Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].NCCC(O)=O.C(O)(=O)C>O>[CH3:16][C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:24]2[NH:18][C:19](=[O:20])[NH:21][C:22]2=[O:23])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])([CH3:15])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CNC(=O)N1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(C=C2NC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 50.6 %

Procedure:
A mixture of 3,5-di-t-butyl-4-hydroxybenzaldehyde (7.0 g, 30 mmoles), hydantoin (3.0 9, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 48 hours the mixture is stirred into water (300 ml), and the precipitate is filtered off, rinsed with water three times, and dried. Recrystallization from acetonitrile gave the pure product (4.8 g), mp 251°-252° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>C(N(CC)CC)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (6.96 g, crude from Preparation A1) in triethylamine (30 ml) and dimethylformnamide (6 ml) at room temperature was added trimethylsilylacetylene (3 ml), cuprous iodide (150 mg) and bis(triphenylphosphine)palladium(II) chloride (300 mg). The mixture was heated at 50-60° C. for one hour, trimethylsilylacetylene (0.3 ml) was then added and stirring and heating continued for a further period of 30 minutes. The cooled reaction mixture was diluted with water (250 ml) extracted with ether (250 ml). The organic layer was separated (aided by the addition of brine). The aqueous layer was re-extracted with ether (250 ml). The combined ether extracts were dried (MgSO4) and evaporated to give the crude product as a gum (4.67 g).
Reaction SMILES: [Cl:1][O-].[Na+].[OH:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].S([O-])([O-])=O.[Na+].[Na+].Cl>[OH-].[Na+].O>[Cl:1][C:11]1[CH:12]=[N:13][C:5]([OH:4])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cccnc1O
Reactant: [O-]Cl
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Cl)cnc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
Sodium hypochlorite (14% available chlorine, 35 mL, 82.21 mmol) solution was added to a stirred solution of 2-hydroxynicotinic acid (7 g, 50.3 mmol) in 10% aqueous NaOH solution. The solution was stirred for 48 h at room temperature. An aqueous solution of sodium sulfite (3.150 g, 25 mmol) was added and further stirred for 30 min at room temperature. The solution was diluted by cold water and pH was adjusted to 2 by cold dilute HCl. The solids formed were filtered, washed by cold water and dried to yield 6.8 g (78%) of 5-chloro-2-hydroxy-nicotinic acid (70) as white solids. MP: 276° C.; 1H-NMR (DMSO-d6): δ 8.23 (d, J=2.8 Hz, 1H), 8.29 (d, J=2.8 Hz, 1H); EIMS: 174 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:21]1[CH2:26][C@@H:25]([CH3:27])[S:24](=[O:29])(=[O:28])[C:23]2[S:30][CH:31]=[CH:32][C:22]1=2.[CH2:33]([NH:35][S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N+:45]([O-:47])=[O:46])(=[O:38])=[O:37])[CH3:34]>>[CH2:33]([N:35]([C@H:21]1[CH2:26][C@H:25]([CH3:27])[S:24](=[O:29])(=[O:28])[C:23]2[S:30][CH:31]=[CH:32][C:22]1=2)[S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[N+:45]([O-:47])=[O:46])(=[O:37])=[O:38])[CH3:34]
Reactant: C[C@@H]1C[C@H](O)c2ccsc2S1(=O)=O
Reactant: CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCN([C@H]1C[C@H](C)S(=O)(=O)c2sccc21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: -30 °C
Yield: 81.8 %

Procedure:
triphenylphosphine (6.8 g); cis-4-hydroxy-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide (5 g) and N-ethyl-2-nitrobenzenesulfonamide (5.54 g) are mixed under nitrogen atmosphere. The mixture is cooled at −30° C. and diisopropyl azadicarboxylate (4.8 mL) is added. It is stirred until completing the transformation. It is filtered, washed and dried. The isolated raw product is column-purified to give 8.07 g of trans-4-[N-ethyl-N-(2-nitrobenzenesulfonyl)amino]-5,6-dihydro-6-methyl-4-H-thieno-[2,3-b]-thiopyran-7,7-dioxide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:5]=2)[CH:18]=1
Reactant: Cc1c[nH]cn1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-amino-5-bromo-benzotrifluoride (17.1 g, 71.24 mmol), 4-methylimidazole (17.6 g, 213.72 mmol), potassium carbonate (9.8 g, 71.24 mmol), cupper (1.1 g, 17.81 mmol), and cupper iode (II) (3.4 g, 17.81 mmol) were added to N,N-dimethylacetamide (100 ml) at room temperature, and mixed therewith at 140˜150° C. for 16 hr. After the reaction was completed, the temperature of the reaction vessel was cooled to RT. Then, ethyl acetate (200 ml) was added thereto and mixed therewith for 30 min. The reaction mixture was filtered with Celite, and an organic layer of the filtered solution was washed with water, dried with magnesium sulfate, distilled under vacuum, and washed with n-hexane to give the titled compound as pale white solid.
Reaction SMILES: [F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][OH:5].CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][C:4]([OH:11])=[O:5]
Reactant: CC(C)=O
Reactant: OCCC(F)=C(F)F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CC(F)=C(F)F

