Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[N:33]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]2([CH3:20])[CH2:19][O:18][CH2:17]2)[C:28](=[O:29])[C:27]2[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[N:33]=[C:25]([C:24]([F:39])([F:23])[F:38])[CH:26]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC1(C)COC1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1(C)COC1)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(3-methyl-oxetan-3-ylmethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 16 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) followed by a second chromatography using preparative HPLC (Gemini NX column) and a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2) as eluant. Colorless solid (12%). MS (ESI): m/z=544.15 [M+H]+.
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21]C[CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.[NH2:33][CH:34]([CH3:44])[CH2:35][C:36]1[CH:37]=[C:38]([CH2:42][OH:43])[CH:39]=[CH:40][CH:41]=1>>[OH:43][CH2:42][C:38]1[CH:37]=[C:36]([CH2:35][CH:34]([NH:33][C:10]2[N:15]=[C:14]([N:16]3[C:17]4=[CH:25][C:24]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:23][C:22](=[O:32])[N:18]4[CH2:19][CH2:21]3)[CH:13]=[CH:12][N:11]=2)[CH3:44])[CH:41]=[CH:40][CH:39]=1
Reactant: CC(N)Cc1cccc(CO)c1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Product: CC(Cc1cccc(CO)c1)Nc1nccc(N2CCn3c2cc(-c2ccccc2)cc3=O)n1

Procedure:
Following the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one, the sulfoxide/sulfone (0.4 g) was displaced with [3-(2-amino-propyl)-phenyl]-methanol (1.2 eq) to give the title compound as a light yellow solid. MS m/e 454 (M+H)+.
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2].Cl.Cl[CH2:28][C:29]1[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:28][C:29]4[C:30]([CH3:35])=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:25])[CH2:4]2)[CH3:2]
Reactant: Cc1ncccc1CCl
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(O)ccc12
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCc3cccnc3C)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 16 and 3-chloromethyl-2 methylpyridine hydrochloride using a procedure analogous to that outlined for Example 2. Product was isolated by flash chromatography eluting with 30% methylene chloride in ethyl acetate. Mass spectrum: m/e 444 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][CH:3]1[CH3:25].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:1][CH:2]1[CH:3]([CH3:25])[CH2:4][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])=[CH:6][CH:7]1[NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:15])(=[O:36])=[O:35]
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(NC(=O)OC(C)(C)C)C1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of tert-butyl 6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) in DCM (0.09 M) was added triethylamine (1.5 equiv.) and the reaction was cooled to 0° C. MsCl (1.2 equiv.) was added to the reaction and stirred for 3 h. Another 1.0 equiv. of MsCl was added to the reaction and stirred for another 2 h. Worked up the reaction by adding water, the organic phase was dried with brine, sodium sulfate, and concentrated. The crude product was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:1) to afford 2-(tert-butoxycarbonylamino)-6-methyl-4-(3-nitropyridin-4-yl)cyclohex-3-enyl methanesulfonate as a white foam in 65% yield. LC/MS=428.2 (M+H), LC: 3.542 min.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@@H:9]([C@H:14]([OH:19])[C@@H:15]([OH:18])[CH2:16][OH:17])[C@H:10]([OH:13])[CH2:11][OH:12])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22].O.C(O)[C@H]1O[C@@H](O[C@@H]([C@H](O)[C@@H](O)CO)[C@H](O)CO)[C@H](O)[C@@H](O)[C@H]1O.O.O>>[CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:19])[C@@:15]([OH:18])([CH2:16][OH:17])[O:13][C@@H:10]2[CH2:11][OH:12])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@H:3]1[OH:22]
Reactant: OC[C@@H](O)[C@@H](O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@@H]2[C@@H](CO)O[C@](O)(CO)[C@H]2O)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
Examples XII-XXVII elucidate the conditions at which lactitol monohydrate and lactitol dihydrate, respectively, may be obtained from aqueous solutions of lactitol. In each instance 200 g lactitol dihydrate was used as the starting material which wasd dissolved in an amount of water varying from 40 g to 50 g at 100° C. Thereupon the solutions obtained were cooled to a temperature varying from 25° C. to 45° C. and seeded with 2 g monohydrate or 2 g dihydrate. The crystallization proper occurred at temperatures between 18° C. and 45° 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)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[CH2:17][C:16]1[CH:19]=[CH:20][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:8][CH2:9]2)=[CH:14][CH:15]=1
Reactant: CNC
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Agent: Cl
Product: CN(C)Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1

