N)OCC
Agent: Br
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of ethyl 3-ethoxyacrylimidate hydrochloride (4.0 g) and 1-ethoxycarbonylformamidine hydrobromide (4.4 g) in methanol (110 ml) was added dropwise a solution of sodium metal (1 g) in methanol (110 ml) at 0° C. The reaction mixture was stirred for an hour at 0° to 5° C. and for additional 4 hours at ambient temperature. The solution was evaporated to dryness and the residue was dissolved in a mixture of ethyl acetate and an aqueous solution of sodium chloride. The organic layer was separated out and the aqueous layer was extracted with ethyl acetate five times. All organic layers were combined, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was triturated with diethylether to give methyl 4-aminopyrimidine-2-carboxylate (1.33 g), which was recrystallized from ethyl acetate, mp. 140°-142.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)c1cc(-c2cccnc2)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 86.8 %

Procedure:
In the same manner as described in Example 139, 505 mg (1.0 mmol) of the product of Example 89 and 515 mg (1.4 mmol) of 3-(tributylstannyl)pyridine provided 437 mg (87%) of the desired product as a pale yellow solid. Electrospray Mass Spec 504 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2nccc(C(F)(F)F)n2)CC1
Yield: 85 %

Procedure:
A mixture of 2-chloro-4-trifluoromethyl-pyrimidine (2.15 g, 11.78 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.07 g, 15.31 mmol, 1.3 equiv; commercially available) in anhydrous DMF (15 mL) and triethylamine (5 mL) was heated to 100° C. for 3 h. The organic phase was concentrated under reduced pressure and the residue extracted with dichloromethane (3×50 mL) from a sat. solution of sodium bicarbonate (100 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with heptane/ethyl acetate (5:1+1% triethylamine) providing 3.47 g (85%) of the title compound. MS (ISP): 347.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+:10]([O-])([OH:12])=[O:11]>C(Cl)Cl>[N+:10]([C:7]1[CH:8]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CSc1ccc(O)cc1
Solvent: ClCCl
Product: CSc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(methylthio)phenol(5.0 g) in methylene chloride (100 mls) was added 30% nitric acid absorbed on silica (9.29 g) and the mixture stirred at room temperature for 3hrs. The mixture was filtered and washed with methylene chloride. The solvent was evaporated and the residue was purified by flash chromatography eluting with ethyl acetate and hexane (15:85 v/v ) to give 2-nitro-4-(methylthio)phenol as an orange solid (2.22 g);
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:20][C:21]([NH:23][C@H:24]([C:40]([OH:42])=O)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:58][C@H:59]([C:65]([OH:67])=[O:66])[CH2:60][CH2:61][C:62]([OH:64])=[O:63]>>[C:1]([O:18][CH:19]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:20][C:21]([NH:23][C@H:24]([C:40]([NH:58][C@H:59]([C:65]([OH:67])=[O:66])[CH2:60][CH2:61][C:62]([OH:64])=[O:63])=[O:42])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Yield: 68.9 %

