Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:9][O:10][CH3:11])[C:5]([O:7][CH3:8])=[O:6].O.O.O.C([O-])(=O)C.[Na+].[NH2:21][C:22]([NH2:24])=[S:23].C(=O)([O-])O.[Na+]>O1CCCC1.O>[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:9][O:10][CH3:11])[C:5]([O:7][CH3:8])=[O:6])[N:21]=1
Reactant: CON=C(C(=O)CBr)C(=O)OC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)OC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
In 350 ml of tetrahydrofuran is dissolved 52 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate, followed by addition of 250 ml of water. Then, 89.1 g of sodium acetate trihydrate and 33.2 g of thiourea are added and the mixture is reacted with stirring at room temperature for 18 hours. To this reaction mixture is added 200 ml of a 5% aqueous solution of sodium hydrogen carbonate and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and distilled under reduced pressure to remove the solvent. To the residue is added 200 ml of ether and the resultant crystals are collected by filtration. By the above procedure is obtained 24.8 g of methyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (syn-isomer) as crystals melting at 164.9° C.
Reaction SMILES: [NH2:1][N:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=[NH2+:12].CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[Cl:26][CH:27]([Cl:32])[C:28](OC)=O.C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:26][CH:27]([Cl:32])[C:28]1[N:12]=[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][N:2]2[N:1]=1
Reactant: Nn1ccc2ncccc2c1=[NH2+]
Reactant: COC(=O)C(Cl)Cl
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: ClC(Cl)c1nc2c3cccnc3ccn2n1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
A mixture of 6-amino-1,6-naphthyridin-5(6H)-iminium-2,4,6-trimethylbenzenesulfonate (3.30 g, 9.17 mmol), methyl 2,2-dichloroacetate (3.93 g, 27.5 mmol) and K2CO3 (3.80 g, 27.5 mmol) in EtOH (30 mL) was refluxed for 14 h. The mixture was then cooled to room temperature, filtered, and washed with DCM (3×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (5×10 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using DCM as eluent to yield 2-(dichloromethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine as a white solid (500 mg, yield 29%). ESI MS: m/z 253, 255 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15]/[C:16](/[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=3)=[N:26]\[OH:27])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(CC(=O)c3ccnc(C)c3)CCCCC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(C2(C/C(=N\O)c3ccnc(C)c3)CCCCC2)cc1

Procedure:
In analogy to example 151, step 3, 2-[1-(4-methoxy-phenyl)-cyclohexyl]-1-(2-methyl-pyridin-4-yl)-ethanone was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=339.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([CH:23]=2)[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S-:24][C:25]#[N:26].[Na+].BrBr.O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[S:24][C:25]#[N:26])[CH2:21][CH2:20][S:19]3)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(-c2nc3n(c2SC#N)CCS3)cc(C(C)(C)C)c1O
Yield: 37.9 %

Procedure:
In 10 ml of acetic acid was dissolved 1.35 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole and after adding thereto 0.64 g of sodium thiocyanate, 0.7 g of bromine was added dropwise to the solution under ice-cooling. After performing the reaction for one hour at room temperature, 30 ml of water was added to the reaction mixture to precipitate crystals, which were recovered by filtration. The crystals were added to a mixture of 20 ml of chloroform and 10 ml of an aqueous 10% potassium carbonate solution followed by stirring. The chloroform layer thus formed was dried and concentrated, and the residue thus formed was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.6 g 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-thiocyanato-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]3[C:13](=[C:24]([CH:27]=[O:28])[NH:25][CH:26]=3)[CH2:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:10]=2[CH:9]=1.C(O)(=[O:33])C>CC(C)=O.S(=O)(O)[O-].[Na+]>[Cl:7][C:8]1[CH:30]=[CH:29][C:11]2[C:12]3[C:13](=[C:24]([C:27]([OH:33])=[O:28])[NH:25][CH:26]=3)[CH2:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:10]=2[CH:9]=1
Reactant: O=Cc1[nH]cc2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1[nH]cc2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A solution of 1.5 g (9.5 mmol) of potassium permanganate in 150 ml of 50% aqueous acetone was added dropwise to a solution of 1.6 g (4.5 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine-3-carboxaldehyde in 100 ml of acetone. After 2.5 hr the mixture was diluted with a saturated aqueous solution of sodium bisulfite, neutralized with the addition of acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. Trituration of the residue with methylene chloride gave yellow crystals, mp 216°-218°. Recrystallization from a mixture of ethanol and ether gave yellow prisms, mp 252°-254° (dec).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:33])(=O)=O.C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]=[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[S:15][C:16]=1[CH2:17][Cl:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCOCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2nc(CCCOCc3ccccc3)c(CCl)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a stirred solution of 1.5 g of {4-[3-(benzyloxy)propyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol in 15 mL of dichloromethane were added 0.484 g of methanesulfonylchloride and 1.03 mL of triethylamine. The solution was stirred for 2 h at room temperature. The mixture was diluted with dichloromethane and poured into water. The aqueous layer was separated and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1.65 g of crude product as a yellow oil. Purification by column chromatography on silica gel (heptane 90/ethyl acetate 10) gave 0.840 g of 4-(3-benzyloxy-propyl)-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[C:7]2[NH:9][N:10]=[C:11]([OH:12])[C:6]2=[CH:5][CH:4]=1.[CH3:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1>>[CH3:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:12][C:11]2[C:6]3[C:7](=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=3)[N:9]([C:22]([N:19]3[CH2:20][CH2:21][CH:16]([CH3:15])[CH2:17][CH2:18]3)=[O:23])[N:10]=2)=[O:23])[CH2:18][CH2:17]1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: Oc1n[nH]c2nc(C(F)(F)F)ccc12
Product: CC1CCN(C(=O)Oc2nn(C(=O)N3CCC(C)CC3)c3nc(C(F)(F)F)ccc23)CC1

