Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH2:25]([NH:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[C:33]([F:46])[CH:32]=1)=[O:29])[CH3:26].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.O.COCCOC>[CH2:25]([NH:27][C:28](=[O:29])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[C:5]3[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:33]([F:46])[CH:32]=1)[CH3:26]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Reactant: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OC(C)(C)C)C3)c(F)c1
Reaction time: 0.25 h
Yield: 11.9 %

Procedure:
A solution of (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 1) (214 mg, 0.603 mmol), 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28) (211 mg, 0.685 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (25 mg, 0.0306 mmol) and sodium carbonate (179 mg, 1.69 mmol) in 2 ml of a 7:3:1 mixture of DME:H2O:EtOH respectively was heated in the microwave at 115° C. for 45 minutes then at 130° C. for 15 minutes. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in a mix of H2O and EtOAc. The aqueous phase was basified by the addition of aqueous NaOH and extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was purified via preparative HPLC at low pH to yield the title compound (36 mg, 13%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Cl>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: ClCc1ccccn1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2ccccn2)c(=O)[nH]c1=O
Yield: 26.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (98 mg, yield: 26.7%).
Reaction SMILES: [C:1]1([C:7]2NN=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]([Cl:34])([Cl:33])[C:14]1[N:19]=[C:18]([C:20]([Cl:23])([Cl:22])[Cl:21])[N:17]=[C:16]([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[N:15]=1>N1C=CC=CC=1>[Cl:23][C:20]([Cl:21])([Cl:22])[C:18]1[N:19]=[C:14]([C:13]([Cl:34])([Cl:12])[Cl:33])[N:15]=[C:16]([C:24]2[CH:25]=[CH:26][C:27]([C:28]3[O:29][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8][N:9]=3)=[CH:31][CH:32]=2)[N:17]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Solvent: c1ccncc1
Product: ClC(Cl)(Cl)c1nc(-c2ccc(-c3nnc(-c4ccccc4)o3)cc2)nc(C(Cl)(Cl)Cl)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Phenyltetrazole (5 pbw) and 4-(4,6-bis-trichloromethyl-s-triazin-2-yl)benzoyl chloride (15.5 pbw) are dissolved in 125 pbv of pyridine and slowly heated to reflux. At about 80° C. nitrogen evolution commences, which comes to an end after about 1 hour. After cooling, the mixture is poured into 500 pbv of ice water, the precipitate that deposits is removed by filtration and is, after drying, recrystallized from 2-methoxy-ethanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=2)([CH3:2])[CH3:3])=[CH:10][CH:9]=1
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: ClCCl
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
1.7 Kilograms of an 8-mass % solution of p-t-butylphenol in methylene chloride were added to the resultant. Next, an alkali aqueous solution of bisphenol A (BPA) (obtained by dissolving 1.14 kg of BPA in 8.98 kg of a 6.4-mass % aqueous sodium hydroxide) was added to the resultant, and then the mixture was stirred at 240 rpm for 55 minutes.
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([OH:40])=O)[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:93][C:94]1([CH2:97][OH:98])[CH2:96][CH2:95]1>C(Cl)Cl>[C:1]([NH:14][C@H:15]([CH2:41][O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:38]([NH:93][C:94]1([CH2:97][OH:98])[CH2:96][CH2:95]1)=[O:40])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NC1(CO)CC1
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-dodecanamido-1-(9H-fluoren-9-yl)-3-oxo-2,11-dioxa-7-thia-4-azaheptacosane-5-carboxylic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (1-aminocyclopropyl) methanol hydrochloride (1.2 eq). The reaction was stirred at room temperature for 2 hr. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-50% EtOAc/Hex to give (9H-fluoren-9-yl)methyl (R)-3-((R)-2-dodecanamido-3-(hexadecyloxy)propylthio)-1-(1-(hydroxymethyl)cyclopropylamino)-1-oxopropan-2-ylcarbamate.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH:26]3[CH2:28][CH2:27]3)(=[O:24])=[O:23])[CH:16]=2)[CH2:11][CH2:10][CH:9]1[NH:29][C:30](=O)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].CC(O)C.[ClH:47]>C1COCC1.C(Cl)Cl>[ClH:47].[CH2:1]([CH:8]1[C:17]2[CH:16]=[C:15]([O:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH:26]3[CH2:28][CH2:27]3)(=[O:24])=[O:23])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH:9]1[NH:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC1CCc2ccc(OCCNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Reaction time: 8 h