Procedure:
Prepared from the product of Example 9 and dimethylamine hydrochloride.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([S:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([S:13][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([OH:19])=[O:2])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A solution of rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid methyl ester (50 mg, 0.16 mmol) in ethanol (3 mL) at 25° C. was treated with a solution of potassium hydroxide (44 mg, 0.79 mmol) in water (1 mL) and the mixture was stirred at 25° C. After 3 h, the reaction was diluted with water and evaporated under reduced pressure. The concentrate was acidified to pH 2 with an aqueous solution of 1N hydrochloric acid and extracted with dichloromethane (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residual material was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) to afford rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid (43 mg, 90% yield) as a colorless oil: EI-HRMS m/e calcd for C13H14Cl2SO2(M+) 304.0091, found 304.0101.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.CS(O[CH:17]1[CH2:20][CH2:19][CH2:18]1)(=O)=O.C(N(CCCC)CCCC)CCC>C(OCC)C>[CH:20]1([CH2:17][N:4]2[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:6][C:2]([CH3:1])=[N:3]2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)OC1CCC1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOCC
Product: CCOC(=O)c1cc(C)nn1CC1CC1
Yield: 54.3 %

Procedure:
A mixture comprising 2.1 g of ethyl 3-methyl-1H-pyrazole-5-carboxylate, 2.1 g of cyclobutyl methanesulfonate and 2.6 g of tri-n-butylamine was allowed to react at 110 ° C. for three hours without using any solvent. Then the reaction mixture was allowed to cool and diethyl ether was added thereto. The obtained mixture was successively washed with 1 N hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (eluent: hexane : ethyl acetate=14 : 1). Thus 0.5 g of the aimed ethyl 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylate (compound No. 1001) (yield: 17.6 %) and 1.54 g of ethyl 1-cyclopropylmethyl-3-methyl-1H-pyrazole-5-carboxylate(yield: 54.3 %) were obtained.
Reaction SMILES: C([O:3][C:4](=[O:62])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([CH3:61])=[C:15]([CH2:17][O:18][C:19]3[CH:58]=[CH:57][C:22]([CH2:23][O:24][C:25]4[C:29](/[CH:30]=[CH:31]/[C:32]5[N:33]=[C:34]([N:38]6[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]6)[S:35][C:36]=5[CH3:37])=[CH:28][N:27]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[N:26]=4)=[CH:21][C:20]=3[O:59][CH3:60])[N:16]=2)=[CH:8][CH:7]=1)C.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[C:47]([O:46][C:44]([N:41]1[CH2:42][CH2:43][N:38]([C:34]2[S:35][C:36]([CH3:37])=[C:32](/[CH:31]=[CH:30]/[C:29]3[C:25]([O:24][CH2:23][C:22]4[CH:57]=[CH:58][C:19]([O:18][CH2:17][C:15]5[N:16]=[C:12]([C:9]6[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:62])=[O:3])=[CH:7][CH:8]=6)[O:13][C:14]=5[CH3:61])=[C:20]([O:59][CH3:60])[CH:21]=4)=[N:26][N:27]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:28]=3)[N:33]=2)[CH2:39][CH2:40]1)=[O:45])([CH3:48])([CH3:50])[CH3:49]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCN(C(=O)OC(C)(C)C)CC5)sc4C)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(N3CCN(C(=O)OC(C)(C)C)CC3)sc2C)ccc1OCc1nc(-c2ccc(CC(=O)O)cc2)oc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 48.2 %

