Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([OH:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].[CH3:57]I>[Ag]=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH3:57])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CI
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=[Ag]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
A suspension of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (20 mg, Example 42)) and silver oxide (20 mg) in 1.5 ml of methyl iodide was refluxed in a gas-tight bottle for 4 days. The yellow solid was filtered off and the excess methyl iodide was removed. Purification of crude material by preparative tlc on silica gel (1:1 hexane/ethyl acetate) gave 4 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](Br)=[CH:5][N:6]=[CH:7]2.[CH2:13](C([Sn])=C(CCCC)CCCC)[CH2:14]CC.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH:13]=[CH2:14])=[CH:5][N:6]=[CH:7]2
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Nc1cccc2cncc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cncc2cccc(N)c12
Temperature: 110 °C
Reaction time: 15 h

Procedure:
A suspension of 5-amino-4-bromoisoquinoline obtained in Reference Example 1 (10 g), tri(n-butyl)vinyltin (21.0 ml, Tokyo Kasei Kogyo), tetrakis(triphenylphosphine)palladium(0) (1.04 g, Aldrich), and 2,6-di-tert-butyl-p-cresol (11.3 mg, Tokyo Kasei Kogyo) in toluene (90 ml) was stirred at 110° C. for 15 hours. The reaction mixture was cooled to room temperature, then added with 10% aqueous potassium fluoride (90 ml), and stirred for 4 hours. The reaction mixture was added with ethyl acetate (100 ml), and the precipitates were removed by filtration. Then, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (7.00 g).
Reaction SMILES: CN1CCOCC1.[CH3:8][C@H:9]1[C:13](=[O:14])[O:12][C:11](=[O:15])[NH:10]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:16]([N:10]1[C@@H:9]([CH3:8])[C:13](=[O:14])[O:12][C:11]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H]1NC(=O)OC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
4-Dimethylaminopyridine (61 mg, 0.5 mmol) and N-methylmorpholine (152 mg, 1.5 mmol) were dissolved in ethyl acetate (15 mL), followed by the addition of (S)-4-methyl-2,5-oxazolidinedione (L-alanine-NCA) (230 mg, 2.0 mmol) under ice cooling. Further, a solution of benzoyl chloride (281 mg, 2.0 mmol) in ethyl acetate (7 mL) was added dropwise under ice cooling over 20 minutes. After the resulting mixture was stirred as was at 0° C. for 2 hours, a precipitated salt was filtered off, and the filtrate was concentrated under reduced pressure. The concentration residue was re-dissolved in a mixed solvent consisting of ethyl acetate (5 mL) and hexane (5 mL), and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to afford the title compound as white crystals (324 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH:32]3[CH2:34][CH2:33]3)[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]3[CH:23]=[C:24]4[N:31]([CH:32]5[CH2:34][CH2:33]5)[CH2:30][CH2:29][N:25]4[C:26](=[O:28])[N:27]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:18])([F:19])[F:20]
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Product: O=c1nc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc2n1CCN2C1CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol and 7-chloro-1-cyclopropyl-2,3-dihydroimi-dazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1>[Pd]>[N:4]1[CH:3]=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:7]=[CH:6][C:5]=1[C:5]1[CH:6]=[CH:7][C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][N:4]=1
Reactant: CCOC(=O)c1cccnc1
Agent: [Pd]
Product: CCOC(=O)c1ccc(-c2ccc(C(=O)OCC)cn2)nc1

Procedure:
Diethyl bipyridine-5,5'-dicarboxylate was prepared from catalytic dehydrogenative coupling reaction of ethyl nicotinate (Aldrich Chemical Co., 51.2 g.) in the presence of 10% Pd/C (Fluka, 15 g.) in a sealed tube at 135-140° C. for 4-7 days according to reported procedure. Subsequent recrystallization from isopropanol afforded the product as off-white needles. M.p. 148-149° C. Yield 12.1 g. (26%). Anal. Calcd for C16H16N2O4 : C, 63.99; H, 5.37; N, 9.33. Found: C, 64.04; H, 5.16; N, 9.05.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>>[C:12]1([CH2:11][CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:25])[N:3]=[CH:4]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC(=O)c1c(N)ncn1CCc1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccnc2)ncn1CCc1ccccc1