Procedure:
In analogy to example, 1, 120 mg (0.59 mmol) of 6-trifluoromethyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 143.3 mg (0.89 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 71 mg (26%), M+H+: 454.27.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9](Cl)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][NH:29][CH2:30][CH2:31][OH:32]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N:29]([CH2:30][CH2:31][OH:32])[CH2:28][C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([CH3:11])=[N:6][C:5]=1[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=1[CH3:21]
Reactant: COC(=O)c1c(Cl)cc(C)nc1Oc1c(C)cc(C)cc1C
Reactant: OCCNCc1cccs1
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(N(CCO)Cc2cccs2)cc(C)nc1Oc1c(C)cc(C)cc1C
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester and 2-[(thiophen-2-ylmethyl)-amino]-ethanol in 1-methyl-2-pyrrolidinone was heated at 130° C. overnight. The mixture was quenched with water, brine and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR (CDCl3) d 7.22(m, 1H), 6.94m, 2H), 6.84(s, 2H), 6.44(s, 1H), 4.52(s, 2H), 3.9(s, 3H), 3.679t, 2H), 3.369t, 2H), 2.279s, 3H), 2.20(s, 3H), 2.07(s, 6H) ppm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](OC)=[S:13].[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21]>O>[C:20]([NH:19][CH2:18][CH2:17][NH:16][C:12](=[S:13])[CH2:11][CH2:10][CH2:9][CH2:8][S:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NCCN
Reactant: COC(=S)CCCCSC1CCCCO1
Solvent: O
Product: CC(=O)NCCNC(=S)CCCCSC1CCCCO1
Temperature: 75 °C

Procedure:
Methyl [3-(tetrahydropyran-2-ylthio)propyl]thioacetate (1 g, 3.7 mmol) was added dropwise to N-(2-aminoethyl)-acetamide (1.25 g, 12.25 mmol) and the mixture heated at 75° C. for 2.5 h. Volatile components were then removed under reduced pressure (45° C. at 0.02 mmHg) to give an oil which was taken up into water. This aqueous solution was then extracted with dichloromethane (adding potassium chloride to the aqueous layer to prevent emulsion formation if necessary). The dichloromethane extracts were then dried (MgSO4), filtered, and the solvent removed under reduced pressure to give the crude N-(2-acetylaminoethyl)-3-(tetrahydropyran-2-ylthio)propylthioacetamide. A pure sample of this material (0.25 g, 22%) was obtained by reverse phase h.p.l.c. using aqueous methanol as the eluant.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].C(O)(=O)C.[CH:16](N)=[NH:17]>C(OCCO)C>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[NH:17][CH:16]=[N:11]2
Reactant: N=CN
Reactant: Cc1cccc(N)c1C(=O)O
Solvent: CCOCCO
Solvent: CC(=O)O
Product: Cc1cccc2nc[nH]c(=O)c12
Yield: 68.1 %