Procedure:
To a mixture of tert-butyl 4-{4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-5-methyl-1,3-thiazol-2-yl}piperazine-1-carboxylate (0.30 g), tetrahydrofuran (6 mL) and ethanol (3 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give [4-(4-{[4-({[4-((E)-2-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]-5-methyl-1,3-thiazol-4-yl}ethenyl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)-2-methoxyphenoxy]methyl}-5-methyl-1,3-oxazol-2-yl)phenyl]acetic acid as crystals (0.14 g, yield 50%). Recrystallization from ethyl acetate-hexane gave brown prism crystals. melting point: 119-120° C.
Reaction SMILES: C(OC([N:8]([CH2:18][CH:19]1[C:27]2[C:22](=[C:23]([C:29]#[N:30])[C:24]([F:28])=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OCC)=[O:14])=O)(C)(C)C.Cl>>[F:28][C:24]1[CH:25]=[CH:26][C:27]2[CH:19]([CH2:18][N:8]3[CH2:9][CH2:10][NH:11][CH2:12][C:13]3=[O:14])[CH2:20][CH2:21][C:22]=2[C:23]=1[C:29]#[N:30]
Reactant: CCOC(=O)CNCCN(CC1CCc2c1ccc(F)c2C#N)C(=O)OC(C)(C)C
Agent: Cl
Product: N#Cc1c(F)ccc2c1CCC2CN1CCNCC1=O
Temperature: 140 °C

Procedure:
To a flask charged with Ethyl N-(2-{(tert-butoxycarbonyl)[(4-cyano-5-fluoro-2,3-dihydro-1H-inden-1-yl)methyl]amino}ethyl)glycinate (30 mg, 0.072 mmol) was treated with HCl (1.78 ml, 7.2 mmol) to removed the BOC group. The solvent was removed when the deprotection was done. The residue was dissolved in EtOH (10 ml). To this solution was added a few drops of Hunig base. The solution was sealed in a microwave tube and heated to 140° C. for 30 minutes. The resulting title product was purified by MPLC. LC-MS (IE, m/z): 274 [M+1]+.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[Sb]#[Sb].OCCOC(=O)CCCCC(OCCO)=O>C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)CO>[C:5]1(=[O:6])[O:7][CH2:8][CH2:14][O:13][C:1](=[O:12])[C:2]2=[CH:11][CH:10]=[CH:9][C:4]1=[CH:3]2
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: O=C(CCCCC(=O)OCCO)OCCO
Solvent: OCCO
Product: O=C1OCCOC(=O)c2cccc1c2
Reaction time: 6 h

Procedure:
Dimethyl isophthalate, 1.37 kg, and ethylene glycol, 0.92 kg, were charged into a reactor together with an ester exchange catalyst which was a mixture of 2.05 g manganese acetate and 1.35 g diantimony trixoide. The ester exchange reaction was carried out as described in Example 1, and 3.29 kg of bis(hydroxyethyl)adipate was added to the product thus obtained. The polymerization was carried out at 265°C. at 1 mm Hg pressure for 6 hours to provide a poly(ethylene isophthalate/adiphate) having a mol ratio of isophthalate to adipate of 33 to 67 and having an intrinsic viscosity of 0.56, as determined in a solvent mixture of 25 volume percent trifluoroacetic acid and 75 volume percent methylene chloride.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([CH2:15][CH3:16])([OH:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].C(N(CC)CC)C.[OH-].[K+]>C1C=CC=CC=1>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([CH2:15][CH3:16])([OH:14])[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:27](=[O:28])[NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:12]=1
Reactant: CCCCN=C=O
Reactant: CCC(O)(c1ccc(O)cc1)c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCNC(=O)Oc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C

Procedure:
8.9 g. of 3-trifluoromethyl-4'-hydroxy-α-ethyl-benzhydrol, 3.3 g. of n-butyl-isocyanate and 0.06 ml. of triethyl amine in 45 ml. of dry benzene are heated up to 50° C. under stirring, and the reaction mixture is kept at the same temperature for one additional hour. The progress of the reaction is monitored by thin layer chromatography. When the reaction is complete, the mixture is cooled to room temperature, the benzene solution is shaken with a 5% aqueous potassium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. The solid residue is crystallized from a mixture of ethyl acetate and n-hexane. 11.4 g. of the named compound are obtained, melting at 99° to 100° C.
Reaction SMILES: C(OC1C(Cl)=CC(C(O)=O)=CC=1Cl)C=C.[CH2:16]([O:23][CH:24]1[CH:28]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37](=[O:55])[CH:38]([NH:40][C:41](=[O:54])[C:42]2[CH:47]=[C:46]([Cl:48])[C:45]([O:49][CH2:50][CH:51]=[CH2:52])=[C:44]([Cl:53])[CH:43]=2)[CH3:39])=[O:31])[CH2:27][C:26](=[O:56])[O:25]1)[C:17]1C=CC=CC=1>>[CH2:16]([O:23][CH:24]1[CH:28]([NH:29][C:30]([CH:32]2[CH2:36][CH2:35][CH2:34][N:33]2[C:37](=[O:55])[CH:38]([NH:40][C:41](=[O:54])[C:42]2[CH:43]=[C:44]([Cl:53])[C:45]([O:49][CH2:50][CH:51]=[CH2:52])=[C:46]([Cl:48])[CH:47]=2)[CH3:39])=[O:31])[CH2:27][C:26](=[O:56])[O:25]1)[CH3:17]
Reactant: C=CCOc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCc2ccccc2)cc1Cl
Agent: C=CCOc1c(Cl)cc(C(=O)O)cc1Cl
Product: C=CCOc1c(Cl)cc(C(=O)NC(C)C(=O)N2CCCC2C(=O)NC2CC(=O)OC2OCC)cc1Cl
Yield: 65 %

