Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)[F:2].[CH2:5]([O:7][P:8]([N:13]1[CH:19]2[CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:18]2)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][P:8]([NH:13][C@H:19]1[C@H:14]([F:2])[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:18]1)([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Reactant: FB(F)F
Solvent: ClCCl
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1F)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.8 %

Procedure:
BF3 etherate (3.10 mL, 24.4 mmol) was added to a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (3.00 g, 8.14 mmol; Example H, step D) in DCM (10 mL) at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 3 days. The solvent was removed in vacuo, ethyl acetate (30 mL) and saturated sodium bicarbonate (20 mL) were added. The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give trans-benzyl 3-(diethoxyphosphorylamino)-4-fluoropiperidine-1-carboxylate (0.53 g, 17%) as oil.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]4[OH:25])[S:17][C:13]=3[CH:12]=2)[CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CC#N.CC(N(C)C)=O>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[O:25])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: O=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
(1R,2R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Example 3 (188 mg, 0.50 mmol) was stirred in a mixture of DCM/MeCN/DMA (4:4:2, v/v/v) at rt. Dess-Martin periodinane (254 mg, 0.60 mmol) was added and the mixture was stirred at rt for 30 min before another batch of periodinane (254 mg, 0.60 mmol) was added. The resulting mixture was heated at 55° C. for 4 h, then another batch of periodinane (254 mg, 0.60 mmol) was added and the reaction mixture was heated at 60° C. for 6 h. LCMS showed that the reaction was mostly complete. The mixture was then cooled to rt and partitioned between DCM and 3% aq NaOH, and then the organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc in hexanes to give (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone (150 mg, 80%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.38 (dd, J=1.2, 4.8 Hz, 1H), 8.22 (d, J=7.3 Hz, 1H), 8.09 (dd, J=1.3, 8.1 Hz, 1H), 7.70 (d, J=1.1 Hz, 1H), 7.26-7.35 (m, 2H), 7.19-7.26 (m, 1H), 5.49 (s, 2H), 4.68 (td, J=6.5, 12.8 Hz, 1H), 2.53-2.67 (m, 1H), 2.42 (ddd, J=2.7, 5.9, 12.3 Hz, 1H), 2.30 (d, J=13.4 Hz, 1H), 1.94-2.12 (m, 1H), 1.82 (br s, 2H), 1.38-1.66 (m, 2H). LCMS (ESI) m/z 378 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([NH:11][CH:12]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:15][CH:14]([CH3:16])[CH2:13][CH:12]([NH:11][C:8]1[CH:7]=[N:6][C:5]([C:3]([OH:4])=[O:2])=[N:10][CH:9]=1)[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(Nc1cnc(C(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
(+/−)-5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid methyl ester (617 mg, 1.39 mmol) was dissolved in tetrahydrofuran (6 mL) and methanol (2 mL), and 1.0 M NaOH (6 mL, 6 mmol) was added. This was stirred at 50° C. for 2.5 h before cooling and bringing to pH 3 with 1 N HCl. This was extracted three times with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give (+/−)-5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid with ethyl acetate (0.636 g) as clear foam. 1H NMR (400 MHz, DMSO-d6, δ): 8.18 (s, 2H) 7.84-7.91 (m, 2H) 7.75-7.81 (m, 2H) 7.71 (d, J=8.2 Hz, 2H) 7.55 (d, J=8.2 Hz, 2H) 7.42 (d, J=7.8 Hz, 1H) 4.63-4.74 (m, 1H) 1.74-1.85 (m, 1H) 1.67 (dt, J=13.1, 6.5 Hz, 1H) 1.51-1.61 (m, 1H) 0.98 (d, J=6.4 Hz, 3H) 0.93 (d, J=6.4 Hz, 3H); MS (M+1): 430.3.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[F:13][C:14]([F:19])([F:18])[CH:15]([OH:17])[CH3:16]>>[NH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:17][CH:15]([CH3:16])[C:14]([F:19])([F:18])[F:13]
Reactant: N#Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(O)C(F)(F)F
Product: CC(Oc1cc(C#N)ccc1N)C(F)(F)F

Procedure:
Is prepared in a similar manner as intermediate III.4 from 3-fluoro-4-nitro-benzonitrile and 1,1,1-trifluoro-propan-2-ol.
Reaction SMILES: Cl.[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13](C)=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3].Br.C(O)(=[O:20])C>>[CH2:2]([S:4][C:5]1[N:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][CH:11]=2)[CH:7]=[CH:8][N:9]=1)[CH3:3]
Reactant: CC(=O)O
Reactant: CCSc1nccn1-c1ccc(C)cc1
Agent: Br
Agent: Cl
Product: CCSc1nccn1-c1ccc(O)cc1
Yield: 72.5 %

