Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C[Mg]Cl.[Cl:14][C:15]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:16]=1C(Cl)=O>O1CCCC1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([C:16]1[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:15]=1[Cl:14])=[O:5])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Cl
Agent: C[Mg]Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A 400 liter glass-lined reactor was charged with 129 liters of dry tetrahydrofuran and 21.7 kg (2.1 equivalents) of potassium ethyl malonate. With slight cooling, 42.4 liters of 3M methyl magnesium chloride was added at a rate to keep the temperature between 20° to 50° C. After a 30 minute stir, the solution was cooled to 0° to -5° C. and 12.8 kg of 2-chloro-4,5-difluorobenzoyl chloride was added at a rate to keep the temperature between 0° and 5° C. The solution was then quenched into 106 liters of 2N HCl. After the addition of 72 liters of toluene, the aqueous layer was removed. The product layer was washed with 53 liters of saturated bicarbonate and salt solution. After removal of the aqueous layer, the product layer was concentrated to an oil and 28 liters of isopropyl alcohol were added. The solution was cooled to -10° to -15° C., granulated and the solids filtered and vacuum dried to give 14.17 Kg (first crop) and 588 g (second crop) of the title compound, 92.8% yield. The high field NMR of the product was typical of that for a mixture of the keto (5%) and enol (95%) forms of the title compound 300 MHz 1H (CDCl3): 12.5 (s, 0.95H), 7.5 (d of d, J=11 Hz, J'=8 Hz, 1H) 7.3 (d of d, J=11 Hz, J'=8 Hz, 1H), 5.6 (s, 0.95H), 4.3 (q, J=6H, 1.9H), 4.2 (q, J=6 Hz, 0.1H), 4.0 (s, 0.1H), 1.4 (t, J=6 Hz,2.85H), 1.2 (t, J=6 Hz, 0.15H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[O:10][C:9](S)=[CH:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:11]2[O:10][C:9]([N:31]3[CH2:32][CH2:33][N:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH2:29][CH2:30]3)=[CH:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1c(OCc2ccccc2)ccc2c(=O)cc(S)oc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1c(OCc2ccccc2)ccc2c(=O)cc(N3CCN(c4ccccn4)CC3)oc12
Yield: 84.5 %

Procedure:
Part B: 8-Methyl-7-(phenylmethoxy)-2-mercapto-4H-1-benzopyran-4-one (2.0 g, 6.7 mmol), 1-(2-pyridyl)piperazine (1.19 g, 7.3 mmol) and TsOH (25 mg) is added to toluene and heated at reflux for 20 hours. The reaction temperature is lowered to room temperature and the toluene removed in vacuo. The resulting dark oil is diluted with EtOAc and the resulting crystals collected on a filter to afford 2.42 g of product. MP 148°-9° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH:3]=1.[C:22]([NH:25][NH2:26])(=[O:24])[CH3:23].C(N(CC)CC)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:22]([NH:25][NH:26][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)=[CH:21][CH:20]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)NN
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(=O)O)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc(Cl)cc(NCCc2ccc(C(=O)NNC(C)=O)cc2)n1
Reaction time: 15 h
Yield: 55.2 %

Procedure:
To a solution of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid (0.41 g, 1.33 mmol), acetic acid hydrazide (0.1 g, 2 mmol), and triethylamine (0.7 mL, 3.99 mmol) in DMF (3 mL) is added [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoro borate (0.51 g, 1.6 mmol) at room temperature. After 15 h at 20° C., the solid is filtered, and washed with water to afford 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N′-acetyl-hydrazide (267 mg). The filtrate is extracted with EtOAc, and concentrated to afford additional amount of 4-[2-(6-chloro-2-methoxy-pyrimidin-4-ylamino)-ethyl]-benzoic acid N′-acetyl-hydrazide (100 mg). LCMS: RT=2 minutes; MS: 364 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.ClCl.BrBr>C(Cl)CCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH:8]=1
Reactant: COc1ccc(NC(N)=S)cc1
Agent: BrBr
Agent: ClCl
Solvent: ClCCCl
Product: COc1ccc2nc(N)sc2c1
Temperature: 40 °C