Procedure:
Prepared from 109 and 4-allyloxy-3,5-dichloro-benzoic acid following the method used in the synthesis of 82 to give the title compound as a white solid (228 mg, 65%). 1H-NMR (500 MHz, CD3OD) δ 1.10-1.30 (m, 4H), 1.32-1.52 (m, 3H), 1.63-2.31 (m, 4H), 2.41-2.50 (d, 0.5H), 2.52-2.61 (dd, 0.5H), 2.67-2.81 (m, 0.5H), 2.94-3.05 (dd, 0.5H), 3.47-3.96 (m, 4H), 4.21-4.81 (m, 5H), 5.22-5.32 (m, 1H), 5.35-5.49 (m, 1.5H), 5.55-5.63 (m, 0.5H), 6.06-6.21 (m, 1H), 7.90 (s, 2H). Analytical HPLC (mixture of 2 diastereomers) 12.56 min. LC-MS (ES+) m/e=542.3(MH+)
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=[N:21][CH:22]=1>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:18]=1
Reactant: O=S(=O)(Oc1cncc(F)c1)C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1cncc(C#Cc2ccccc2)c1
Temperature: 60 °C
Yield: 65 %

Procedure:
Add phenylacetylene (0.180 mL, 1.6 mmol), copper (I) iodide (0.015 g, 0.08 mmol) bis(triphenylphosphine)palladium (II) dichloride (0.027 g. 0.04 mmol) and triethylamine (0.85 mL, 6 mmol) to a solution of trifluoromethanesulfonic acid 5-fluoro-pyridin-3-yl ester, (prepared essentially as described in PREPARATION 6), (0.367 g, 1.5 mmol) in degassed ethyl acetate (1.5 mL) and heat at 60° C. for 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, wash with ethyl acetate, and concentrate. Purify the residue by silica gel chromatography, eluting with dichloromethane, to give the title compound (0.192 g, 65%).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](O)(=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: NCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)NCCO
Temperature: 140 °C

Procedure:
To a solution of 24 g (0.4 mole) ethanolamine in 100 ml toluene was added 40 g (0.2) lauric acid at 50° C. The mixture was refluxed for 6 hours. Toluene was gradually removed to increase the final pot temperature to 140° C. The distillate was collected in a Stark & Dean trap. The toluene was removed by vacuum stripping and the residue was crystallized from n-hexane. The title compound (44 g) thus obtained melted at 80°-84° C.
Reaction SMILES: [CH2:1]([N:3]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].C([O-])(=O)/C=C/C([O-])=O>CN(C)C=O.C(O)CC>[C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:9]2[CH2:8][CH2:7][CH:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1)(=[O:14])[CH3:12]
Reactant: CCN(CC)C1CCNCC1
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: CN(C)C=O
Product: CCN(CC)C1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 52.3 %