Procedure:
6-Methylanthranilic acid (5 g, 33 mmol) and formamidine acetate (0.4 g, 41 mmol) were refluxed in 2-ethyoxyethanol (50 ml) for 16 h. On cooling the solvent was removed in vacuo, the residue slurried in diethyl ether, the solid filtered, washed with diethyl ether and dried to yield 3.6 g of the title compound. δH (DMSO d6), 7.97 (1H, s), 7.60 (1H, dd, J 7.9, 7.6 Hz), 7.43 (1H, d, J 8.0 Hz), 7.21 (1H, d, J 7.3 Hz), 2.76 (3H, s); m/z (ES+70V)161 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:46])[C@@H:15]([NH:28]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].N1CCOCC1>CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:46])[C@@H:15]([NH2:28])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCCCOCc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCCCOCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
To a solution of 650 mg (S)-4-[6-Benzyloxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoyl]-piperazine-1-carboxylic acid butyl ester in 3.6 ml DMF were added at room temperature 0.91 ml morpholine. After stirring for 2 h the reaction mixture was evaporated and the crude product thus obtained used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (84 mg, 66%), MS (ISP) m/z=449.6 [(M+H)+], mp 259° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (intermediate O) (0.1 g, 0.285 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.11 g, 0.37 mmol).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C([Mg]Cl)C.[Mg].[CH2:15]([N:22]1[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCCC.C(OCC)(=O)C.O>[CH2:15]([N:22]1[CH2:28][CH2:27][CH2:26][C:25]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])([OH:29])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Reactant: OCc1ccccc1Br
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: OCc1ccccc1C1(O)CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To a solution of 2-bromobenzyl alcohol (7.8 g, 42 mmol) in tetrahydrofuran (80 ml) was added dropwise a 2.8 M solution of ethylmagnesium chloride in tetrahydrofuran (15 ml, 42 mmol). The reaction was exothermic, and the rate of addition was adjusted to maintain a gentle reflux. After completed addition magnesium turnings (1.0 g, 42 mmol) were added in portions. The mixture was heated at reflux for 2 h before addition of a solution of 1-benzyl-azepan-4-one (8.5 g, 42 mmol) in tetrahydrofuran (40 ml). The reaction mixture was heated for another 4 h at reflux. Cooling to room temperature was followed by slow addition of saturated ammonium chloride solution (50 ml), water (100 ml) and ethyl acetate (300 ml). The layers were separated, and the organic layer was concentrated to give a green oil. Flash column chromatography using a 2:1 mixture of heptane and ethyl acetate as eluent gave the title compound as a light yellow oil (8.0 g, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:22]#[C:23][CH3:24])[CH2:18][C:19](O)=[O:20])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.C1COCC1.[NH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>O>[S:44]1[CH:45]=[CH:46][N:47]=[C:43]1[NH:42][C:19](=[O:20])[CH2:18][CH:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)[C:22]#[C:23][CH3:24]
Reactant: CC#CC(CC(=O)O)c1ccc(OCc2ccc(OC)cc2)cc1
Reactant: Nc1nccs1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: C1CCOC1
Product: CC#CC(CC(=O)Nc1nccs1)c1ccc(OCc2ccc(OC)cc2)cc1
Yield: 1.6 %

Procedure:
A pear-shaped flask was charged with a stir bar, compound 12 (50 mg, 0.154 mmol), carbonyl diimidazole (25 mg, 0.154 mmol) and THF (4 mL). The mixture was refluxed for 1 hour, and 2-amino thiazole (16 mg, 0.154 mmol) was then added. The reaction was refluxed for 48 hours, poured into water and extracted with ethyl acetate. The organic layer was concentrated and the resulting residue was purified via HPLC to yield 1.0 mg (2%) of 3-[4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid thiazol-2-ylamide (24) as a film. 1H NMR (400 MHz) (acetone-d6) δ 7.39 (4H, m), 7.11 (1H, s), 6.95 (3H, m), 5.03 (2H, s), 3.82 (3H, s), 2.95 (2H, m), 1.79 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32](C(OCC4C=CC=CC=4)=O)[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:29])[F:28])[CH:20]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCNC2)CC1
Yield: 98.2 %

