Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:27])[NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[N:18]=1)[CH2:9][C@@H:10]([O:12][CH2:13][CH3:14])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[Cl:36]CCl>>[ClH:36].[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][N:19]1[CH:20]=[CH:21][C:17]([NH:16][C:15](=[O:27])[C@@H:8]([NH2:7])[CH2:9][C@@H:10]([O:12][CH2:13][CH3:14])[CH3:11])=[N:18]1
Reactant: CCO[C@@H](C)C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccn(CC(C)(C)O)n1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@@H](C)C[C@H](N)C(=O)Nc1ccn(CC(C)(C)O)n1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {(1S,3S)-3-ethoxy-1-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylcarbamoyl]-butyl}-carbamic acid t-butyl ester (486 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 30 min. Solvents were evaporated and the residue was dried in vacuo. The resulting waxy material was dissolved in a methanolic hydrogen chloride solution (5 mL). The solvents were evaporated and the residue was dried in vacuo. The white solid was triturated with dry diethyl ether and filtered to afford (2S,4S)-2-amino-4-ethoxy-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (477 mg). For the neutral free amine, LR-ES-MS m/z calculated for C14H26N4O3 [M]+ 298, observed [M+H]+ 299.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.Cl[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1
Temperature: 150 °C

Procedure:
50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 2 ml of isopropanol, 32.3 mg (0.233 mmol) of 6-chloronicotinonitrile and 30.09 mg (0.233 mmol) of DIPEA are added, and the mixture is heated in a microwave at 150° C. for 1 h. Purification by preparative HPLC results in 47 mg (71% of theory) of the product.
Reaction SMILES: O[N:2]([C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17](OC=C)(=O)[CH3:18]>>[C:9]([N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:18]=[CH:17]1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=COC(C)=O
Reactant: O=C(c1ccccc1)N(O)c1ccccc1
Product: O=C(c1ccccc1)n1ccc2ccccc21

Procedure:
8.3 g of N-hydroxybenzanilide are heated with 125 ml of vinyl acetate and 250 mg of Li2PdCl4 for four and a half hours at 60° C. The reaction mixture is washed with brine, dried over magnesium sulfate, and concentrated by evaporation. The solid residue is shaken with diethyl ether, in the process of which a small amount of crystalline benzanilide precipitates. The organic phase is concentrated by evaporation, and chromatographed through silica gel (toluene/diethyl ether 1:1). As the first fraction are obtained 6.2 g of N-benzoylindole, m.p. 54°-55° C.; IR spectrum (CHCl3): 1710 (CO): NMR spectrum (100 MHz, CDCl3) 6.52 (d, J=4, CH); 7.1-7.7 (m, 9H); 8.38 (m, 1H) ppm.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[H][H].[CH3:16]NCC1C=CC=CC=1>>[CH3:16][NH:13][CH2:12][CH2:1][C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: CNCc1ccccc1
Reactant: [H][H]
Reactant: COc1ccc(CC#N)cc1OC
Product: CNCCc1ccc(OC)c(OC)c1
Yield: 70 %

Procedure:
205 ml of a 28% strength solution of veratryl cyanide in methylbenzylamine (molar ratio 1:3.7) were pumped each hour upwards through a vertical hydrogenation reactor (diameter: 16 mm; height of packing: 600 mm; oil-heated jacket) which was packed with 511 g (800 ml) of catalyst (0.5% by weight of palladium on alumina) at 160° C. under 200 bar. Simultaneously, 100 l(STP)/h hydrogen were passed upwards through the reactor. After decompression to atmospheric pressure, excess methylbenzylamine was removed by distillation, and the discharge was analyzed by quantitative gas chromatography. 40 g (70%) of N-methylhomoveratrylamine were obtained per hour.
Reaction SMILES: [CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[O:17])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:18][C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:17])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccccc1NC(=O)CCCCCCCCCCCSC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)SCCCCCCCCCCCC(=O)Nc1ccccc1OCCCC(=O)O
Yield: 17.1 %