Procedure:
2.1 g (13.25 mmol) of 4-(N,N-diethylamino)piperidine, 1.8 g (13.25 mmol) of 4-fluoroacetophenone and 7.3 g of potassium carbonate in 100 ml of dimethylformamide/n-propanol (1:1) were refluxed for 20 h. 1.9 g of 1-(4-acetylphenyl)-4-(N,N-diethylamino)piperidine were obtained as crystalline fumarate. Melting point 125°-127° C.
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]([O:11][C:12]1[C:13]([Br:25])=[C:14]([OH:24])[CH:15]=[C:16]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C(OCC)C>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:15]=[C:14]([O:24][CH2:2][CH3:3])[C:13]=1[Br:25])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cnc(-c2cc(O)c(Br)c(OCc3ccccc3)c2)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1Br
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Iodoethane (111 uL, 1.37 mmol) was added to a mixture of 3-(benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol (412 mg, 1.14 mmol) and potassium carbonate (632 mg, 4.58 mmol) in DMF (2.8 mL). After stirring for two hours, the solution was diluted with 1:1 ethyl acetate/diethyl ether, washed with water (5×), brine, dried over magnesium sulfate and concentrated to provide 2-(3-(benzyloxy)-4-bromo-5-ethoxyphenyl)-5-methyloxazole as a white crystalline solid (421 mg). MS (M+1)=388.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52 (d, J=7.07 Hz, 2H), 7.36-7.43 (m, 2H), 7.28-7.35 (m, 2H), 7.23 (d, J=1.52 Hz, 1H), 6.86 (d, J=1.52 Hz, 1H), 5.24 (s, 2H), 4.21 (q, J=6.74 Hz, 2H), 2.41 (d, J=1.01 Hz, 3H), 1.50 (t, J=6.82 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:19]([OH:21])=O.[CH:22]1[CH:23]=[CH:24][C:25]2N(O)N=[N:28][C:26]=2[CH:27]=1.C(Cl)CCl.NC1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[C:26]1([NH:28][C:19]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][C:7]([NH:11][S:12]([C:15]([F:16])([F:18])[F:17])(=[O:14])=[O:13])=[CH:8][CH:9]=3)=[O:21])[CH:27]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cn1c(C(=O)O)cc2cc(NS(=O)(=O)C(F)(F)F)ccc21
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: Cn1c(C(=O)Nc2ccccc2)cc2cc(NS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To 1-Methyl-5-Trifluoromethansulfonylamino-1H-Indole-2-Carboxylic Acid (0.21 g, 0.65 mmol) in 8 ml of DMF was added HOBt (96 mg, 0.71 mmol), EDC (145 mg, 0.78 mmol), TEA (131 mg, 1.3 mmol), and aniline (0.65 ml, 72 mmol). The reaction mixture was stirred at room temperature for a day. The reaction was diluted with 200 ml of methylene dichloride and washed with water and brine, then concentrated. The residue was purified by flash column with 50% EtOAc/Hexane to give 0.13 g of 1-Methyl-5-trifluoromethansulfonylamino-1H-indole-2-carboxylic acid phenylamide as a beige solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H, SNH), 10.37 (s, 1H, NHCO), 7.78 (d, J=8 Hz, 2H, ArH-o), 7.63 (d, J=9 Hz, 1H, H-7), 7,61 (d, J=2 Hz, 1H, H-4), 7.37 (t, J=8 Hz, 2H, ArH-m), 7.32 (s, 1H, H-3), 7.20 (dd, J=2, 9 Hz, 1H, H-6), 7.12 (t. J=7.4 Hz, 1H. ArH-p).MS m/z 396 (M−H).
Reaction SMILES: CC1C=CC(C)=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:13](Cl)=O.[C:20]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=C)=[CH:26][CH:25]=1)(=[O:22])[CH3:21].CN1CCOCC1>CC([O-])=O.CC([O-])=O.[Pd+2].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[C:20]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[CH:13][C:12]2[CH:11]=[C:10]([F:9])[CH:18]=[C:17]([F:19])[CH:16]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: Cc1ccc(C)cc1
Product: CC(=O)Oc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 74.4 %

Procedure:
A 25 mL round bottom flask was charged with p-xylene (10 mL), Pd(OAc)2 (11.3 mg, 0.05 mmol), 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride (21.4 mg, 0.05 mmol), 3,5-difluorobenzoyl chloride (0.89 g, 5 mmol), 4-acetoxystyrene (0.97 g, 6 mmol), and N-methyl morpholine (0.69 g, 6 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (1.02 g, 74%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.51 (d, J=8.4 Hz, 2H), 7.12-6.97 (m, 6H), 6.70 (t, 1H), 2.31 (s, 3H).