Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si](C)(C)N[Si](C)(C)C.[Na].[NH2:22][C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][O:28][C:29]2=O)=[CH:25][CH:24]=1>C(COC)OC>[NH2:22][C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][O:28][C:29]2=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:25][CH:24]=1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: COCCOC
Product: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 38.9 %

Procedure:
To a solution of 5-chlorooxindole (0.629 g, 3.78 mmol) in 10.0 mL monoglyme was added 7.51 mL sodium hexamethyldisilazane (1.0 M in THF) over 3 min. After stirring at room temperature for 8 min, a slurry of 6-aminophthalide (0.561 g, 3.78 mmol) in 4.0 mL of monoglyme was added in one portion. The mixture was stirred for 40 min and then quenched into 100 mL of 4% aqueous HCl solution. The yellow solid was filtered and then partitioned between EtOAc and saturated NaHCO3 (heated to dissolve the solid). The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue was triturated with MeOH to give the title compound (439 mg, 39%) as a yellow solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][C:30]=1[O:37][CH3:38])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1.C1COCC1>[CH2:21]([O:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]([OH:34])[C:16]([CH3:20])([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]([OH:19])=[O:18])=[CH:31][C:30]=1[O:37][CH3:38])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1cc(C(O)C(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A stirred solution of LDA in cyclohexane (1.5 M) was cooled to −20° C., to which a solution of 2-phenoxypropionic acid (10 g, 60.2 mmol) in THF (80.3 mL) was slowly added, keeping the temperature below −10° C. The resulting dianion solution was stirred for 15 min, then a solution of 4-benzyloxy-3-methoxybenzaldehyde (14.58 g, 60.2 mmol) in THF (80.3 mL) was added over 1 h, maintaining temperature below −10° C. Fifteen minutes after completion of aldehyde addition, the reaction mixture was poured onto ice water (200 mL), and extracted using 1:2 Et2O:hexane (500 mL). The aqueous layer was isolated, extracted again with 1:2 Et2O:hexane (240 mL), then acidified with concentrated HCl until pH=3. The product acid was extracted into EtOAc (2×165 mL), which was dried over Na2SO4 and concentrated to an orange paste (16.5 g crude, 67%): MS (EI) 426.2 (M+NH4)+, 407.2 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:20])([C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15])[CH2:6][CH2:5]2.[O:22]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:22][C:7]([CH3:20])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:21])[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CCCNC(=O)C(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O

Procedure:
Oxidation as described in protocol B, using 90.6 mg (0.311 mmol) of 6-hydroxy-2,5,7,8-tetramethyl-N-propylchroman-2-carboxamide and 374.9 mg CAN (0.684 mmol) yielded 2-hydroxy-2-methyl-N-propyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow powder.
Reaction SMILES: [Na].[C:2](O)(=O)C.C[N:7]1[CH:13]2[CH2:14][C:15](=[N:17]O)[CH2:16][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12]2>>[CH3:2][NH:17][CH:15]1[CH2:14][CH:13]2[NH:7][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:16]1
Reactant: CN1C2CCCCC1CC(=NO)C2
Reactant: CC(=O)O
Agent: [Na]
Product: CNC1CC2CCCCC(C1)N2

Procedure:
15 g of sodium are reacted in analogous manner to that disclosed below in Example (j) with 9.69 g 10-methyl-10-azabicyclo-[4.3.1]decan-8-one oxime acetate [m.pt. 253°-253.5° C. prepared in analogous manner to that disclosed in Example A-1b] giving an oil bpt 105°/0.9, mm after working up in conventional manner.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[CH:4]=[N:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>CC1C=CC=CC=1C>[CH2:6]([N:5]1[CH:4]([C:3]2[C:2]([Cl:1])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:17])[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][C:18]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1cccc(Cl)c1C=NCc1ccccc1
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1C
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1c1c(Cl)cccc1Cl
Reaction time: 5 h