Procedure:
The synthesis was performed starting from ethyl 1-benzyl-7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (synthesized in analogy to example 3), which was dissolved in THF (50 ml), after which LiAlH4 was added at room temperature and the mixture was stirred for 8 h under reflux. Addition of 2N aqueous NaOH, extraction with CH2Cl2, washing of the organic layers with saturated NaHCO3 solution and saturated NaCl solution and evaporation of the solvent gave a residue that was treated with iPrOH/HCl after which the product precipitated. After filtration a white salt (287 mg, 58%) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH3:12][C:13]([CH:15]=[CH2:16])=O>O.O.O.O.O.O.[Fe](Cl)(Cl)Cl.C(O)(=O)C>[CH3:11][O:10][C:9]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:6]=[CH:12][CH:13]=[C:15]2[CH3:16]
Reactant: COc1ccc(N)cc1OC
Reactant: C=CC(C)=O
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2nccc(C)c2cc1OC
Temperature: 60 °C
Yield: 38 %

Procedure:
The Reference Compound No. 1-1 was prepared following the method described in J. Org. Chem., 62, 568-577 (1997). Namely, iron (III) chloride hexahydrate (5.7 g, 21 mmol) and 3,4-dimethoxyaniline (3.1 g, 20 mmol) were added to acetic acid (60 mL), and then the mixture was stirred at 60° C. After all the solids were dissolved, methylvinylketone (1.8 mL, 22 mmol) was added dropwise for 5 minutes. Then the mixture was stirred at 140° C. for 1 hour, and allowed to cool down to room temperature, and the resulting solid was filtered off. Ethyl acetate (200 mL) was added to the solid, and the resulting organic solution was washed with 0.1N sodium hydroxide aqueous solution (200 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with diethyl ether to give 1.6 g of the title reference compound as a light brown solid (Yield: 38%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:33])[C:5]([C:34](O)=[O:35])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:33])[C:5]([CH2:34][OH:35])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Agent: CC(C)COC(=O)Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCn1cc(CO)c(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a suspension of 1-ethyl-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (22 g, 44.9 mmol) in Tetrahydrofuran (THF) (300 mL) was added TEA (6.89 mL, 49.4 mmol) and isobutyl chloroformate (6.49 mL, 49.4 mmol). The resulting mixture was stirred at r.t. for 1 h. Then the mixture was cooled down to −78° C. and a solution of DIBAL-H (90 mL, 135 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 1.5 h, LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), and subsequently warmed up to r.t. concentrated, diluted with sat. NH4Cl and extracted with dichloromethane twice. The organic phase was filtered through Celite to remove gummy precipitate, and was then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford 1-ethyl-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (20 g, 23.55 mmol, 52.4% yield) as yellow solid, which was used in the next oxidation step without further purification. LCMS: (M+H)+: 476.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)NC(C)Cc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC(C)Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
2.20 g (6.14 mmol) 4-[4-(2-Acetylamino-propyl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (VI.1) in 100 mL methanol are hydrogenated (50 psi) for 7.0 h at rt using 250 mg palladium on charcoal(10%). After that time, the catalyst is filtered off and the solvent is evaporated to yield the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CCC(C)C)CCCC1=O
Yield: 72.6 %

