Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:23])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:30])=[CH:32][CH:33]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (200 mg, 0.42 mmol) in DCM (5 mL) solution were added ethyl 2-aminoacetate (65 mg, 0.63 mmol), HATU (238 mg, 0.63 mmol) and iPr2NEt (0.22 mL, 1.25 mmol). The mixture was stirred at room temperature for 16 hs. The solvent was removed under vacuum. The residue was purified via silica gel column (EtOAC/Hexanes 20% to 40%) to give ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate (240 mg, 100%) as white solid. LC-MS (Condition A), MS m/z 565.1 (M++H).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[C@@H:7]1[CH2:17][C@H:10]2[CH2:9][CH2:8]1)C=C.[C:18]1(C)[CH:23]=C(C)C=C(C)[CH:19]=1>>[CH2:23]([C:14]1[CH:13]=[C:12]([O:15][CH3:16])[C:11]2[C@H:10]3[CH2:17][C@H:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]=1[OH:4])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(OC)c2c1[C@H]1CC[C@@H]2C1
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(OC)c2c(c1O)[C@H]1CC[C@@H]2C1
Yield: 80 %

Procedure:
Treatment of (1R*,4S*)-5-(allyloxy)-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalene (15.8 g, 0.069 mol) in refluxing mesitylene generally according to the procedure described for Intermediate 1 gave 12.58 g (80%) of (1R*,4S*)-6-allyl-8-methoxy-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-ol as a colorless oil. Anal. calcd. for C20H22O.0.2H2O: C, 77.02; H, 7.93. Found: C, 76.68; H, 7.88.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Br:13][CH2:14][C:15](Br)=[O:16]>C(Cl)Cl.O>[Br:13][CH2:14][C:15]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[C:3]([O:11][CH3:12])=[CH:4][C:5]=1[O:9][CH3:10])=[O:16]
Reactant: O=C(Br)CBr
Reactant: COc1cc(OC)c(Cl)cc1N
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Reaction time: 0.08 h

Procedure:
A cooled (0° C.) solution of 5-chloro-2,4-dimethoxyaniline (5 g) in DCM under an atmosphere of argon is treated dropwise with bromoacetyl bromide (2.4 ml). After 5 minutes, TEA (7.5 ml) is added dropwise and after stirring for 20 minutes the reaction mixture is diluted with water and extracted with DCM). The organic phase is washed with distilled water, dried over Na2SO4, filtered and evaporated to give a beige solid. This is purified by flash column chromatography on silica, eluting with 20-100% n-hexane in DCM to afford the title compound. [M+H]+ 308.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1)#[N:2].[NH2:19][OH:20]>CCO>[NH2:2][C:1](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[C:5]([F:18])[CH:4]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C#N)cc1F
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
Tert-butyl (4-cyano-2-fluorophenoxy)acetate (3.50 g; 13.93 mmol; 1 eq.) was suspended in EtOH (70 mL). hydroxylamine (2.05 mL; 69.65 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 12 hours. The reaction mixture was concentrated affording the title compound as a white solid (3.57 g, 90%). 1H NMR (DMSO-d6, 300 MHz) δ 9.61 (br s, 1H), 7.51-7.41 (m, 2H), 7.09-7.03 (t, J=8.84 Hz 1H), 5.81 (br s, 2H), 4.78 (s, 2H), 1.42 (s, 9H). LC/MS (Method 13): 285.1 (M+H)+. HPLC (Method A) Rt 2.91 min (Purity: 94.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[S:18][C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)=[CH:20][N:21]=2)=[O:15])[CH2:10][CH2:9]1.CCN=C=NCCCN(C)C.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:42][S:43]([NH:46][C:26]([C:25]1[CH:29]=[CH:30][C:22]([C:19]2[S:18][C:17]([NH:16][C:14]([N:11]3[CH2:12][CH2:13][C:8](=[CH:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:9][CH2:10]3)=[O:15])=[N:21][CH:20]=2)=[CH:23][CH:24]=1)=[O:28])(=[O:45])=[O:44]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(-c2cnc(NC(=O)N3CCC(=Cc4ccccn4)CC3)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC(=O)c1ccc(-c2cnc(NC(=O)N3CCC(=Cc4ccccn4)CC3)s2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
The compound (100 mg, 238 μmol) obtained in Example 20 was dissolved in DMF (4 mL), and N,N-dimethyl-4-aminopyridine (hereinafter referred to as DMAP) (6.0 mg, 48 μmol) and WSC (50 mg, 262 μmol) were added thereto, followed by stirring at room temperature for 10 minutes. Methanesulfonamide (34 mg, 357 μmol) was added to the resulting mixture, followed by stirring at room temperature for 16 hours. Water was added to the resulting mixture, and after extraction with methanol:chloroform (1:10), the extract was dried over anhydrous sodium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:15), thereby giving the title compound (15 mg, 13%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[O:8].[Br:9]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:9][C:5]1[N:4]=[C:3]([CH:7]=[O:8])[N:2]([CH3:1])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccnc1C=O
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(Br)nc1C=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 43.1 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (10 g, 90 mmol) in deoxygenated DMF (300 mL) was treated with N-bromosuccinimide (17.8 g, 100 mmol) and the resulting solution stirred at RT for 6 days. Water (750 mL) was added and the resulting mixture was extracted with EtOAc (4×200 mL) the combined extracts were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (n-heptane/EtOAc=4/1) to yield the title compound (7.33 g, 40%) as a white solid. LC-MS: m/z=191.2 (MH+), tR=0.48 minutes, method A. 1H NMR (600 MHz, DMSO-d6): δ 9.62 (s, 1H), 7.80 (s, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.C(O)=O.[ClH:37]>C(O)C>[ClH:37].[ClH:37].[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][N:31]1[CH2:30][CH2:29][N:28]([CH:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[CH2:33][CH2:32]1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(OC)c1
Temperature: 25 °C
Yield: 25 %