Procedure:
A stirred solution of ester (7) (0.124 g, 0.258 mM) in methanol (10 mL) was treated at room temperature under a nitrogen atmosphere with 2.5N sodium hydroxide solution (0.6 mL). Methanol (2×2 mL) was used to clear the mixture, and the reaction allowed to continue until TLC analysis showed no ester remained. The filtered mixture was concentrated in vacuo and the residue obtained stirred with water (30 mL). After aging, the mixture was filtered (The cake is the sodium salt of the product (100 mg), and the stirred filtrate acidified with dilute hydrochloric acid, aged, filtered, washed with water and dried to give product 8 (0.02 g) as a white solid. M.P. 82-84° C., with softening from 66° C.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:12]([C:13](OC)=O)=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3].O.[C:18](OCC)(=[O:20])[CH3:19]>C1COCC1>[CH2:1]([C:4]1[NH:5][C:6]2[C:12]([CH2:13][CH:18]([OH:20])[CH3:19])=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cccc(C(=O)OC)c2[nH]1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2cccc(CC(C)O)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
[step 1] To a mixture of methyl 2-amino-5-bromobenzoate (2.3 g, 10.0 mmol) and propionic anhydride (14 mL) was added dropwise fuming nitric acid (2.1 mL, 50.0 mmol) under ice-cooling. After stirring at 70° C. for 15 min, water and ethyl acetate were added to the mixture, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give methyl 3-amino-5-bromo-2-butylamidobenzoate (1.23 g, 36%). [step 2] Methyl 3-amino-5-bromo-2-butylamidobenzoate (1.22 g, 3.53 mmol) obtained in step 1 was dissolved in methanol (20 mL) and the mixture was stirred in the presence of 10% palladium carbon (240 mg) under a hydrogen atmosphere at room temperature for 7 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetic acid (1 mL), and the mixture was stirred at 100° C. for 1 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give methyl 2-propylbenzimidazole-4-carboxylate (0.299 g, 39%). [step 3] Methyl 2-propylbenzimidazole-4-carboxylate (0.295 g, 1.35 mmol) obtained in step 2 was dissolved in THF (10 mL), 3 mol/L methylmagnesium chloride THF solution (4.5 mL, 13 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the mixture were added water and ethyl acetate, and the mixture was extracted. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10) to give the title compound (0.201 g, 68%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: CC#CCO
Reactant: Fc1ncnc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.78 ml of N,N-diisopropylethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.57 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12](=[O:14])[NH2:13].[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1CBr)([O-:17])=[O:16].[C:26]([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:26][C:24]3[CH:23]=[CH:22][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:25]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:12](=[O:14])[NH2:13]
Reactant: Cn1c(C(N)=O)cc2cc(O)ccc21
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Cs+]
Solvent: CC#N
Product: Cn1c(C(N)=O)cc2cc(OCc3cccc([N+](=O)[O-])c3)ccc21
Temperature: 90 °C
Yield: 86 %

Procedure:
A mixture of 1-methyl-2-carbamoyl-5-hydroxy-1H-indole (0.875 g; 4.6 mmol), 2-nitrobenzyl bromide (1 g; 4.63 mmol) and Cs2CO3 (1.5 g; 4.63 mmol) in acetonitrile (55 ml) was heated at 90° C. under argon atmosphere for 2 h 30. After evaporation to dryness, the residue was extracted with CH2Cl2/H2O. The organic phase was evaporated and the residue triturated in CH2Cl2/ether to give 1-methyl-2-carbamoyl-5-(3-nitrobenzyloxy)-1H-indole as a solid.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:8][C:9]1[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=2)[N:19]=[CH:18][N:17]=1>>[CH3:14][N:11]1[CH:12]=[CH:13][C:9]([NH:8][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[N:10]1
Reactant: Fc1cccnc1
Reactant: Cn1ccc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4cccnc4)cc23)n1

Procedure:
The compound of Example 117 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 3-fluoropyridine, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:24]=[CH:23]N=C1.C(Cl)(=O)C.Cl.[NH2:30][CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[C:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:23]([CH3:24])[N:30]([CH:31]1[CH2:36][CH2:35][C:34](=[O:37])[NH:33][C:32]1=[O:38])[C:4]2=[O:6])([CH3:19])([CH3:18])[CH3:17]
Reactant: c1c[nH]cn1
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)c(C(=O)O)c1
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CC(=O)Cl
Solvent: O
Product: Cc1nc2ccc(CNC(=O)OC(C)(C)C)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a stirred solution of 2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid (9.3 g, 34.9 mmol), imidazole (2.85 g, 41.9 mmol) in acetonitrile (120 mL), was added acetyl chloride (3.0 mL, 41.9 mmol) and stirred at room temp overnight. Then to the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (5.74 g, 34.9 mmol), imidazole (4.76 g, 69.8 mmol) and triphenyl phosphite (11.0 mL, 41.9 mmol), and the mixture was heated to reflux for 6 hours. The mixture was allowed to cool to room temperature, and water (about 400 mL) was added. The suspension was filtered, washed with water (50 mL), ethyl acetate (20 mL), ether (50 mL), and suction dried to give [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-carbamic acid tert-butyl ester as an off-white solid (9.7 g, 70% yield): HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.95 min (96.7%); mp, 212.5-214.5° C.; 1HNMR (DMSO-d6) 1.40 (s, 9H, CMe3), 2.15-2.18 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.23 (d, J=6 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, Ch), 7.52 (t, J=6 Hz, 1H, CH2NH), 7.56-7.88 (m, 3H, Ar), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.92, 23.40, 28.20, 30.62, 42.97, 56.52, 77.94, 119.98, 123.50, 126.51, 133.74, 138.76, 145.75, 154.52, 155.79, 160.44, 169.47, 172.61. LCMS MH=401; Anal Calcd For C20H24N4O5: C, 59.99; H, 6.04; N, 13.99. Found: C, 59.83; H, 5.98; N, 13.85.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3]([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)CBr
Reaction time: 0.17 h
Yield: 24.1 %