Procedure:
2,6-Dichlorobenzylidene-benzylamine [100 gm. 0.39 mole] and succinic anhydride [39.0 gm. 0.39 mole] were refluxed with O-xylene [500 ml] for 12 hours. On cooling, the precipitate was filtered and washed with a littleethanol. The solid was recrystallized from ethanol to give white needles. After drying over boiling isobutyl methyl ketone and under vacuum for 5 hours, the title compound had a melting point of 179°-181° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][OH:18])=[O:14].ClC(Cl)(Cl)C(=N)O[CH2:34][CH:35]=[CH2:36].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:13]([NH:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][O:18][CH:34]=[CH:35][CH3:36])=[O:14]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC=COC[C@H](NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dissolve N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-L-serine, methyl ester (25 g, 63 mmol) in methylene chloride/cyclohexane (1:1, 600 mL). Add allyl trichloroacetimidate (26 g, 128 mmol) and trifluoromethanesulfonic acid (5 mL), 56.6 mmol). Stir at room temperature under a nitrogen atmosphere for 5 hours and dilute with methylene chloride. Wash with saturated aqueous sodium hydrogen carbonate, water, dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography (gradient 20% ethyl acetate/hexane to 35% ethyl acetate/hexane) to give the title compound; mp 95°-97° C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:23][O:22][N:20]([CH3:21])[C:18]([CH:17]1[CH2:4][CH:16]1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1)=[O:19]
Reactant: CON(C)C(=O)C=Cc1ccc(F)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
NaH (8 g, 60% oil dispersion) was added to a suspension of trimethylsulfoxonium iodide (44 g) in DMF (150 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 0.5 h. A solution of 3-(4-fluoro-phenyl)-N-methoxy-N-methyl-acrylamide (20.4 g) was added to the above reaction mixture at 0° C., and the resulting reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo to give a residue. The residue was purified by flash chromatography over silica gel (elution with 50% hexanes in ethyl acetate) to give the title compound (15 g) as an oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15])[CH2:7][CH2:6]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1>C(Cl)(Cl)(Cl)Cl>[CH:8]1([CH2:11][CH2:12][CH2:13][C:14]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=2[O:25][CH3:26])=[O:15])[CH2:9][CH2:10][CH2:5][CH2:6][CH2:7]1
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)CCCC1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)CCCC2CCCCC2)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
3.53 g of AlCl3 and 5 g of 4-cyclohexanebutyryl chloride in 100 ml of CCl4 are mixed together and 5 g of 1,3-dimethoxybenzene are added dropwise, at 0° C. After stirring for 3 hours at 0° C., the entire mixture is poured onto dilute ice-cold HCl solution. The organic phase is separated out by settling and is then washed with 0.5N NaOH. After drying over MgSO4 and evaporation of the solvent, the residue is chromatographed on a column of silica H, eluting with toluene, to give 4.5 g of the expected compound in the form of an oil.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:21][C:22]1([CH2:28][C:29]([NH2:31])=[O:30])[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>>[NH2:31][C:29](=[O:30])[CH2:28][C:22]1([NH:21][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])[CH2:23][S:24](=[O:26])(=[O:27])[CH2:25]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2(F)CCC2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3(F)CCC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (example 285a) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (16 mg, 21%); MS (ESI, m/z): 454.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4c(Cl)cccc4Cl)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,6-dichlorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 587.1 ([M+H]+)
Reaction SMILES: C([O:4][C@H:5]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7])(=O)C.[H][H]>C(O)(=O)C.[Pd]>[OH:4][C@H:5]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)O[C@H](CC(=O)c1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)[C@H](O)CCc1ccccc1

Procedure:
(R)-2-acetoxy-4-oxo-4-phenylbutyric acid (2.36 g) was dissolved in 15 ml of acetic acid, and 0.21 g of 5% by weight palladium on carbon (water content 50%) were added thereto. The mixture was stirred in a hydrogen atmosphere at 60° C. for 24 hours. Palladium on carbon was separated by filtration, and the solvent was then distilled off. Thirty milliliters of 1−N hydrochloric acid were added to the resulting (R)-2-acetoxy-4-phenylbutyric acid, and the mixture was heat-refluxed for 3 hours while being stirred.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][CH2:2][CH3:3])[CH:31]=[C:30]([F:37])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC)c4)cc23)CC1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Product: CCCNCc1cc(F)cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 72 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting propylamine (21 mg, 0.42 mmol) for methanamine to afford 31 mg of the title compound (72%).
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1.[S:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=O)=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[O:20][CH2:31][C:30]2[CH:34]=[CH:35][C:27]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:28][CH:29]=2)[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH3:21])=[CH:8][C:7](=[O:22])[CH2:6][CH2:5]1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OCc3ccc(S(N)(=O)=O)cc3)[C@@]1(C)C[C@@H]2F
Reaction time: 8.5 h
Yield: 38.9 %