Procedure:
A mixture of 14 parts of 2-(ethylthio)-1-(4-methylphenyl)-1H-imidazole monohydrochloride and 113 parts of hydrobromic acid solution 48% in glacial acetic acid is stirred and refluxed for 3 hours. The reaction mixture is evaporated and the residue is dissolved in water. The solution is neutralized with sodium hydrogen carbonate. The precipitated product is filtered off and crystallized from 2-propanol, yielding 8.3 parts (72.5%) of 4-[2-(ethylthio)-1H-imidazol-1-yl]phenol; mp. 165.2° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][O:20][C:21]2[C:22]([C:27]([O:29]CC)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][N:4]([C:7]([C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:8])[CH2:3]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(OCC)=O)=NC=1>>[CH3:1][C:2]1([CH2:19][O:20][C:21]2[C:22]([C:27]([OH:29])=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:5][N:4]([C:7]([C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]([F:18])([F:16])[F:17])[CH2:13][CH2:14]2)=[O:8])[CH2:3]1
Reactant: CCOC(=O)c1ncccc1OCC1(C)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1
Agent: CCOC(=O)c1ncc(OC)cc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Product: CC1(COc2cccnc2C(=O)O)CCN(C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 31 using ethyl 3-((3-methyl-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-3-yl)methoxy)picolinate (EXAMPLE 86 Step 3) in stead of ethyl 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinate.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1)=O.[NH2:23][OH:24]>N1C=CC=CC=1.CCO>[F:1][C:2]([F:22])([F:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1)=[N:23][OH:24]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)C(F)(F)F)cc1
Reactant: NO
Solvent: c1ccncc1
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
tert-Butyl 1-(4-(2,2,2-trifluoroacetyl)phenyl)ethylcarbamate (1.02 g, 3.21 mmol) was mixed with NH2OH*HCl (223 mg, 3.21 mmol) in pyridine (25 ml) and EtOH (12 ml). The mixture was stirred at 80° C. for 16 hours and then evaporated. The residue was dissolved in EtOAc (60 ml), washed with H2O (2*40 ml), dried over MgSO4, filtered and evaporated. The product was purified by flash chromatography using CH2Cl2/MeOH (20:0→20:1) as eluent to give 640 mg (60%) of the title compound as pale solids.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([O:28][CH2:29][CH3:30])[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:8]1=[O:27])C.[OH-].[Na+].Cl.O>CO>[CH2:29]([O:28][CH:6]([N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:18]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:19]=3[S:20][CH:21]=2)[C:8]1=[O:27])[CH2:5][C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)CC(OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid ethyl ester (50 mg, 0.11 mmol) in MeOH (3.0 mL) is added 2.0 N NaOH solution (1.0 mL). The reaction mixture is stirred at room temperature for 2 h. Then 1.0 M HCl solution (3.0 mL) and water (10 mL) are added and the reaction mixture is extracted with EtOAc (3×20 mL). The organic layers are combined, dried and concentrated to give 45 mg (96%) of the crude 3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid which is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.C(N(C(C)C)CC)(C)C.CS([Cl:24])(=O)=O>ClCCl>[Cl:24][CH2:8][C:7]1[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=1[F:10]
Reactant: OCc1c(F)cncc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cncc(F)c1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under argon, 5.0 g of (3,5-difluoropyridine-4-yl)methanol (Example 114A, 34.5 mmol, 1 equivalent) were initially charged in 100 ml of dichloromethane at −20° C., and 5.7 ml of diisopropylethylamine (34.5 mmol, 1 equivalent) and 2.95 ml of methanesulphonyl chloride (37.9 mmol, 1.1 equivalent) were added in succession. The mixture was warmed to RT and stirred at RT for 16 h and then at 40° C. for 3 h. The reaction solution was then concentrated, and twice 50 ml of toluene were added and the mixture was re-concentrated. This gave 13 g (230% of theory) as a crude product which were reacted further without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16](=[O:24])OC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:25][NH2:26]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16]([NH:25][NH2:26])=[O:24])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(N2CCN(NC(=O)Oc3ccccc3)CC2)cc1
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(NC(=O)NN)CC2)cc1
Yield: 84 %