Procedure:
Bromoacetyl bromide (20 g, 99.1 mmol) was added to a solution of 1-octanol (12.9 g, 99.1 mmol) and 10 ml of pyridine in 100 ml of methylene chloride at 0° C. After 10 minutes, the mixture was quenched with 100 ml of ice/water, and the aqueous layer was extracted with methylene chloride, and the combined organic layer was washed with 1N HCl (3×100 ml) and brine. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and the product was distilled under high vacuum to afford 6 g of 1-octyl bromoacetate as an oil, b.p. 93° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH3:31][NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:31][N:32]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and Methyl-phenethyl-amine. MS (ESI): 476.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:12]2[N:16]([CH2:17][CH3:18])[N:15]=[N:14][N:13]=2)C=O)=[CH:4][CH:3]=1.C1(P(=[CH:45][CH:46]=[O:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:48]1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:9]([C:12]2[N:16]([CH2:17][CH3:18])[N:15]=[N:14][N:13]=2)[CH:48]=[CH:45][CH:46]=[O:47])=[CH:6][CH:7]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: c1ccccc1
Product: CCn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 79.7 %

Procedure:
A solution of 3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenal (0.65 g, 1.9 mmoles) and 0.64 g (2.1 mmoles) of triphenylphosphoranylidene acetaldehyde in benzene was heated at reflux temperature for 2 hours. The solution was concentrated in vacuo and the residue purified by silica gel column chromatography eluting with CH2Cl2 to give 0.55 g (79.7%) of the title compound, m.p.=163°-165° C.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:29]4[CH2:30][CH2:31][CH2:26][CH2:27][CH2:28]4)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1C(F)(F)F
Reactant: OC1CCNCC1
Product: FC(F)(F)c1cc(N2CCC(CN3CCCC3)CC2)ccc1CN1CCCCC1

Procedure:
Prepared from the product of Example 65 and 4-hydroxypiperidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH:11]1([SH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:18]=O.Cl>C(O)C.O>[CH:11]1([S:17][CH2:18][S:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C=O
Reactant: SC1CCCCC1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1ccc(SCSC2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
In 100 g of ethanol were dispersed 12.6 g (0.1 mol) of 4-hydroxythiophenol and 4.0 g (0.1 mol) of sodium hydroxide. The dispersion was heated at 70° C. for dissolution. To the solution, 16.5 g (0.1 mol) of chloromethylcyclohexylsulfidei which was separately prepared from cyclohexanethiol, formaldehyde and hydrochloric acid according to the teaching of U.S. Pat. No. 2,354,230, was added dropwise. The solution was ripened at 70° C. for 4 hours. Thereafter, the solution was cooled, combined with 50 g of water, which was extracted twice with 100 g of dichloromethane. The organic layer was concentrated in vacuum, obtaining 26 g of the crude end product. It was subject to the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH:4]1([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([N:17]3[CH2:20][CH:19]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:28]([O:30]CC)=O)=[N:26][CH:27]=4)[CH2:18]3)=[O:16])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5]1>C(OCC)C>[CH:4]1([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([N:17]3[CH2:18][CH:19]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:19]([OH:21])([CH3:20])[CH3:18])=[N:26][CH:27]=4)[CH2:20]3)=[O:16])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5]1.[CH:4]1([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([N:17]3[CH2:18][CH:19]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:28](=[O:30])[CH3:1])=[N:26][CH:27]=4)[CH2:20]3)=[O:16])[CH2:10][CH2:9]2)[CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Product: CC(C)(O)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Temperature: 25 °C
Yield: 1 %
Yield: 37 %