Procedure:
182 parts of p-methoxyphenyl-thiourea are suspended in ethylene chloride, and dehydrated, as described in Example 1. 35.5 parts of chlorine gas are then passed in over 1 hour at 20° C., but without addition of bromine. After stirring for a further hour, 6 parts of bromine are added, the mixture is heated to 40° C., and a further 35.5 parts of chlorine gas are introduced at this temperature over one hour. The reaction product is isolated as described in Example 1. 168 parts of 6-methoxy-2-amino-benzothiazole of melting point 160°-163° C. are thus obtained, corresponding to 93% of theory.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H][H]>O1CCCC1.[Pt]>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccc(F)cc2)cc1
Yield: 98.7 %

Procedure:
To a solution of 56.6 gm (0.217 mole) 4-(4-fluorobenz-oyl)aminonitrobenzene in 875 mL tetrahydrofuran were added 5.7 gm 5% platinum on carbon. The reaction mixture was hydrogenated at room temperature for 18 hours at initial hydrogen pressure of 60 p.s.i. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure to give 49.3 gm (98.5%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[ClH:19]>C(O)C.[Pd]>[ClH:19].[NH2:15][C:11]1[C:10]([CH3:18])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)Oc1cccc([N+](=O)[O-])c1C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)(C)Oc1cccc(N)c1C
Reaction time: 3 h

Procedure:
1.33 g (5.25 mmol) of methyl 2-methyl-2-(2-methyl-3-nitrophenoxy)propanoate were dissolved in 60 ml of ethanol, and 1 ml of concentrated hydrochloric acid and 0.30 g of palladium on carbon (10%) were added. Under an atmosphere of hydrogen, the mixture was hydrogenated at atmospheric pressure and room temperature for 3 h. The reaction mixture was then filtered through Tonsil. The filter residue was washed with ethanol and the collected filtrates were concentrated under reduced pressure. This gave 1.39 g (89% of theory) of the target compound.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.COC(C1C=CC2SCC(=O)NC=2C=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CCOCC.O>[S:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[O:12])=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1
Reactant: OCc1ccc2c(c1)NCCS2
Agent: COC(=O)c1ccc2c(c1)NC(=O)CS2
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)NCCS2
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
(3,4-Dihydro-2H-benzo[1,4]thiazin-6-yl)-methanol. To a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (750 mg, 3.4 mmol) in Et2O (32 mL) was added LiAlH4 (240 mg, 6.3 mmol) and the resulting suspension was stirred at RT for 24 h. The reaction mixture was cooled to 0° C. and treated with H2O (0.5 mL), 15% aq. NaOH (0.5 mL), and H2O (1.5 mL). The resulting suspension was filtered. The filtrate was concentrated to provide 340 mg (58%) of the title compound as an amber oil. MS (ESI): exact mass calculated for C9H11NOS, 181.06; m/z found, 182.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 6.96 (d, J=7.9, 1H), 6.60 (dd, J=7.9, 1.6, 1H), 6.49 (d, J=7.9, 1H), 4.52 (s, 2H), 3.65-3.62 (m, 2H), 3.06-3.04 (m, 2H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].C[N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.N.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]([NH:4][C:5]1[C:10]([C:11]([NH2:17])=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CSc1ncc(C(=O)O)c(NC(C)C)n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(N)=O)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
4-(Isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (8.38 g, 36.9 mmol) and HATU (21.03 g, 55.3 mmol) were combined in a 250 mL round-bottomed flask followed by the addition of DMF (92 mL). After that ammonia hydrochloride (9.86 g, 184 mmol) and DIEA (32 mL, 184 mmol) were added and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and water (150 mL) was added. The resulting suspension was filtered, washed with water and dried under high vacuum overnight to afford 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxamide (8 g, 35.4 mmol, 96% yield); MS (ESI) m/z 227.4 [M+1]+.
Reaction SMILES: [O:1]=[P:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.O1CCOCC1>Cl>[O:1]=[P:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]2[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)c1ccc(CCN2CCP(=O)(c3ccccc3)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(CCN2CCP(=O)(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-[2-(4-oxido-4-phenyl-1,4-azaphosphinan-1-yl)ethyl]benzoate (215 mg, 0.538 mmol) was taken up in 4.0 M HCl in 1,4-dioxane (8.0 mL, 32.0 mmol) and stirred at room temperature overnight. The white slurry was concentrated to dryness, resuspended in MeOH, and concentrated again to afford the title compound as a colorless solid. MS: cal'd 344 (MH+), exp 344 (MH+).
Reaction SMILES: [ClH:1].[F:2][C:3]([F:19])([F:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1>O1CCOCC1>[ClH:1].[ClH:1].[F:19][C:3]([F:2])([F:18])[CH2:4][N:5]1[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)CN1CCNCC1
Yield: 95 %