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.00 g (8.69 mmol) of 4-amino-1-(2-phenylethyl)-5-imidazolecarboxamide prepared in the same manner as in Example 56 and nicotinic acid instead of 3-pyridylacetic acid hydrochloride to obtain crude 1-(2-phenylethyl)-4-(3-pyridylcarbonylamino)-5-imidazolecarboxamide.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:38]C(=O)OCC2C=CC=CC=2)[C@H:18]([OH:37])[CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH:12]=[C:13]([F:15])[CH:14]=1.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[NH2:38][C@@H:17]([CH2:16][C:11]1[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([F:8])[CH:10]=1)[C@H:18]([OH:37])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:23]=1[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36]
Reactant: C=CCCCc1ccc(C(F)(F)F)cc1CNC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCc1ccc(C(F)(F)F)cc1CNC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 113 %

Procedure:
Step AM (2): To a solution of benzyl (2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-(2-(pent-4-enyl)-5-(trifluoromethyl)benzylamino)butan-2-ylcarbamate trifluoroacetate salt (88 mg, 0.128 mmol) in DME (9.0 mL) and water (6.0 mL) was added barium hydroxide monohydrate (852 mg, 4.5 mmol). The reaction mixture was stirred at 110° C. in a high pressure vial for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by reverse phase chromatography to give (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-(2-(pent-4-enyl)-5-(trifluoromethyl)-benzylamino)butan-2-ol double trifluoro-acetate salt (64 mg, 74%) as a colorless oil. LC-MS (M+H)+=443.36.
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]([CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:30][CH2:31][CH3:32])[C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[CH3:10])=[O:8])=[CH:3][CH:2]=1.O.[OH-].[Li+].O.CO>C1COCC1>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]([CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:30][CH2:31][CH3:32])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[CH:15]=[CH:16][CH:17]=2)[CH3:10])=[O:8])=[CH:5][CH:6]=1
Reactant: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccc(-c4ccccc4)cc3)c2)cc1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(-c2cccc(CN(C)C(=O)c3ccc(-c4ccccc4)cc3)c2)cc1)C(=O)O
Reaction time: 4 h

Procedure:
360 mg (0.7 mmol) of methyl (S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionate in 10 ml of THF are introduced into a round-bottomed flask. 60 mg (1.4 mmol) of lithium hydroxide monohydrate, 1 ml of water and 1 ml of methanol are added and the mixture is stirred for 4 hours. The reaction medium is poured into water, acidified to pH 1, extracted with ethyl acetate, the organic phase decanted off, dried over magnesium sulphate and evaporated off. The residue obtained is purified by chromatography on a silica column eluted with a heptane and ethyl acetate (50/50) mixture and 280 mg (80%) of (S)-3-(3′-{[(1-biphenyl-4-ylmethanoyl)methylamino]methyl}biphenyl-4-yl)-2-ethoxypropionic acid are obtained in the form of an amorphous white solid.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=1)[CH3:5])([OH:3])=[O:2].S(Cl)(Cl)=O.[C:24]1(C)[CH:29]=CC=C[CH:25]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[N:9]1[CH:10]=[N:11][C:7]([O:6][CH:4]([C:1]([O:3][CH:24]([CH3:29])[CH3:25])=[O:2])[CH3:5])=[N:8]1
Reactant: Cc1ccccc1
Reactant: CC(Oc1ncn(-c2ccc(Cl)cc2Cl)n1)C(=O)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2Cl)n1