Procedure:
The first method involves hydrolysis of 4-bromo-1,1,2-trifluoro-1-butene (H) with water in the presence of N-methyl pyrrolidinone to give 3,4,4-trifluoro-3-buten-1-ol (III), followed by Jones oxidation under conditions not previously known. These conditions are at a temperature of about 51°-54° C. In addition, the 3,4,4-trifluoro-3-buten-1-ol in acetone solvent and the Jones reagent are added to the reaction vessel simultaneously to afford 3,4,4-trifluoro-3-butenoic (IV) add in 52% overall yield. ##STR4## Method 2, Scheme 1, Compound IV
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C([Li])CCC.Br[C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][CH2:33][O:34][CH3:35])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-].CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][CH2:33][O:34][CH3:35])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:19][CH:18]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: COCCN(Cc1ccc(Br)nc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCN(Cc1ccc(-c2cc3nccc(Cl)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (6) (8.84 g, 52.1 mmol) in THF (100 μL) at −78° C. was added n-butyllithium (20.86 mL, 52.1 mmol). After 30 min, zinc chloride (52.1 mL, 52.1 mmol) (1M in ether) was added at −78° C. and the reaction mixture was allowed to warm to r.t. After 1 h, palladium tetrakistriphenylphosphine (1.004 g, 0.869 mmol) and tert-butyl (6-bromopyridin-3-yl)methyl(2-methoxyethyl)carbamate (10) (6 g, 17.38 mmol) in THF (25.00 mL) were added and the mixture was heated to reflux for 1 h and cooled to room temperature. To the cooled reaction mixture were added NaHCO3 (sat. aq.) (100 mL) and EtOAc (100 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4 and evaporated under reduce pressure. The residue was purified by flash column chromatography (eluent hexane/EtOAc:5/5, 3/7, 0/100), to afford intermediate 11 (5.41 g, 72% yield). MS (m/z): 434.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.65 (d, J=5.1 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.39 (s, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.1, 2.1 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 4.48 (s, 2H), 3.43-3.35 (m, 4H), 3.22 (s, 3H), 1.43-1.33 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:12].[BH4-].[Na+].Cl>C(O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([CH3:13])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][CH:7]2[OH:12]
Reactant: CCOC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)c2c(c1C)C(O)CCS2
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
88.4 g (311 mmol) of the 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-one obtained in the above step (5) was dissolved in 200 ml of ethanol, and further dissolved in 200 ml of dichloromethane. This solution was cooled to 5°~10° C., and 5.9 g (155 mmol) of sodium borohydride was added. The reaction mixture was stirred at the above temperature for 30 minutes, and further stirred at room temperature for 3 hours. Then, the reaction mixture was poured into 400 ml of a 5% hydrochloric acid aqueous solution and extracted with 900 ml of dichloromethane, and then the resultant organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to give 86.8 g (yield 97%) of 8-chloro-6-ethoxycarbonyl-5-methylthiochroman-4-ol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].C(N(CC)CC)C.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C(C)=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6]1=[O:16]
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCCn1cc(-c2ccccc2)n(C(=O)c2ccccc2)c1=O

Procedure:
Approximately 4.36 g. of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 3 g. of triethylamine and 3 g. of benzoyl chloride are refluxed together for three hours in chloroform. The solution is cooled, washed with water, dried and the solvent removed to give an oil which is the O-benzoyl ester. The ester is refluxed for three hours in 20 ml. of xylene. The xylene is removed at reduced pressure. Recrystallization from ether gives the title compound as a pale yellow solid; m.p. 112°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:20](OC)=[O:21].CC(C)([O-])C.[K+]>>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:20][OH:21]
Reactant: COC(=O)Cc1cc(Cl)ccc1Oc1ccccc1
Reactant: COC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)C(=CO)c1cc(Cl)ccc1Oc1ccccc1