Procedure:
A solution of hydrochloric acid (4.0 M, 10 mL) in dioxane was added to a solution of tert-butyl 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate (0.736 g, 2.74 mmol) in dioxane (5 mL). The reaction mixture was stirred until analysis by thin layer chromatography indicated completion of reaction (approx. 3 h). The volatiles were evaporated and the residue was dried under vacuum to yield 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride (0.631 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH2:11][CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1.[Ru]>[CH:5]1([CH2:4][CH2:3][C:2]([CH3:1])([OH:13])[CH2:11][CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCC(C)(O)CCc1ccccc1
Agent: [Ru]
Solvent: C1CCOC1
Product: CCC(C)(O)CCC1CCCCC1
Reaction time: 10 h

Procedure:
A 300 ml autoclave was initially charged with 5.6 g of 3-methyl-1-phenyl-3-pentanol, dissolved in 94.4 g of tetrahydrofuran, and 1.6 g of a catalyst prepared according to Example 1 (0.35% ruthenium on silicon dioxide). The autoclave was flushed three times with nitrogen and then hydrogenated for 10 hours at 160° C. and a hydrogen pressure of 160 bar. The product was analyzed by gas chromatography (polydimethylsiloxane DB1, 30 m, internal diameter: 0.25 mm, film thickness: 0.25 μm, 50° C., 5 min isotherm, −6° C./min, 290° C., 219 min isotherm). The conversion was 99.9%, the selectivity 93%.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:18])[CH2:14][CH2:15][CH2:16]O>C([O-])(=O)C.[Li+]>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:16][CH2:15][CH2:14][CH2:13][OH:18])=[O:11])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: OCCCCO
Agent: CC(=O)[O-]
Agent: [Li+]
Product: O=C(OCCCCO)c1ccc(C(=O)OCCCCO)cc1