Procedure:
Three g of the compound of Example 23 was added to 50 ml of toluene, and 5 ml of thionyl chloride was then added. The mixture was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. Fifty ml of additional toluene was added and removed under vacuum, and then 50 ml of isopropanol was added to the residue. The mixture was heated under reflux for 2 hours, and was then cooled and evaporated under vacuum. The residue was recrystallized from isopropanol to obtain 2.6 g of the desired product, m.p. 55°-57°.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].[Cl:13][C:14]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]=[CH:20][O:19]1>O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:13][C:14]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:15]=1[O:16][CH2:17][C@@H:18]1[O:19][C@@H:20]([O:12][CH:3]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=2[Cl:11])[CH2:2][Br:1])[CH2:21][CH2:22][CH2:23]1
Reactant: Clc1ccc(OCC2CCC=CO2)c(Cl)c1
Reactant: OC(CBr)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(OC[C@H]2CCC[C@H](OC(CBr)c3ccc(Cl)cc3Cl)O2)c(Cl)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To 10 ml of an ethereal solution of 425 mg of α-bromomethyl-2,4-dichlorobenzyl alcohol and 340 mg of 2-(2,4-dichlorophenoxymethyl)-3,4-dihydro-2H-pyran was added a catalytic amount (2 drops) of phosphorus oxytrichloride, and the mixture was stirred at room temperature for 4 days. 3 drops of triethylamine were then added and the solvent was evaporated off under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 40:2:1 by volume mixture of hexane, benzene and ethyl acetate, to give 681 mg of the isomer of lesser polarity of trans-6-(2,4-dichlorophenoxymethyl)-2-[2-bromo-1-(2,4-dichlorophenyl)ethoxy]tetrahydropyran as colorless crystals melting at 104°-105° C.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[F:12][C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:2]3[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=3[CH3:8])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
The product (790 mg) is obtained according to the method of stage 1 of Example 4, by using 900 μL of 2-fluoro-3-methyl-nitrobenzene and 2.6 g of 4-(4-fluoro-phenoxy)-phenylamine obtained in stage 2 of Example 5 in the presence of 2.36 g of potassium tert-butanolate in 80 mL of DMSO.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.ClC1N=C(C(N[C@H]2CCN(C(OC(C)(C)C)=O)C[C@H]2OC)=O)NC=1CC.C1(C)C=CC(S(O[CH2:55][CH:56]([F:58])[F:57])(=O)=O)=CC=1>CN(C=O)C>[F:57][CH:56]([F:58])[CH2:55][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Agent: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCC(F)F
Yield: 84.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (4.6 g, 17.6 mmol), sodium hydride (55% content, 1g, 22.9 mmol), 2,2-difluoroethyl p-toluenesulfonate (5 g, 21.6 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.85 g of the title compound as a colorless oily substance (85%).
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[CH3:18][C:19]1([CH3:30])[S:23][CH:22]([C:24](OCC)=[O:25])[C:21](=O)[CH2:20]1>C(O)C>[CH3:18][C:19]1([CH3:30])[S:23][C:22]2[C:24](=[O:25])[O:10][C:9]3[CH:11]=[C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])[CH:6]=[C:7]([OH:12])[C:8]=3[C:21]=2[CH2:20]1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CCOC(=O)C1SC(C)(C)CC1=O
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SC(C)(C)C3
Reaction time: 72 h

Procedure:
To 100 ml. of ethanol was added 6.2 g. of 5-(3-methyl-2-octyl)resorcinol and 6.2 g. of ethyl 5,5-dimethyl-3-oxotetrahydrothiophene-2-carboxylate. The mixture was cooled in ice and hydrogen chloride was bubbled in for one-half hour. The mixture was stoppered and held at room temperature for 3 days. It was then concentrated and ether added, extracted with water and then washed with dilute aqueous sodium bicarbonate solution. The etheral solution was dried over magnesium sulfate and concentrated. The product was crystallized from acetonitrile to give 5.0 g., m.p. 155°-163°C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[N+]([O-])=O.C([Sn](CCCC)(CCCC)[CH:20]=[CH:21][O:22][CH2:23][CH3:24])CCC.O.CCOC(C)=O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:21]([O:22][CH2:23][CH3:24])=[CH2:20])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C=C(OCC)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 4-bromo-2-nitro-benzoic acid methyl ester (10 g, 38.5 mmol) tetrakis-(triphenylphosphine)-palladium (4.44 g, 3.84 mmol), and tributyl-(ethoxyvinyl)-tin (21.5 g, 57.8 mmol) in dioxane (125 mL) was heated to 140° C. for 19 h. The mixture was allowed to cool to r.t., and then water and EtOAc were added. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were dried (Na2SO4) and concentrated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (4:6) to give 4-(1-ethoxy-vinyl)-benzoic acid methyl ester (7.63 g, 30.4 mmol, 79%) as a brown solid. ES-MS: m/z 252 [M+H]+, rt 6.04 min
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][C:9]([CH2:18][NH2:19])([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].N=C=N.[Cl:23][C:24]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>ClCCl>[Cl:23][C:24]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:25]=1[C:26]([NH:19][CH2:18][C:9]1([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][O:14]2)[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:27]
Reactant: CCS(=O)(=O)N1CCC(CN)(CC2CCCO2)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Cl
Agent: N=C=N
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(C(F)(F)F)cc2Cl)(CC2CCCO2)CC1
Reaction time: 0.5 h