Procedure:
A solution of 500 mg of 11β-fluoro-17β-hydroxy-7α-methylestr-4-en-3-one in 7.5 ml of pyridine was mixed at room temperature with 750 mg of 4-sulfamoylbenzoic acid, 800 mg of N,N-dicyclohexylcarbodiimide as well as 125 mg of p-toluenesulfonic acid and stirred for 8.5 hours. Then, it was added to sodium bicarbonate solution, extracted four times with dichloromethane, washed neutral, dried on sodium sulfate, concentrated by evaporation in a vacuum, and chromatographed on silica gel with dichloromethane/acetone. 302 mg of 11β-fluoro-17β-(4-sulfamoylbenzoxy)-7α-methylestr-4-en-3-one with a melting point of 232° C. was obtained. [α]D=+100.5° (CHCl3).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:29]C)=[C:10]([CH:28]=1)[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])(=[O:5])CCC.N1C(C)=CC(C)=[CH:33][C:32]=1[CH3:39].[I-].[Li+].Cl>>[F:22][C:20]([F:23])([F:21])[C:18]1[CH:19]=[C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:28]=[C:6]([C:1](=[O:5])[CH:32]([CH3:39])[CH3:33])[CH:7]=[CH:8][C:9]=2[OH:29])[CH:15]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:17]=1
Reactant: CCCC(=O)c1ccc(OC)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: Cc1cc(C)nc(C)c1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Product: CC(C)C(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 65.3 %

Procedure:
A mixture of 5-butyryl-N-[3,5-bis(trifluoromethyl)phenyl]-2-methoxy-benzamide (143.4 mg, 0.33 mmol), 2,4,6-collidine (3 ml) and lithium iodide (53.1 mg, 0.40 mmol) was refluxed for 1 hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) and crystallized (ethyl acetate/isopropyl ether) to give the title compound (90.3 mg, 65.3%) as a white crystal.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH:3]([CH3:4])[CH2:2]1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[Cl:15])[NH2:11]>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[Cl:15])[NH:11][CH:3]([CH3:4])[CH2:2][C:1]([OH:5])=[O:6]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CC1CC(=O)O1
Solvent: CCOCC
Product: CC(CC(=O)O)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
86 g (1.00 mole) of β-butyrolactone was added to 162 g (1.00 mole) of 3,4-dichloroaniline, and this mixture was stirred at 110°-120° C. for 1 hour and then allowed to cool to room temperature. To the resulting reaction solution was added 1000 ml of ether. This mixture was filtered to remove any insoluble matter, and the filtrate thus obtained was extracted with 750 ml of a 2N aqueous solution of sodium hydroxide. This extract was acidified with 130 ml of concentrated hydrochloric acid and then extracted with 1000 ml of ether. The ether layer was separated, dried over anhydrous sodium sulfate and then evaporated to dryness. Thus, there was obtained 128 g (51.6% yield) of 3-(3,4-dichloroanilino) butyric acid in the form of pale-yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(C)CCOc1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Reaction time: 0.5 h

Procedure:
2-Chloro-5-{hydroxy-[4-(3-methyl-butoxy)-phenyl]-methyl}-benzenesulfonamide is dissolved in acetone (10 mL), and treated with a solution of Jones reagent (3 M in water, 0.91 mmol). The reaction is allowed to stir for 30 minutes. The reaction is diluted with water and extracted with dichloromethane. The organic phase is separated and concentrated in vacuo. The residue is purified by silica gel chromatography (gradient of ethyl acetate in hexanes 25-75%) followed by recrystallization from ether affording 25 mg of the title compound. 1H NMR (DMSO) 0.93 (s, 3H), 0.95 (s, 3H), 1.64-1.82 (m, 3H), 4.13 (t, 2H, J=6.41 Hz), 7.12 (d, 2H, J=8.67 Hz), 7.75-7.91 (m, 4H), 8.24 (d, 1H, J=1.89). MS (m/z): 380 (M−1). CHN Calc C, 56.62; H, 5.28; N, 3.67. Found C, 56.54; H, 5.04; N, 3.73.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)=[O:4].CC#N.[OH2:19]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([Cl:15])[CH:9]=[CH:8][C:7]=2[C:6]1=[O:19])=[O:4]
Reactant: O
Reactant: COC(=O)N1CCc2nc(Cl)ccc2C1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)N1CCc2nc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-Chloro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid methyl ester (226.7 mg, 1 mmol) was dissolved in CCl4 (3.57 mL) and MeCN (0.357 mL) at room temperature before adding NaIO4 (0.643 g) in 1 mL of H2O, followed by RuCl3.hydrate (62.2 mg). The reaction mixture was stirred vigorously at room temperature for 2 hours. After dilution with DCM, it was filtered through Celite and the filter cake was washed three times with DCM. The combined organic solution was concentrated in vacuo to give a crude product. Flash column chromatography separation (silica gel, 12 g, 20% EtOAc in hexane) then afforded the tile compound (143 mg, 60%) as a white solid. MS: 241.1 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6](O)[CH2:7][CH2:8][CH3:9]>>[Cl:1][CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCO
Reactant: O=C(O)CCl
Product: CCCCOC(=O)CCl