Procedure:
An autoclave equipped with a stirrer and distillation outlet was charged with 166 g (1.00 mole) of terephthalic acid, 180 g (2.00 moles) of 1,4-butanediol, and a small amount of lithium acetate as a catalyst. After the autoclave was provided with nitrogen at 3 kg/cm2, the mixture was reacted at 260° C. for 3 hours to obtain BHBT.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[C:23]2[C:22]([C:24]#[N:25])=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]([CH3:26])[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:26][N:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:24]#[N:25])[C:23]=2[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:16]1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cn1cc(Br)c2c(C#N)cccc21
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cn(C)c3cccc(C#N)c23)C1=O
Yield: 23.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 110 mg, 0.621 mmol) was reacted with 3-bromo-1-methyl-1H-indole-4-carbonitrile (I-146b: 175 mg, 0.744 mmol), 1,4-dioxane (15 mL), copper iodide (11 mg, 0.0573 mmol), trans-1,2-diamino cyclohexane (21 mg, 0.1843 mmol) and potassium carbonate (171 mg, 1.239 mmol) to afford the crude product. Purification by column chromatography on silica gel (3% MeOH in CHCl3) afforded 49 mg of 1-Methyl-3-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-1H-indole-4-carbonitrile (23.90% yield).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([S:7][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Cl:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCCBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCCSc1ccccc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Benzenethiol (3.0 g), 1-bromo-5-chloropentane (5.7 g) and potassium carbonate (4.15 g) were suspended in N,N-dimethylformamide (50 ml), and the mixture was stirred at 50° C. for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. Thus, 5-phenylthiopentyl chloride was obtained. This compound was dissolved in formic acid (50 ml) and 2 equivalents of 30% aqueous hydrogen peroxide solution was added thereto, and the mixture was stirred at room temperature for 6 hr.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:33][CH3:34])[CH:29]=3)[CH2:24]2)=[C:17]([NH:19][C:20](=O)[CH3:21])[CH:18]=1.N>O1CCCC1>[CH2:20]([NH:19][C:17]1[CH:18]=[C:13]([O:12][CH3:11])[CH:14]=[CH:15][C:16]=1[CH:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:33][CH3:34])[CH:29]=2)[CH2:24]1)[CH3:21]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(C)=O)C2
Agent: N
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.0 g) in pyridine (5 ml) was added acetic anhydride (5 ml), and the solution was stirred for 10 minutes at room temperature. An ice water was added thereto, the solution was stirred, was neutralized with a saturated aqueous solution of sodium bicarbonate, and the resulting solid was filtered and purified by silica gel column chromatography (hexane-ethyl acetate system) to provide N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (1.1 g). To a suspension of lithium aluminum hydride (400 mg) in tetrahydrofuran (20 ml) was added aluminum chloride (1.4 g) on an ice bath under a nitrogen atmosphere, the solution was stirred for 15 minutes at room temperature, then N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide (1.1 g) was added thereto followed by stirring for 1 hour at room temperature. Tetrahydrofuran and aqueous ammonia were sequentially added thereto, the resulting suspension was filtered through celite pad, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (604 mg).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32].[OH-].[Na+].Cl>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32]
Reactant: CCOC(=O)C(Cc1ccncc1)n1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(C(Cc3ccncc3)C(=O)O)c(=O)c1Br)C2(C)C
Yield: 111.6 %

Procedure:
Ethyl 2-[5-bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-3-(pyridin-4-yl)propanoate (165 mg, 0.294 mmol) in 1,4-dioxane (4 mL) was stirred with 1 M aqueous sodium hydroxide (1 mL) at room temperature for 4 hours. After completion of the reaction, the reaction solution was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (156 mg, quant).
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42])([CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[F:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[O:35][C:5]([CH3:34])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:11][CH:12]=1)[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3cccc(C(F)(F)F)c3)C(=O)N2C)cc1)Oc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2cccc(C(F)(F)F)c2)CC1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is diluted with 1N HCl, extracted with CH2Cl2, dried, concentrated in vacuo, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.53-7.42 (m, 2H), 7.29-6.93 (m, 7H), 6.85-6.73 (m, 3H), 4.49-4.29 (m, 2H), 3.99-3.95 (m, 2H), 3.81-3.68 (m, 1H), 3.46-3.41 (m, 1H), 3.28, 3.16 (ABq, 2H, J=13.7 Hz), 3.09-3.04 (m, 1H), 2.86 (d, 3H, J=5.6 Hz), 2.25-2.21 (m, 1H), 1.93-1.87 (m, 1H), 1.40 (s, 3H). MS [ES+] m/z exact mass calcd for C30H31N2O5F4 575.2169, found 575.2156.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].[CH3:15][C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O>O.CO.[Pd]>[CH2:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:17][C:16]([CH3:21])([CH3:20])[CH3:15]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: CC(C)(C)CC=O
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CCN[C@@H](CC(=O)O)C(=O)O
Reaction time: 48 h
Yield: 72.9 %