Procedure:
Under vigorous agitation, 34.67 g (purity of 90%) of ethyl 2-oxocyclopentane carboxylate was added to 112.65 g (purity of 98%,) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 51.36 ml (purity of 98%) of 1-bromo-iso-pentane. Upon the completion of the addition, the reaction mixture was heated for reflux for 6 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 32.80 g of colorless liquid as a distillate cut of 142-147° C./15 mmHg was collected. Yield: 72.60%. MS: m/e 227(M30 +1), 226(M+), 211 (M+—CH3) 198(M+—CH2CH2) 171 (M+—OCH2CH3), 156 (M+—C5H11, base), 153(M+—CO2 CH2CH3), 127(155-CH2CH2), 111(156-OCH2CH3), 55.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:25][CH:24]=2)=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:36].ClN1C(=O)CCC1=O>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[CH:27][CH:28]=2)=[C:16]([Cl:36])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCOc1ccc(C(=Cc2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Reactant: ClC(Cl)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: ClCCCCOc1ccc(C(=C(Cl)c2ccccc2)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 18 h

Procedure:
Combine 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy) phenyl)-2-phenyl ethylene (3.5 g, 7.5 mmol) and chloroform 935 mL). Add N-chlorosuccinimide (1.99 g, 14.9 mmol). Heat a t reflux. After 18 hours, cool the reaction mixture and extract with water, aqueous saturated sodium bicarbonate solution and water. Dry the organic layer over MgSO4, filter, and dry in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% ethyl acetate/hexane to give 1-(4-benzyloxyphenyl)-1-(4-(4-chlorobutyloxy)phenyl)-2-chloro-2-phenyl ethylene.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[I:10]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCOCC1.CN1CCCC1=O>[I:10][C:7]1[CH:6]=[C:5]([CH3:9])[C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1
Reactant: II
Reactant: Cc1cccc(C)c1N
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1cc(I)cc(C)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2,6-dimethyl aniline (50 gm) in 1,4-dioxane (400 ml) and N-methylpyrrolidone (40 ml) was added iodine (157.3 gm) slowly at 0° C. The solution was stirred for 1 hour at 0° C. and the temperature was raised to room temperature. The solution was stirred for 1 hour at room temperature and then added a saturated solution of sodium thiosulfate. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried with anhydrous sodium sulfate and the solvent was evaporated in vacuum to obtain 91 gm of 4-iodo-2,6-dimethyl benzenamine.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4 mL of ethyl acetate was added to 678 mg (2.07 mmol) of tert-butyl [4-(adamantan-1-yl)phenyl]carbamate, and then 4 mL of 4N hydrogen chloride/ethyl acetate was added at 0° C. The mixture was stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue. The resultant was washed with an aqueous sodium hydrogen carbonate solution and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, thereby quantitatively giving 4-(adamantan-1-yl)aniline.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][CH2:19][CH:18]([OH:25])[CH2:17]2)=[C:12]([OH:26])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][CH2:19][C:18](=[O:25])[CH2:17]2)=[C:12]([OH:26])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CCC1CCC(O)CC1c1ccc(C(C)(C)CCCCCC)cc1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.3 %

Procedure:
To a solution of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-4-(2-propenyl)cyclohexanol (2.15 g, 6.03 mmole) (mixture of isomers) in dichloromethane (15 ml) was added pyridinium chlorochromate (2.59 g, 12.1 mmole). The reaction mixture was stirred for 2 hours at room temperature, diluted with ether, diatomaceous earth added and the mixture filtered through magnesium sulfate. The evaporated filtrate was purified via column chromatography on 200 g of silica gel eluted with 20% ether-pentane to yield 250 mg of crude title compound. This was further purified via preparative layer chromatography on two 20 cm×20 cm×2 mm silica gel plates eluted twice with 20% ether-pentane to yield 200 mg (9.3%) of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]([CH3:15])=[C:8]2[C:4]=1[C:5]1[CH2:19][CH2:18][O:17][C:16]([CH2:23][C:24]([O:26]CC)=[O:25])([CH2:20][CH2:21][CH3:22])[C:6]=1[NH:7]2)#[N:2].[OH-].[Na+].Cl>CCO>[C:24]([CH2:23][C:16]1([CH2:20][CH2:21][CH3:22])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:19][CH2:18][O:17]1)=[C:3]([C:1]#[N:2])[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]=3[CH3:15])([OH:26])=[O:25]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)O)cc(C#N)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC1(CC(=O)O)OCCc2c1[nH]c1c(C)c(C(=O)O)cc(C#N)c21
Reaction time: 18 h
Yield: 98.4 %