Procedure:
A mixture of 8 parts of phenyl [4-(4-methoxyphenyl)-1-piperazinyl]carbamate, 15 parts of hydrazine and 50 parts of 1,4-dioxane is stirred and refluxed for 4 hours. The reaction mixture is evaporated. The residue is triturated in 2-propanol. The product is filtered off and crystallized from 1-butanol, yielding 6.5 parts (84%) of N-[4-(4-methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].Br[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:15]#[N:16])=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1c(O)ccc(Cl)c1[N+](=O)[O-]
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(OCC#N)ccc(Cl)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-2-methyl-3-nitrophenol (7.6 g), bromoacetonitrile (3.4 mL), and potassium carbonate (16.8 g) in 2-butanone (80 mL) was heated at 80° C. for 2 hr under an atmosphere of nitrogen. The reaction mixture was cooled to room temperature, then filtered to remove the salts. The filtrate was diluted with ethyl ether (200 mL), washed with saturated sodium chloride solution, and dried over magnesium sulfate. Evaporation of the solvent afforded a yellow solid (9.1 g).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Si:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:29][CH:28]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[Si:45]([O:52][C@@H:53]1[CH2:58][CH2:57][C@H:56]([C:59](=[O:70])[C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:61])[CH2:55][CH2:54]1)([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]>C1COCC1>[Si:19]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[C:59]([C@H:56]2[CH2:57][CH2:58][C@@H:53]([O:52][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:54][CH2:55]2)([OH:70])[C:60]([O:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)=[O:61])=[CH:29][CH:28]=1)([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](C(=O)C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)OCc2ccccc2)C(O)(C(=O)OCc2ccccc2)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M n-butyllithium solution in hexane (0.49 ml, 1.22 mmol) was added to a solution of diisopropylamine (0.18 ml, 1.29 mmol) in anhydrous THF (3.0 ml) at −78° C. under an argon stream. The mixture was brought to 0° C., and the mixture was stirred for 30 min and was again cooled to −78° C. A solution of benzyl 3-(4-((tert-butyldimethylsilyl)oxy)phenyl)propanoate (300 mg, 0.81 mmol) in anhydrous THF (4.0 ml) was added dropwise thereto at −78° C., and the mixture was stirred for additional one hr. A solution of benzyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-oxoacetate (304 mg, 0.81 mmol) in anhydrous THF (4.0 ml) that had been cooled to −78° C. was added through a cannula to the resultant enolate solution over 10 min. The mixture was stirred at −78° C. for one hr, was quenched and adjusted to pH 4 with acetic acid and was allowed to cool to room temperature. The reaction solvent was removed by distillation under reduced pressure, and the residue was diluted with ethyl acetate, and the diluted solution was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=95:5) to give the title compound as an oil (a diastereomeric mixture; 120 mg, yield 19%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CC3)Cc3ccccc3O4)nn2)n1

Procedure:
The object product (49 mg, 56%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (50 mg), 3H-spiro[1-benzofuran-2,4′-piperidine] (50 mg) and potassium carbonate (50 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>O.C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([NH:19][C:20]([C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[CH2:25][CH2:24][N:23]2[C:34]([C@@H:36]2[CH2:39][C@H:38]([CH2:40][C:41]([OH:43])=[O:42])[CH2:37]2)=[O:35])=[O:21])[CH:12]=[CH:13][C:14]=1[Si:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)O)C1)[C@H]2C(=O)Nc1ccc([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Cooled TFA (2.0 mL) was added to tert-butyl 2-(cis-3-((R)-1-((3-fluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (160 mg, 0.28 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was neutralized with ice and aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (46.9 mg, 0.091 mmol, 32.5%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([O:17]C)[CH:10]=2)[CH2:4]1)[CH3:2].[BrH:19]>>[BrH:19].[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:17])[CH:10]=2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCCC(c2ccc(OC)c(OC)c2)C1
Agent: Br
Product: CCN1CCCC(c2ccc(O)c(O)c2)C1