Procedure:
2,4-Dimethoxybenzaldehyde (6.7 g; 40.3 millimoles) and 11.5 g (39.9 millimoles) of bis(4-fluorophenyl)methylpiperazine were melted in an oil bath at 100° C., and 2.0 ml (53.0 millimoles) of formic acid was added dropwise. The mixture was stirred under heat for 30 minutes, and allowed to cool to room temperature. A mixture of 8 ml of conc. hydrochloric acid and 80 ml of ethanol was added, and the precipitated crystals were collected by filtration. Recrystallization of the crystals from ethanol gave 5.1 g (yield 25.0%) of 1-(2,4-dimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride as colorless crystals.
Reaction SMILES: [O:1]=[C:2]([CH3:7])/[CH:3]=[CH:4]/[CH:5]=[O:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]=[CH:20]/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([N:19]2[CH:20]=[CH:21][C@H:22]([CH2:23][CH2:24][CH3:25])[C@H:4]([CH2:3][C:2](=[O:1])[CH3:7])[C:5]2=[O:6])(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: CC(=O)/C=C/C=O
Reactant: CCC/C=C/C=NS(=O)(=O)c1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Product: CCC[C@H]1C=CN(S(=O)(=O)c2ccc(OC)cc2)C(=O)[C@H]1CC(C)=O
Yield: 70 %

Procedure:
The title compound was prepared according to the general procedure from (E)-4-oxopent-2-enal and trans-N-(4-methoxybenzenesulfonyl)-hex-2-en-1-imine using 10 mol % 9 as the catalyst in 70% yield as a yellow oil. [α]D20 (c 0.91, CHCl3)=−5.7; 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, 2H, J=6.9, 2.0 Hz), 6.97 (dd, 2H, J=6.9, 2.0 Hz), 5.54 (dd, 1H, J=8.0, 6.6 Hz), 3.87 (s, 3H), 3.24 (q, 1H, J=6.3 Hz), 2.82 (dd, 1H, J=16.6, 7.2 Hz), 2.41-2.38 (m, 1H), 2.24 (dd, 1H, J=16.6, 7.0 Hz), 1.22 (t, 3H, J=7.2 Hz), 1.25-1.02 (m, 4H), 0.73 (t, 3H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 206.0, 170.7, 164.1, 131.0, 129.6, 128.8, 124.1, 115.1, 114.4, 114.1, 55.9, 42.4, 39.8, 34.7, 32.1, 30.6, 19.5, 14.3; IR (thin film) ν 3010, 2957, 1713, 1595, 1497, 1362, 1262, 1092, 1023 cm−1; HRMS (ESI) calcd for C18H23NO5S [M+Na]+ 388.1189, found 388.1175; 98% ee (3S,4S)-isomer as determined by HPLC (AS-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=68.1 min, tr (3R,4R)=55.1 min.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)[CH2:13][CH2:14][CH2:15]CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCCCCC(=O)CC(=O)OC
Yield: 95.8 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 148.0 g (1.1 mol) of hexanoyl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.2. This gave 165 g (GC purity 78.5%) of methyl hexanoylacetate (yield 75.0%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][C@H:13]1[C@@H:17]([O:18]C2CCCCO2)[CH2:16][C@@H:15]([O:25]C2CCCCO2)[C@@H:14]1[CH2:32][O:33][C:34](=[S:44])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=1)=[O:6].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[OH:18][C@H:17]1[CH2:16][C@@H:15]([OH:25])[C@H:14]([CH2:32][O:33][C:34](=[S:44])[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[C@H:13]1[CH2:12]/[CH:11]=[CH:10]\[CH2:9][CH2:8][CH2:7][C:5](=[O:6])[NH:4][CH2:3][CH2:2][OH:1]
Reactant: O=C(CCC/C=C\C[C@@H]1[C@@H](COC(=S)NCc2cccc(Cl)c2)[C@H](OC2CCCCO2)C[C@@H]1OC1CCCCO1)NCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C(CCC/C=C\C[C@@H]1[C@@H](COC(=S)NCc2cccc(Cl)c2)[C@H](O)C[C@@H]1O)NCCO
Yield: 66.5 %