Procedure:
Example 8 of the European Patent EP 1710241 B1 also describes an alternative process for the synthesis of the lactam (VI), see Scheme 4. In this example, (5-chloro-2-phenoxyphenyl)acetic acid methyl ester (compound VIIIa) is reacted with methyl formate in the presence of potassium tert-butoxide to give 2-(5-chloro-2-phenoxyphenyl)-3-hydroxyacrylic acid methyl ester (compound IXa, E/Z mixture 9:1), which is directly cyclized with pyrophosphoric acid to obtain methyl 2-chlorodibenzo[b,f]oxepin-11-carboxylate (compound Xa), referred to us 8-chlorodibenzo[b,f]oxepin-10-carboxylic acid methyl ester in EP 1710241 B1, with 85% yield. This compound is then reacted with nitromethane in the presence of tert-butyl-tetramethylguanidine to give methyl 2-chloro-10-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIa), referred to us 8-chloro-1′-nitromethyl-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, with a trans to cis ratio of 8:1, which is directly hydrogenated in the presence of a sponge nickel catalyst to give methyl 10-aminomethyl-2-chloro-10,11-dihydrodibenzo[b,f]oxepine-11-carboxylate (compound XIIa), referred to us 11-aminomethyl-8-chloro-10,11-dihydrodibenzo[b,f]oxepine-10-carboxylic acid methyl ester in EP 1710241 B1, which after treatment with potassium tert-butoxide and dimethyl sulphate, is converted into the lactam (VIa) with an overall yield of 81% from compound (Xa), but predominantly corresponding to the undesired cis-isomer (approximately 85:15 ratio with respect to the trans-isomer), being therefore necessary to carry out one of the above described low-yield processes for the conversion of undesired cis-(VI) to trans-(VI).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: COc1ccc(CNc2ncccc2C#N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(CNc2ncccc2CN)c(OC)c1

Procedure:
A solution of 2-(2,4-Dimethoxybenzylamino)pyridine-3-carbonitrile (0.55 g, 2.04 mmol) and LiAlH4 (2.2 ml of 1N, 4.4 mmol) was stirred at RT until the reaction was judged complete by LCMS. The reaction was quenched with sat. aq. Na2CO3 and the layers were separated. The organic layer was dried (Na2SO4) and the solvents removed under reduced pressure giving the desired product which was used without further purification. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=274; tR=0.28.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Yield: 99.4 %

Procedure:
100 g (540 mmol) of 4-bromobenzaldehyde together with 200 mg of ptoluenesulfonic acid and 30 ml (540 mmol) of anhydrous ethylene glycol are initially introduced in 600 ml of toluene, and the mixture is refluxed on a water separator with monitoring by TLC. When the reaction is complete, the reaction solution is washed twice with sat. NaHCO3 solution and once with water, dried over Na2SO4 and evaporated in a rotary evaporator, giving 123 g (99% of theory) of the dioxolane as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(O)c(F)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid (Aldrich, 4.0 mmol, 624 mg) in ethanol (10 mL), was added thionyl chloride (2 mL, Aldrich). The reaction mixture was heated at 80° C. for 4 h, and concentrated in vacuo to remove the solvent and excess thionyl chloride to afford the desired product (736 mg, 100% yield) as a white solid. MS(ESI+) m/z 185.33 (M+H)+.
Reaction SMILES: [OH-].[K+:2].[O:3]=[C:4]([OH:16])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([C:13]([O-:15])=[O:14])[OH:12])[OH:10])[OH:8])[OH:6].[K+]>O>[O:3]=[C:4]([O-:16])[C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([C:13]([O-:15])=[O:14])[OH:12])[OH:10])[OH:8])[OH:6].[K+:2].[K+:2]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)[O-]