Procedure:
A mixture of 5.9 g of N-ethyl-3-(3',4'-dimethoxyphenyl)-piperidine and 30 ml of 66% hydrobromic acid was refluxed for an hour and was then evaporated to dryness under reduced pressure. The residue was crystallized from ethanol to obtain 5.9 g of N-ethyl-3-(3',4'-dihydroxyphenyl)-piperidine hydrobromide melting at 207° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH3:19])[N:15]=[CH:14][N:13]=2)=[C:6]([CH3:22])[CH:5]=1.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[Cl:18][C:17]1[C:12]([NH:11][CH2:10][CH2:9][O:8][C:7]2[CH:20]=[CH:21][C:4]([CH2:3][CH2:2][NH:25][CH2:23][CH3:24])=[CH:5][C:6]=2[CH3:22])=[N:13][CH:14]=[N:15][C:16]=1[CH3:19]
Reactant: Cc1cc(CCBr)ccc1OCCNc1ncnc(C)c1Cl
Reactant: CCN
Solvent: CCO
Product: CCNCCc1ccc(OCCNc2ncnc(C)c2Cl)c(C)c1

Procedure:
1.9 g of 4-{2-[4-(2-bromoethyl)-2-methylphenoxy]-ethylamino}-5-chloro-6-methylpyrimidine and 5 ml of a 70% w/v aqueous solution of ethylamine were dissolved in 20 ml of ethanol, and the mixture was charged into an autoclave. The mixture was allowed to react at 120° to 130° C. for 10 hours. At the end of this time, ethanol was removed by distillation under reduced pressure and the oily product obtained was subjected to column chromatography (Wakogel C-200, eluted with ethanol), to afford 1.3 g of the title product as a pale yellow oily liquid, n24.1 =1.5610.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[C@@H:7](O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.N12CCCN=C1CCCCC2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F>C1(C)C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[C@H:7]([F:27])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@@H](O)C1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1C[C@H](CBr)[C@H](F)C1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
Process B: (3S,4R)-3-Bromomethyl-1-tert-butoxycarbonyl-4-hydroxypyrrolidine (561 mg) was dissolved in toluene (20 mL). To this solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) was added and perfluoro-1-octanesulfonylfluoride (0.93 mL) was then added dropwise while the mixture was chilled in an ice water bath. After stirred at 2° C. for 1 hour, the reaction mixture was poured on a silica gel pad and was eluted with ethyl acetate (100 mL). The eluate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-3-bromomethyl-1-tert-butoxycarbonyl-4-fluoropyrrolidine as a yellow oil (447 mg).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([CH3:26])[C:24]=1O)[CH:20]=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[O:8][C:9]([CH3:15])=[C:10]([CH2:12][CH2:13][O:14][C:24]3[C:23]([CH3:26])=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=3[CH3:16])[N:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: Cc1oc(C2CCCCC2)nc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cc(C=O)cc(C)c1OCCc1nc(C2CCCCC2)oc1C
Reaction time: 2 h

Procedure:
0.400 g of the above prepared 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethanol (1.91 mmol) was dissolved in 10 ml of toluene and treated successively at 0° C. with 0.287 g of 3,5-dimethyl-4-hydroxybenzaldehyde (1.91 mmol), 0.501 g of triphenylphosphine (1.91 mmol), and 0.387 g (1.91 mmol) of DIAD. The cooling bath was then removed and stirring continued for 2 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with dil. NaOH and water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=85/15) delivered finally 0.415 g of the title compound as colorless oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:13][C:14](=[O:20])[C:15]#[C:16][CH:17]1[CH2:19][CH2:18]1)[CH3:12].C(N(CC)CC)C>C(OCC)C.C(OC)(C)(C)C.O>[CH2:11]([O:13][C:14]([C:15]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:2][O:1][C:16]=1[CH:17]1[CH2:19][CH2:18]1)=[O:20])[CH3:12]
Reactant: CCOC(=O)C#CC1CC1
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)noc1C1CC1
Reaction time: 72 h
Yield: 50.1 %

Procedure:
To a solution of N-hydroxybenzenecarboximidoyl chloride (Tetrahedron Letters, 47(9), 1457-1460, 2006, 500 mg, 3.21 mmol) and cyclopropyl-propynoic acid ethyl ester (Organic Syntheses, 66, 173-179, 1988, 515 mg, 3.21 mmol) in diethyl ether (5 mL) was added dropwise over a period of 2 min at ambient temperature triethylamine (0.54 ml, 3.86 mmol) and the reaction mixture was stirred for 3 d at this temperature. The resulting suspension was diluted with tert-butylmethylether (5 mL) and water (10 mL). The aqueous layer was extracted with tert-butylmethylether (10 ml) and the organic layers were washed with water (10 mL) and brine (10 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=98:2 to 80:20) afforded the title compound (414 mg, 50%) as a colorless liquid. MS: m/e=258.1[M+H]+.