Procedure:
A solution of bis-THP ether 8a (40 mg, 0.062 mmol) and pyridinium p-toluenesulfonate (5 mg) in MeOH (1.5 mL) was stirred at 23° C. for 16 h. The solvent was removed in vacuo and the residue was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% EtOAc followed by 9:1 EtOAc/MeOH) provided 20 mg of the above titled compound.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([O:15][Si](C(C)(C)C)(C)C)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h

Procedure:
(3R,5S)-N-Boc-3-tert-Butyldimethylsiloxy-5-ethynyl-pyrrolidine (700 mg, 2.15 mmol) (Example 99B above) was dissolved in a mixture of THF (20 mL) and H2O (1 mL). TBAF (1M in THF) (Aldrich) was added (2.15 mL, 2.15 mmol) at 0° C. and the reaction mixture was allowed slowly to warm up to room temperature. After 21 hr at room temperature and 2 hrs at 50° C. the mixture was concentrated to a small volume diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated. (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine was obtained after silica gel column chromatography with a 0-100% EtOAc in hexanes gradient. (Yield 390 mg, 81%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([C:34]2[N:35]([CH3:43])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:28][C:25]=1[CH:26]=O>CO.C(Cl)Cl>[CH3:22][O:23][C:24]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([C:34]2[N:35]([CH3:43])[C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:28][C:25]=1/[CH:26]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1/C=C/C(=O)c1ccc(S(=O)(=O)NO[Si](C)(C)C(C)(C)C)cc1
Yield: 19 %

Procedure:
The title compound was prepared in an analogous manner as Ex-1 using 4-acetyl-N-(tert-butyldimethylsiloxy)benzenesulfonamide (Ex-33A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 19% yield after preparative TLC (MeOH/CH2Cl2, 1:10), yellow solid, mp 129–131° C. 1H-NMR (300 MHz, CDCl3) δ 8.18 (d, J=15 Hz, 1H), 8.12 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=15 Hz, 1H), 7.36 (d, J=7 Hz, 1H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 1H), 6.58 (s, 1H), 6.50–6.51 (m, 2H), 4.03 (s, 3H), 3.90 (s, 3H), 3.59 (s, 3H), 0.90 (s, 9H), 0.20 (s, 6H). HRMS (ESI) Calcd. for C32H39N2O6SSi: 607.2298 (M+H)+; Found: 607.2306.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1.BrBr.O>C(O)(=O)C>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[S:1][C:2]([NH2:3])=[N:5][C:6]2=[CH:7][CH:8]=1
Reactant: N#C[S-]
Reactant: COc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nc(N)sc2n1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Potassium thiocyanate Fluka 60519 (38.8 g, 400 mmol, 8.0 equiv.) and 5-amino-2-methoxypyridine Aldrich A6, 120-9 (6.2 g, 50 mmol, 1.0 equiv.) were added to 100 mL glacial acetic acid precooled to 5° C. (semi solid) with mechanical stirring. Bromine (23.9 g, 150 mmol, 3.0 equiv.) dissolved in 30 mL glacial acetic acid was added dropwise to the reaction mixture over 1.5 hr at 0° C. The thick slurry was stirred 2 hrs at 0° C. and overnight at RT. Then 30 mL water was added to the orange suspension, which was heated to 85° C. and filtered hot. The residue was treated again with acetic acid, heated and filtered like before. The combined filtrates were cooled and neutralized with NH4OH at pH 6. The red precipitate was filtered, dissolved in ethyl acetate and washed with NaHCO3 and brine, dried over Na2SO4, evaporated and crystallized from ethyl acetate-hexane using charcoal to give 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine m/e 182.0 (MH+).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][CH2:27][C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:27](=[O:26])[CH2:28][OH:29])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)CO
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CO)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (14.9 mg, 46.9%), MS (ISP) m/z=389.1 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 2-hydroxyacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[F:11]
Reactant: CO
Reactant: Nc1ccc(F)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)ccc1F
Temperature: 25 °C