Procedure:
Hydrogenate a solution of 4-[1-((R)-1-benzyloxycarbonyl-piperdin-3-yl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.71 mmol; 1.08 g) in methanol (20 mL) with 10% Palladium on carbon (100 mg) and 1 atmosphere of hydrogen gas for 60 min. Add Celite® and filter, rinse with DCM and evaporate to provide the title compound (834.3 mg; 1.68 mmol; 98%). MS (ES+): m/z=497 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na].Cl.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:17]1([CH2:16][C@H:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:34]3[CH2:35][CH2:36][CH:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:32][CH2:33]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:13]([OH:15])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: [Na]
Product: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (S)-2-(4-fluoro-benzenesulfonylamino)-3-phenyl-propionic acid, sodium salt and 4-phenyl-piperidine hydrochloride were condensed to give the title compound, mp=167-169° C.
Reaction SMILES: [C:1]([C:6]1[CH:18]=[C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([O:12]CC)=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:18]=[C:17]([C:19]([CH2:22][CH3:23])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(C(C)(C)CC)cc1C(C)(C)CC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1ccc(OCC(=O)O)c(C(C)(C)CC)c1
Reaction time: 6 h
Yield: 133.8 %

Procedure:
The above ethyl 2-(2,4-di-t-amylphenoxy)acetate (293 g) and 27% aqueous sodium hydroxide (401.4 g) were placed in a 3-liter flask. The mixture was kept at 98° C. for 6 hours, and the hydrolysis reaction was completed. After completion of the reaction, the mixture was adjusted to pH 2 or lower by the addition of 40% aqueous sulfuric acid (349.9 g) and water (250 g), and toluene (289.5 g) was added thereto, followed by extraction. The water layer was separated with a separatory funnel, and the toluene layer was washed with water (289.5 g). Then, the toluene layer was concentrated by distillation under ordinary pressure for the recovery of toluene, which afforded a concentrated solution (357.6 g) of the carboxylic acid compound in toluene. The analysis revealed that the concentrated solution contained the desired carboxylic acid compound in a yield of 99% on the basis of the raw material ester compound.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42].[NH4+].[Cl-]>N1CCCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: C1CCNCC1
Product: CCCCCCCCCCCCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
4-(Dodecyloxy)iodobenzene (4.04 g, 1.04×10−2 mol), triphenylphosphine (0.165 g, 6.29×10−4 mol), CuI (0.108 g, 5.67×10−4 mol) and Pd(PPh3)2Cl2 (0.153 g, 2.18×10−4 mol) were dissolved in 40 ml of dry piperidine under N2. (Trimethylsilyl)acetylene (3.00 ml, 2.12×10−2 mol) was added and the mixture was stirred at 50° C. for 6 h under N2. After cooling, the reaction mixture was poured into aq. NH4Cl and extracted with CH2Cl2 (three times). The combined organic layers were washed with aq. NH4Cl, water, and dried over Na2SO4. The crude product was chromatographed on silica gel with 4:1 hexane:CH2Cl2 as the eluent. Yield=3.633 g (97% based on 4.04 g of 4-(dodecyloxy)iodobenzene). 1H NMR (250 MHz, CDCl3): δ 7.39 (d, 2H, J=8.9 Hz, Ph), 6.80 (d, 2H, J=9.0 Hz, Ph), 3.94 (t, 2H, J=6.6 Hz, —OCH2—), 1.77 (quint, 2H, J=6.6 Hz, —OCH2CH2—), 1.17-1.50 (m, 18H, —CH2—), 0.88 (t, 3H, J=6.6 Hz, —CH3), 0.24 (s, 9H, Si—CH3). CI MS m/z: 358.268 (M+) (calcd 358.269).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([NH:19][CH3:20])=[CH:8][N:7]=1.CCN(C(C)C)C(C)C.[F:31][C:32]([F:47])([F:46])[C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[N:7]=[CH:8][C:9]([N:19]([CH3:20])[C:36](=[O:37])[C:35]2[CH:34]=[C:33]([C:32]([F:47])([F:46])[F:31])[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=2)=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:11]=1
Reactant: CNc1cnc(N(C)CCOC)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCN(C)c1cc(-c2ccccc2C)c(N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 1 h
Yield: 32.9 %

Procedure:
A solution of N2-(2-methoxyethyl)-N2,N5-dimethyl-4-o-tolylpyridine-2,5-diamine (32 mg, 0.11 mmol) and DIPEA (43 μL, 0.25 mmol) in CH2Cl2 (1 mL) was treated with 3,5-bis-trifluoromethylbenzoyl chloride (46 mg, 0.17 mmol, CAS RN 1271-19-8). After stirring for 1 h, the reaction mixture was loaded directly onto a silica gel column. Elution with 25% EtOAc in n-hexane afforded the title compound as a yellow solid (19 mg, 33%). MS (ESI): m/z=526.2 [M+H]+.