Procedure:
MeMgBr (0.96 ml of a 3M solution in diethyl ether, 2.88 mmol) was added dropwise to a solution of ethyl 5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}oxy)pyridine-2-carboxylate (386 mg, 0.96 mmol) in diethyl ether (20 ml) at 0° C. The reaction was warmed to room temperature and after 1 hour was quenched and washed with water (2×20 ml), dried (MgSO4) and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give the title compound (179 mg, 37%) as colourless oil and 1-[5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}oxy)pyridin-2-yl]ethanone (2.5 mg, 1%) as colourless oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9][OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl:29]CCl>>[Cl:29][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][CH2:9][O:10][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: ClCCl
Reactant: OCCc1sccc1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2sccc2CCl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
1.5 g of the compound obtained in Example 2 was dissolved in 40 mL of dichloromethane, and the resulting solution was cooled to below 5° C. To the solution, 3.6 g of p-toluenesulfonyl chloride and 1.9 g of triethylamine were added dropwise, and the resulting mixture was warmed to room temperature, stirred for 6 hours and washed twice with 20 ml portions of water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to obtain 1.5 g (yield of 48%) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]([O:10][C:11]([CH2:13][S+](C)C)=[O:12])[CH3:9]>C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:3][C@H:2]1[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:12])[CH3:9]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C[S+](C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Temperature: 22 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
Ethyl acrylate (99%, 270 g, 1.4 eq.) was added to a solution of 2 (282 g, 1.91 mol) in CHCl3 (1500 mL) at 5° C. Cooling was removed and the reaction was stirred at 22° C. for 12 h. Evaporation of the solvent and excess acrylate left an orange oil, which was vacuum distilled (bp 70-75° C./1 mm) to produce 3 (286 g, 80.6%) as a clear thick oil. 1H NMR (250 MHz, CDCl3) δ4.15 (q, J=7.1, 4H); 2.16 (dd, J=7.5, 5.7, 2H); 1.41 (dd, J=7.5, 5.7, 2H); 0.88 (t, J=7.1, 6H). 13C NMR (62.5 MHz, CDCl3) δ 171.69; 60.96; 22.26; 15.18; 14.08.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[SH:7].[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.CN([CH:23]=[O:24])C>>[CH3:8][O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:7][C:2]2[N:3]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([O:24][CH3:23])=[CH:13][CH:12]=3)[CH:5]=[CH:6][N:1]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Sc1ncccn1
Reactant: CN(C)C=O
Product: COC(=O)c1ccc(CSc2nccc(-c3ccc(OC)cc3)n2)cc1
Temperature: 60 °C

Procedure:
To a solution of 444-methoxy-phenyl)-pyrimidine-2-thiol (225a) (1.00 g, 4.58 mmol) in DMF (30 mL) was added 4-bromomethyl-benzoic acid methyl ester (1.05 g, 4.58 mmol). The mixture was heated at 60° C. for 1 h and evaporated to dryness to form the compound 226a, which was used in the next without purification. LRMS=366.4(calc.), 367.4 (found).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[CH2:6]([O:9][C:10]([N:12]1[C@H:16]([CH:17]([OH:26])[C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)=[O:11])[CH:7]=[CH2:8]>CN(C=O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:3][C@H:14]1[CH2:15][C@@H:16]([CH:17]([OH:26])[C:18]2[N:19]3[CH:25]=[N:24][CH:23]=[C:20]3[S:21][CH:22]=2)[N:12]([C:10]([O:9][CH2:6][CH:7]=[CH2:8])=[O:11])[CH2:13]1)(=[O:4])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)c1csc2cncn12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(O)c1csc2cncn12
Temperature: 80 °C
Reaction time: 12 h
Yield: 41.2 %

Procedure:
Potassium thioacetate (149 mg) is added to a solution of 355 mg of crude (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]-3-methanesulfonyloxypyrrolidine (stereoisomer B) in a mixture of 3 ml of dry DMF and 1.5 ml of dry toluene, and the mixture is stirred in an argon atmosphere at a bath temperature of 80° C. for 12 hr. The mixture is diluted with 100 ml of ethyl acetate and washed twice with 40 ml of a 5% aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure. The residue is dried under reduced pressure by means of a vacuum pump for 2 hr. The resultant brown oil is successively purified by column chromatography on silica gel (ethyl acetate) and on Sephadex LH-20 (chloroform:methanol=1:1) to give 139.1 mg of the title compound as a slightly red amorphous material.