Procedure:
L-aspartic acid (4 g, 0.03 mol) was added to a Parr bottle containing a solution of sodium bicarbonate (5.04 g, 0.06 mol) in water (50 mL) to form a clear solution, with effervescence. A solution of 3,3-dimethylbutyraldehyde (3 g, 0.03 mol) in methanol (50 mL) was then added to the Parr bottle, followed by Pd/C (4% palladium on carbon, 50% wet, 0.4 g). The mixture was hydrogenated at 50 psi/room temperature for 2 days. If the reaction was not complete, fresh Pd/C (0.2 g) would be added and hydrogenation continued for an additional 8 hrs. The mixture was filtered through a Celite® bed, and the bed was washed with methanol (20 mL). The filtrate and washings were combined and concentrated under reduced pressure at 40-50° C. The pH of the remaining aqueous solution was adjusted to 3 with concentrated hydrochloric acid. The precipitated solid was filtered and dried in a vacuum oven at 50° C. for 4 hrs to give 4.75 g (73%) of crude N-neohexyl-L-aspartic acid. The crude product was slurried with aqueous ethanol (47.5, 80% ethanol, 20% water) for 15 minutes and filtered to give 3.3 g (51%) of >98% pure N-neohexyl-L-aspartic acid. M.P. 184-186° C.; [α]D +12.35 (c=1, water); NMR (D2O) δ3.37(t, 3H); 2.25-2.65 (m, 4H); 1.27-1.47 (m, 2H); 0.89(s, 9H); Anal. Calc'd. for C10H19NO4 ; C, 55.28; H, 8.81; N, 6.45; Found: C, 55.35; H, 8.86; N, 6.50.
Reaction SMILES: Cl[CH:2]([Cl:10])[C:3]([NH:5][CH2:6][C:7](=[O:9])[CH3:8])=[O:4].[CH2:11](O)[CH2:12][OH:13].ClC(Cl)C.C(=O)([O-])[O-].[K+].[K+]>C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O.O>[CH3:8][C:7]1([CH2:6][NH:5][C:3](=[O:4])[CH2:2][Cl:10])[O:9][CH2:11][CH2:12][O:13]1
Reactant: OCCO
Reactant: CC(=O)CNC(=O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Agent: [K+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CC1(CNC(=O)CCl)OCCO1
Yield: 34.4 %

Procedure:
Six g of 3-(dichloroacetylamino)-2-propanone (0.03 mole), 2.0 g (0.03 mole) of ethylene glycol, 0.2 g of β-naphthalene sulfonic acid, and 100 ml of dichloroethane were combined in a reaction flask and refluxed until water stopped coming off. Then the reaction was stirred with potassium carbonate and filtered over Florisil. The filtrate was evaporated to yield 2.0 g of 2-methyl-2-(chloroacetylamino)methyl-1,3-dioxolane, a white solid. m.p.=128°-130° C. Structue was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:7])[CH2:4][CH2:5][OH:6].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:21][C:9]([F:8])([F:20])[C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:7])(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: COC(C)CCO
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(C)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 42.4 %

Procedure:
To a solution of 3-methoxybutane-1-ol (12) (0.58 g, 4.9 mmol) in pyridine (5 mL) was added p-(trifluoromethyl)-benzenesulfonyl chloride (0.98 g, 4 mmol). The solution was stirred at rt for 3.5 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 1 M HCl (6×25 mL), saturated aqueous NaHCO3 (1×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give an oil (13) (0.53 g, 40%). 1H NMR (400 MHz CDCl3) δ 8.03 (d, 2H, J=8.1 Hz), 7.81 (d, 2H, J=8.3 Hz), 4.19 (m, 2H), 3.35 (m, 1H), 3.18 (s, 3H), 1.78 (m, 2H), 1.09 (d, 3H, J=6.0 Hz); 19F δ (s). Anal. Calcd. For C12H15F3O4S: C, 46.15; H, 4.84. Found: C, 45.99; H, 4.64.