Procedure:
Aqueous potassium hydroxide solution (27 mL, 2 M) was added to a slurry of monopotassium D-glucarate (10.2 g, 41.1 mmol) in water (50 mL) until all of the solid dissolved and a constant pH of 10 was reached. The solution was concentrated to a syrup and seeded with the title compound. Crystals grew slowly from the syrup. After two weeks, the crystals were isolated by filtration, washed with cold 1:1 ethanol/water (3×5 mL), and dried under reduced pressure to give dipotassium D-glucarate as colorless crystals (8.14 g, 26.8 mmol as the monohydrate, 65.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])=[CH:5][C:4]=2[CH2:3]1>C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:11](=[O:12])[NH:10][C:9]2[N:8]=[CH:7][C:6](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:5][C:4]=2[CH2:3]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CC(C)(C)C(=O)N2
Solvent: ClCCl
Product: CC1(C)Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
To a stirred solution of (E)-tert-butyl 3-(6,6-dimethyl-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate (W) (1.2 g, 3.97 mmol) in CH2Cl2 (10 mL) was added trifluoro acetic aid (5 mL) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 3 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was triturated with diethyl ether to get the desired compound as an off-white solid (700 mg, 77%); 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.55 (d, J=16.1 Hz, 1H), 6.51 (d, J=15.6 Hz, 1H), 2.80 (s, 2H), 1.08 (s, 6H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:23])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)CC)cc1
Agent: [Li+]
Agent: [OH-]
Product: CCS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 95.9 %

Procedure:
A solution of 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid ethyl ester (2.50 g, 7.39 mmol) in tetrahydrofaran (30 mL) was treated with a 0.8M aqueous lithium hydroxide solution (11.1 mL, 8.86 mmol). The reaction mixture was stirred at 25° C. for 23 h. The resulting reaction mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous hydrochloric acid solution (15 mL). The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-ethanesulfonyl-phenyl)-propionic acid (2.20 g, 96%) as a white solid which was used without further purification: mp 137-138° C.; FAB-HRMS m/e calcd for C16H22O4S (M+H)+ 311.1317, found 311.1321.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.CCN(C(C)C)C(C)C.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(NCc2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (0.5 g, 3.1 mmol) in EtOH (10 mL) was added Hunig's base (1.1 mL, 6.1 mmol) followed by benzylamine (0.37 mL, 3.35 mmol) and the reaction mixture was stirred overnight at 100° C. The reaction mixture was poured onto water and EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound (670 mg) as a yellow solid. LC-MS (ES) m/z=235 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:15]1(C)[C:19]2(CS(O)(=O)=O)[C:20](C[CH:16]1[CH2:17]C2)=[O:21].O1C=CCCC1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH:20]2[CH2:19][CH2:15][CH2:16][CH2:17][O:21]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: C1=COCCC1
Solvent: ClCCl
Product: c1ccc(CN2CC[C@@H](OC3CCCCO3)C2)cc1
Reaction time: 14 h
Yield: 120 %

Procedure:
To a stirred solution of (R)-(+)-1-benzyl-3-pyrrolidinol (5.00 g, 28 mmol) and D-camphor-10-sulfonic acid (6.97 g, 30 mmol) in CH2Cl2 (10 ml) was added 3,4-dihydro-2H-pyran (20 ml) at rt and the reaction mixture was stirred for 14 h (in most cases, the reaction was completed after exothermic reaction subsided). The reaction mixture was diluted with CH2Cl2 (100 ml), washed with saturated NaHCO3 aqueous solution, dried (Na2SO4), and concentrated to give brown oil. This tas purified by column chromatography (silica gel:200 g, CH2Cl2 /MeOH:40/1 as eluent) to give 8.78 g (97.6%) of desired compound as brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][CH2:17][O:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCC1OCCCO1
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cccc(OCCC2OCCCO2)c1
Yield: 112.3 %

Procedure:
3-tert-butyl-phenol (1.50 g, 10 mmol), 2-(2-bromo-ethyl)-[1,3]dioxane (1.38 g, 10 mmol) and potassium carbonate (2.15 g, 11 mmol) in 20 ml acetonitrile was heated to reflux for 16 hours. After cooling, the solvent was removed under reduced pressure and the residue partitioned between diethyl ether and water. The isolated organic layer was washed with water, dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give 2.97 g of crude 2-[2-(3-tert-butyl-phenoxy)-ethyl]-[1,3]dioxane, which was used without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CS(C)=O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 30 °C
Yield: 89.4 %

Procedure:
To a solution of 65% sodium hydride (1.1 g, 0.03 mole) in dimethylsulfoxide (30 ml) were added 2-(4-methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole) and 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole). After heating to 30° C. for 5 hours with stirring, the reaction mixture was treated in the same manner as in Example 12 to obtain 4.6 g of 4-[2-(4-methylphenyl)ethoxy]nitrobenzene (VI) as white crystals (yield, 89.5%).