Procedure:
Following the procedure described in Examples 1 and 2, but heating while stirring for 4 hours to 105° a mixture comprising of 181 parts of butanol and 189 parts of chloroacetic acid, there is obtained butyl chloroacetate; nD20 =1,428.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[CH2:14]([O:16][C:17](=[O:22])[CH2:18][C:19](=[NH:21])[NH2:20])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:18]1[CH:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=2)[CH:8]=[C:9]([CH3:10])[NH:21][C:19]=1[NH2:20])=[O:22])[CH3:15]
Reactant: COc1ccc(C=CC(C)=O)cc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(C)=CC1c1ccc(OC)cc1
Yield: 52 %

Procedure:
Heating a solution of 17.5 g of 4-methoxybenzylideneacetone and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours yields 2-amino-6-methyl-4-(4-methoxyphenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 160°-161°C (ethanol). Yield: 52 percent theory.
Reaction SMILES: [Br-].[N+:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[H-].[Na+].[CH2:33]([O:40][C:41]1[C:48]([C:49]2[C:50]([O:55][CH3:56])=[N:51][CH:52]=[CH:53][CH:54]=2)=[CH:47][C:46]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:45][C:42]=1[CH:43]=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([O:40][C:41]1[C:42]([CH:43]=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:30][CH:29]=2)=[CH:45][C:46]([C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:47][C:48]=1[C:49]1[C:50]([O:55][CH3:56])=[N:51][CH:52]=[CH:53][CH:54]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ncccc1-c1cc(C(C)(C)C)cc(C=O)c1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1cc(C(C)(C)C)cc(C=Cc2ccc([N+](=O)[O-])cc2)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
step 3—To a solution of 4-nitro-benzyltriphenylphosphonium bromide (1.07 g, 2.238 mmol) in DMF (8 mL) at 0° C., was added NaH (60% in oil dispersion, 156 mg, 3.90 mmol). The reaction was stirred for 30 min at 0° C. then a solution of 50 (281 mg, 0.749 mmol) in DMF (6 mL) was added. The resulting mixture was gradually warmed to RT and stirred overnight. The reaction was quenched with 1N aqueous HCl solution (6 mL) and diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (5 to 10% EtOAc) to afford 311 mg (84%) of 3-{2-benzyloxy-5-tert-butyl-3-[2-(4-nitro-phenyl)-vinyl]-phenyl}-2-methoxy-pyridine (52) as a yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(N(CC)CC)C.[CH:19]#[C:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1COCC1.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:19]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])#[C:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CCCCC
Reactant: COc1ccc(C=O)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC#Cc1cc(C=O)ccc1OC
Yield: 94.8 %

Procedure:
A mixture of 3-iodo-4-methoxybenzaldehyde (5.2 g, 20 mmol), tetrakis(triphenylphosphine)palladium (0.29 g), Cul (0.38 g, 2 mmol) and triethylamine (5 ml) in THF (25 ml) is cooled to +10° C., and 1-hexyne (3.5 ml, 30.5 mmol) is then added. The cooling bath is removed, and the temperature of the reaction mixture rises slowly to +30° C. before decreasing slowly. 3 hours after the end of the addition, the crude reaction product is concentrated to dryness, and the residue obtained is purified by flash chromatography on silica (15/85 ethyl acetate/heptane). 4.1 g (yield: 95%) of the expected product are obtained.