Procedure:
Starting from N-hydroxysuccinimide ester of Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysine (3 g) prepared above and L-glutamic acid (1.18 g), N-[Nα -(3-hexadecanoyloxyoctadecanoyl)-Nε -benzyloxycarbonyl-L-lysyl]-L-glutamic acid (2.4 g) was obtained as crystals according to a similar manner to that of Example 16(2).
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]=1[CH:19]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)C>[Cl:6][C:7]1[C:8]([CH:19]=[CH2:1])=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: O=Cc1c(Cl)cccc1-c1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Under a dry argon atmosphere n-butyllithium (1.3 g, 0.020 mole) was added slowly to a stirred ice cold mixture of (methyl)triphenylphosphonium bromide (7.3 g, 0.0203 mole) in 30 ml of tetrahydrofuran. The mixture was warmed to room temperature, stirred for two hours, and 3-chloro-[1,1'-biphenyl]-2-carboxaldehyde (4.4 g, 0.0203 mole) in 30 ml of tetrahydrofuran added. The reaction mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then cooled. The reaction mixture was diluted with 300 ml of diethyl ether and washed with 100 ml of water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a residue. Distillation of the residue at 88°/0.05 mm gave 3-chloro-2-ethenyl-[1,1'-biphenyl] (2.3 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[N:3]1.[Cl:19]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Cl:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (356 mg, 1.35 mmol) and N-chlorosuccinimide (180 mg, 1.35 mmol) in tetrahydrofuran (6.7 ml) was stirred in a sealed tube for 1 h at 70° C. 6N sodium hydroxide (2.2 ml, 13.47 mmol) was added in one portion and the solution stirred an additional 12 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly without further purification yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (357 mg, 1.25 mmol, 93% yield) as a yellow oil: LCMS (ES) m/e 271, 273 (M, M+2)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
A mixture of 4-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-amine (150 mg, 0.47 mmol) produced in Example 2, cyclopropanecarbonyl chloride (0.13 mL, 1.40 mmol) and pyridine (5 mL) was stirred at room temperature for 6 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (0.085 mL, 0.94 mmol) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0), and 1N aqueous sodium hydroxide solution (0.5 mL), methanol (5 mL) and tetrahydrofuran (10 mL) were added to the crude product. The mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the obtained residue. After neutralization with 1N hydrochloric acid, the resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (145 mg, 80%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][NH:42][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and cyclopropylmethylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.1-0.3 (m, 4 H), 0.97 (bs, 1 H), 2.75-3.02 (m, 2 H) 3.26 (s, 4 H), 3.76 (s, 4 H), 6.25 (bd, 1 H), 7.03 (d, J=12.4 Hz, 1 H), 7.24-7.27 (m, 2 H), 7.38-7.41 (m, 1 H), 7.48 (s, 1 H), 7.56-7.59 (m, 3 H), 7.80-7.83 (m, 1 H), 7.98 (d, J=7.3 Hz, 1 H), 8.20 (s, 1 H), 10.45 (s, 1 H).
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+].Cl[CH2:35][C:36]1[N:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:38][N: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][C:36]2[N:40]=[C:39]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:38][N: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: ClCc1noc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2noc(-c3ccccc3)n2)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 (1.24 g), potassium carbonate (0.94 g), 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (0.68 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 (0.79 g, 45%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[Na].Cl.Cl[CH2:9][C:10]1[C:15]([O:16][CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[C:15]([O:16][CH2:17][CH3:18])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cccnc1CCl
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOc1cccnc1CSCCN
Reaction time: 8 h
Yield: 89.5 %

Procedure:
Cysteamine hydrochloride (2.76 g) was added to a stirred mixture of sodium (1.576 g) in ethanol (75 cc) at 12°, 2-Chloromethyl-3-ethoxypyridine hydrochloride (4.60 g) in ethanol (70 cc) was added over 30 minutes to this mixture stirred at 10°-12°. The mixture was left to stand overnight, filtered and the filtrate was evaporated to dryness. The residue was dissolved in water, acidified to pH4 with hydrochloric acid and extracted with chloroform (discarded). The aqueous phase was adjusted to pH 12 with aqueous sodium hydroxide and was extracted with chloroform. The chloroform extracts were evaporated to give 2-(2-aminoethylthiomethyl)-3-ethoxypyridine (4.2 g) as an oil.
Reaction SMILES: [CH:1]1([C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[CH2:3][CH2:2]1.[Li][CH2:11]CCC.S(OC)(OC)(=O)=O>CCOCC>[CH3:7][Si:6]([CH3:9])([CH3:8])[C:5]#[C:4][C:1]1([CH3:11])[CH2:3][CH2:2]1
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)C#CC1CC1
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CC1(C#C[Si](C)(C)C)CC1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol) in ether (20 mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at 0° C. The reaction mixture was stirred at ambient temperature for 24 h before dimethyl sulfate (6.85 g, 54.3 mmol) was added dropwise at −10° C. The resulting solution was stirred at 10° C. and then at 20° C. for 30 min each. The reaction was quenched by adding a mixture of sat. aq. NH4Cl and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at ambient temperature for 1 h. The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic layers were washed successively with 5% aqueous hydrochloric acid (100 mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were dried over anhydrous NaSO4 and concentrated at ambient pressure. After fractional distillation under reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ 1.25 (s, 3H), 0.92-0.86 (m, 2H), 0.58-0.56 (m, 2H), 0.15 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([O:18]C)=[O:17])[C:13](=[O:20])[C:12]([CH2:23][CH3:24])([CH2:21][CH3:22])[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[OH-].[ClH:27]>C1COCC1.O>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13](=[O:20])[C:12]([CH2:23][CH3:24])([CH2:21][CH3:22])[NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)OC)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl [(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate from Step C (43 mg, 0.126 mmol) in THF (0.75 mL) and H2O (0.25 mL) was added 1 N aqueous LiOH (0.139 mL, 0.139 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was adjusted to pH 4 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=327 (M+1).