Procedure:
To a stirred solution of 5-amino-2-fluoro-benzoic acid (25 g, 161 mmol) in methanol (300 mL) was added thionyl chloride (30 mL, 403 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-amino-2-fluoro-benzoic acid methyl ester (27.5 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8FNO2 (M+H)+: 170.16, observed: 169.9.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCN(CCC)c1c(SC)nc2c(Br)cc(C)cn12
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CCCN(CCC)c1c(SC)nc2c(-c3ccc(Cl)cc3Cl)cc(C)cn12
Yield: 72.5 %

Procedure:
N-[8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (50 mg) was dissolved in a mixed solvent of 1,2-dimethoxyethane (6 mL) and water (1 mL). 2,4-Dichlorobenzeneboronic acid (53 mg), barium hydroxide octahydrate (88 mg) and tetrakistriphenylphosphine palladium complex (16 mg) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give N-[8-(2,4-dichlorophenyl)-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (43 mg) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.Cl[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][N:23]=1>>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][O:9][C:10]=3[C:11]([F:14])([F:12])[F:13])[N:3]=[CH:2]2)=[N:23][CH:24]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: COC(=O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 76 %

Procedure:
As described for Example 4, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (450 mg, 0.1.6 mmol) was converted, using methyl 6-chloronicotinate instead of 4-fluorobenzotrifluoride, to the title compound (510 mg, 76%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].C(O)(C)C.[H][H]>[Pd].O>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCC(O)COc1ccccc1C(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CC(C)O
Product: CCC(O)COC1CCCCC1C(C)(C)C
Yield: 73.9 %

Procedure:
To a 500 ml autoclave, 50 g (0.23 mol) of 1-(2-tertbutylphenyloxy)-2-butanol, 150 g of isopropanol and 1.0 g of 5 weight % palladium catalyst supported on active carbon containing 50 weight % water (produced by N. E. Chemcat Co.) were added, and the mixture obtained was reacted at 190° C. at a hydrogen pressure of 70 kg/cm2 for 27 hours until absorption of hydrogen had stopped. After the reaction was finished, the catalyst was filtered to remove it, and the reacted solution was distilled and 38.8 g of 1-(2-tert-butylcyclohexyloxy)-2-butanol (cis:trans=63:37) were obtained in a 74% yield of product.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[O:15][CH2:14][CH2:13][O:4]1
Reactant: OCCO
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C2(CBr)OCCO2)cc1
Reaction time: 5 h
Yield: 98.9 %

Procedure:
2-bromo-1-(4'-methoxy-phenyl)-ethanone (20 g, 87 mmol), ethylene glycol (54 g, 870 mmol), para-toluenesulfonic acid hydrate (1.7 g, 8.7 mmol) and benzene (50 ml) are heated and stirred together for 5 h in a flask beneath a Dean-Stark trap. The reaction mixture is added dropwise to a well stirred saturated sodium carbonate solution (0.4 l) and extracted with ethyl ether (3×70 ml). The combined organic extract is washed with a 2% sodium hydrogen carbonate solution, dried (Na2CO3) and filtered. The solvent is evaporated under reduced pressure to give 2-bromomethyl-2-(4'-methoxy-phenyl)-1,3-dioxolane (23.5 g, 86 mmol; yield: 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][CH3:38])=[O:36])=[CH:30][CH:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][CH3:38])=[O:36])=[CH:30][CH:29]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CNC(=O)Nc1ccc(OCCCBr)cc1
Product: CNC(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1

Procedure:
Following the procedure of Example 1, [α,α-bis(p-fluorophenyl) ]-4-piperidinemethanol and N-[4-(3-bromopropoxy)phenyl]-N'-methylurea are reacted to give the title compound.