Procedure:
In a large glass container with a sealable lid was placed 1-[1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]methanamine (16, 3.4 g, 11.71 mmol), dichloromethane (50 ml) and PS-carbodiimide resin (35.1 mmol) along with 2-chloro-4-(trifluoromethyl)benzoic acid (3.41 g, 14.05 mmol). The lid was sealed and the bottle was shaken for 0.5 hours. The resin was filtered off and washed with EtOAc (3×25 ml) and the organics concentrated in vacuo to give an off-white solid. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 2-chloro-N-{[1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidin-4-yl]methyl}-4-(trifluoromethyl)benzamide (17) as a white solid. Calculated HRMS 497.1483 Found 497.1513. 1H NMR (300 MHz CDCl3): δ 7.70 (m, 2 H), 7.59 (d, J=7.8 Hz, 1 H), 3.86 (m, 3 H), 3.68 (q, J=5.7 Hz, 1 H), 3.57 (m, 2 H), 3.38 (m, 2 H), 3.16 (dt, J=10.2 Hz, 1 H), 2.99 (q, J=7.5 Hz, 2 H), 2.00 (m, 1 H), 1.85 (m, 2 H), 1.57 (m, 7 H), 1.38 (t, 7.8 Hz, 3 H.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[F:6][C:7]([F:17])([F:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.O.C(OCC)(=O)C>C1COCC1.C(OCC)C>[CH:1]1([CH:12]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([F:6])([F:16])[F:17])=[CH:15][CH:14]=2)[OH:13])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Br[Mg]C1CC1
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC(c1ccc(C(F)(F)F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 ml (17.2 mmol) of 0.5N cyclopropylmagnesium bromide solution in THF were added to 2.00 g (11.5 mmol) of 4-(trifluoromethyl)benzaldehyde in 44 ml of diethyl ether at 0° C., and the mixture was warmed to RT and stirred at RT overnight. The reaction mixture was added to water and ethyl acetate, the phases were separated, the aqueous phase was extracted twice with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 95/5) to result in 1.77 g (71% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.CC1(C)COB([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:3]1[C:2]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)=[CH:6][S:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1scc(Br)c1OC
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1scc(-c2ccnn2C)c1OC
Reaction time: 12 h
Yield: 852.2 %

Procedure:
Methyl 4-bromo-3-(methyloxy)-2-thiophenecarboxylate (250 mg, 0.10 mmol) [prepared according to Corral, C.; El-Ashmawy, M. B.; Lissavetzky, J.; Basilio, A.; Giraldez, A.; Eur. J. Med. Chem. Chim. Ther. 22; 1987; 251-254.], 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (250 mg, 1.20 mmol), Pd(PPh3)4 (58 mg, 49.8 μmol) and K2CO3 (550 mg, 3.98 mmol) in dioxane (5 mL) and H2O (1 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (215 mg, 86%) as a brown residue: LCMS (ES) m/z=253 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]=[CH:12][N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Br)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc(Br)s1
Yield: 49 %

Procedure:
Using analogous reaction conditions and workup as described in Example 1, step 1, 5-bromo-thiophene-2-carbaldehyde (5 g, 26.17 mmol) in ethanol (100 mL) was reacted with nitro methane (1.4 mL, 26.17 mmol) and 10N NaOH (1.4 mL, 27.47 mmol) to afford 3 g of the product (48.99% yield).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CO>[C:6]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 16.0 g (79.2 mmoles) of p-trimethylsilylethynylbenzaldehyde in 50 ml of methanol was treated with 1 gm of potassium carbonate and the mixture was stirred under argon at 25° C. for two hours. The solvent methanol was removed and 100 ml of methylene chloride was added. The mixture was washed with aqueous sodium bicarbonate solution. The organic phase was separated, dried over magnesium sulfate and concentrated to a solid mass. The crude yield of p-ethynylbenzaldehyde was 10.3 g (79.2 moles, 100%). Further purification was carried out by sublimation at 80°-90° C./0.025-0.25 mm Hg to give white crystals: mp 88°-90°; ir (KBr) 3240 (medium, sharp, C≡CO), 2860, 2740 (weak, sharp, O=CH), 2100 (weak, sharp, C≡C), 1690 (strong broad, C=O) and 1590 cm-1 (medium, sharp C=C); mass spectrum: m/e 130 (100%, M.+), 129 (90.7%, M.+ --H), 101 (59.0% M.+ --CHO); nmr (CDCl3): δ3.21 (s, 1H, C≡C--H), 7.62 (distorted q, 4H, aromatic) and 9.88 ppm (s, 1H, CHO).