Procedure:
To a solution of 5-Cyano-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid (27.9 mg, 0.073 mmol) in EtOH (2 mL) was added 10% NaOH (200 μL). The solution was stirred for 18 hours, acidified with 3% HCl, and extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to afford 25.6 mg (99%) of the title compound as an off-white solid. 1H NMR (d6-DMSO) δ 11.42 (br s,1 H), 7.93 (s, 1H), 3.97 (m, 2H), 3.00 (d, J=13.8 Hz, 1H), 2.88 (m, 2H), 2.81 (s, 3H), 2.76 (d, J=13.8 Hz, 1H), 2.04 (m, 2H), 1.30 (m,1H), 0.80 (m, 4H). ESI MS m/z 355 (M−H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[Br:25][C:26]1[CH:31]=[C:30](Br)[CH:29]=[C:28]([F:33])[C:27]=1[Cl:34].[OH-].[Na+].O>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>[CH2:1]([O:8][C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:30]1[CH:29]=[C:28]([F:33])[C:27]([Cl:34])=[C:26]([Br:25])[CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCNC(=O)OCc1ccccc1
Reactant: Fc1cc(Br)cc(Br)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCCCCc1cc(F)c(Cl)c(Br)c1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
A solution of but-3-enyl-carbamic acid benzyl ester (5.00 g, 24.36 mmol, 1 eq) in anhydrous toluene (60 mL) was cooled under argon to 0-5° C. 9-BBN (0.50 M, solution in THF; 54.6 mL, 26.80 mmol, 1.1 eq.) was added dropwise, and the mixture was allowed to reach room temperature. After 24 h, the resulting solution was added dropwise at room temperature to a mixture of 2a (7.03 g, 24.36 mmol, 1 eq.), 1N NaOH/H2O (40 mL, 40 mmol, 1.6 eq.), and toluene (20 mL). The mixture was then degassed with argon and Pd(PPh3)4 (1.13 g, 0.98 mmol, 0.04 eq.) was added. The mixture was rapidly stirred under argon at 60° C. for 24 h, before cooling to room temperature. The mixture was partitioned between EtOAc (150 mL) and brine (150 mL). The organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (0-50% EtOAc in Heptane) to afford 3a as a colorless oil (3.54 g, 35%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[Na+].[Na+].[O:13]=[CH:14][CH2:15][CH2:16][C:17](OCC)=O>O>[CH2:16]1[CH:17]2[NH:6][C:4]([CH2:3][N:2]2[C:14](=[O:13])[CH2:15]1)=[O:5]
Reactant: CCOC(=O)CCC=O
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CN2C(=O)CCC2N1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
A solution of 2.56 g (22.7 mmol) of glycinamide hydrochloride (purity 98%) in 200 ml of water is heated to 95° C. and the pH adjusted to 6.6 with Na2CO3 20% w/v in water. Then ethyl 4-oxobutanoate (purity 97%) (7.60 g, 56.6 mmol) are added dropwise during four hours maintaining the temperature at 95° C. and the pH at 6.6 by automated addition (pHstat) of Na2CO3 20% w/v in water. The solution is stirred at 95° C. for 1.5 hours and then concentrated to a small volume under vacuum. The obtained suspension is treated with 50 ml of isopropanol and the solvent is evaporated at atmospheric pressure. This operation is repeated once again. The residue is diluted with 50 ml of isopropanol and the resulting suspension heated to 60° C. and then filtered. The filtrate is concentrated to about 15 ml, cooled to room temperature and stirring continued for about 2 hours. The white precipitate is collected by suction filtration, washed with 4 ml of isopropanol and dried under vacuum at 60° C. for 12 hours, resulting in 1.8 g of crude dimiracetam (12.8 mmol, 55.5%). Recrystallization from isopropanol (10 volumes) affords 1.6 g (50%) of pure dimiracetam (>99.5% as determined from area % HPLC). Melting point: 154° C.