Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[CH3:3][C:4]1([Zr+2:10]C2(C)C=CC(C)=C2)[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5]1.[C:18]([OH:24])(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:18]([O-:24])(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[C:18]([O-:24])(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[C:18]([O-:24])(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[CH3:3][C:4]1([Zr+3:10])[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5]1
Reactant: CC1=CC(C)([Zr+2]C2(C)C=CC(C)=C2)C=C1
Reactant: CC(C)(C)C(=O)O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)[O-]
Product: CC1=CC(C)([Zr+3])C=C1
Yield: 88 %

Procedure:
To a solution of bis(1,3-dimethylcyclopentadienyl)zirconium dichloride (1.390 g, 3.99 mmol) and pivalic acid (1.520 g, 14.9 mmol) in toluene at 25° C. was added neat triethylamine (1.815 g, 18.10 mmol) with stirring. A white precipitate formed immediately which was removed by filtration. The compound was isolated as a pale-yellow powder in 88% yield and exhibited purity above 99% based on NMR results. 1H NMR (toluene-d8): δ 5.84 (m, 2H), 5.53 (m, 1H), 2.18 (s, 6H), 1.13 (s, 27H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][C:32]1[C:33]([F:41])=[C:34]([CH:37]=[CH:38][C:39]=1[F:40])[C:35]#[N:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:31][C:32]3[C:39]([F:40])=[CH:38][CH:37]=[C:34]([C:35]#[N:36])[C:33]=3[F:41])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(F)c(CCl)c1F
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(C#N)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 80 mg (0.20 mmol) of rac-(1-{[(7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl)carbonyl]amino}-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 141A and 56 mg (0.27 mmol) of 3-(chloromethyl)-2,4-difluorobenzonitrile from Example 135A in 3 ml of DMF was admixed with 129 mg (0.396 mmol) of caesium carbonate. The resulting suspension was stirred at RT for 72 h and then diluted with dichloromethane (15 ml) and extracted with saturated aqueous sodium hydrogencarbonate solution (10 ml). The organic phase was concentrated under reduced pressure, which gave a crude product that contained the target compound in a multicomponent mixture (20% pure). This crude material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)C=C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Br:17][C:18]1[CH:25]=[C:24]([CH:11]2[C:3]3[C:4](=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=3[Cl:1])[NH:5][CH:12]([C:13]([OH:15])=[O:14])[CH2:10]2)[CH:23]=[CH:20][CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCC(=O)C(=O)[O-]
Reactant: C=Cc1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CC(c2cccc(Br)c2)c2c(Cl)cc(Cl)cc2N1

Procedure:
Compound 38 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 3-bromostyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.
Reaction SMILES: C1(C)C=CC([N:7]2C(N)=CC(C3C=CC(N)=CC=3)=N2)=CC=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:7])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-n2nc(-c3ccc(N)cc3)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-tolyl)-3-(4-aminophenyl)-5-aminopyrazole (0.6 g, 2.27 mmol) in THF (20 mL) and H2O (8 mL) at room temperature was added 4-methoxybenzenesulfonyl chloride (0.94 g, 4.55 mmol) and potassium carbonate (0.95 g, 6.88 mmol). The mixture was stirred at room temperature overnight and was then partitioned between H2O (20 mL) and EtOAc (100 mL). The layers were separated and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparatory TLC, eluting with 2:1 hexanes/EtOAc to yield N-[4-5-amino-1-(4-methylphenyl)-1H-pyrazol-3-yl]phenyl]-4-methoxy benzenesulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1ccc(N2CCOCC2)cc1C(=O)O
Yield: 90.8 %

Procedure:
The mixture of 6 g of 2-nitro-5-(morpholin-4-yl)benzoic acid, 15 mL of cyclohexene and 3 g of Pd/C (10%) is heated under reflux conditions in 120 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 4.8 g of the title compound. m.p.: 242° C.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].NC1C=[CH:12][C:11]([NH:14][NH:15][CH:16]=[O:17])=[CH:10][CH:9]=1.[N:18]1C(C)=CC=[CH:20][C:19]=1C>C(#N)C>[CH2:19]([NH:18][C:4]([O:3][C:1]1[CH:9]=[CH:10][C:11]([NH:14][NH:15][CH:16]=[O:17])=[CH:12][CH:2]=1)=[O:5])[CH3:20]
Reactant: Cc1cccc(C)n1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CC#N
Product: CCNC(=O)Oc1ccc(NNC=O)cc1
Reaction time: 3 h

Procedure:
Ethylchloroformate (9.01 g., 0.066 mol) was added dropwise to a suspension of 4-amino-1-(2'-formylhydrazino)benzene (10.0 g., 0.066 mol) and 2,6-lutidine (7.1 g, 0.066 mol) in acetonitrile (250 ml). Upon heating to reflux, the reaction mixture became homogeneous. After three hours the reaction had gone to completion as evidenced by thin layer chromatographic examination. The solvent was removed under reduced pressure. The resulting solid was slurried in water and filtered to remove any water soluble amine starting material. The collected solid was slurried in diethyl ether and filtered to remove ether soluble impurities. The collected solid was recrytallized from methanol to yield a white solid (11.4 g., 77% of theoretical yield, melting point 134° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[C:7]2[CH3:13].[C:24](=O)([O-])[O-].[K+].[K+].BrCBr>O>[CH3:13][C:7]1[C:6]2[C:11]3=[C:2]([O:1][CH2:24][N:10]3[C:9](=[O:12])[CH:8]=1)[CH:3]=[C:4]([C:14]([OH:23])([C:19]([F:22])([F:20])[F:21])[C:15]([F:16])([F:17])[F:18])[CH:5]=2
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(=O)[nH]c2c(O)cc(C(O)(C(F)(F)F)C(F)(F)F)cc12
Agent: [K+]
Solvent: O
Solvent: BrCBr
Product: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)OC2
Reaction time: 4 h

Procedure:
To a solution of 6.8 gm. (0.02 mole) of 8-hydroxy-4-methyl-6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2(1H)-quinolinone is added 2.8 gm. (0.02 mole) of potassium carbonate and 25.3 gm. (0.15 mole) of dibromomethane. The solution is heated and stirred at 70° in a nitrogen atmosphere for 4 hours. At the end of this period the solution is cooled and added to 50 ml. of water. The resultant solid is filtered and purified by chromatography on silicic acid. Elution with 97.5% chloroform/2.5% methanol gives 2.0 gm. of 6-methyl-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-2H,4H-oxazolo[5,4,3-ij]quinolin-4-one, recrystallized from acetonitrile, m.p. 262°-264°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH2:21]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:21][CH3:20])=[O:10])[CH2:6]1
Reactant: CN
Reactant: O=C(Cl)N1CC(Oc2cc(C(F)(F)F)ccc2Cl)C1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cc(C(F)(F)F)ccc2Cl)C1
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A stirred solution of 5.2 g (0.017 mol) of 3-(2-chloro-5-trifluoromethylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 4 g (0.05 mol) of 40% aqueous monomethylamine and stirred for 16 hr. The reaction mixture was diluted with 200 mL of water and the oil globules which separated slowly solidified on standing. Filtration yielded 4 g of crude product which was recrystallized from benzene/ligroin yielding 3.3 g (62.9%) of fine white crystalline product, mp 132°-133° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1([CH2:13][OH:14])[CH2:11][OH:12])[CH2:8]2.[C:15](O)(=[O:19])[C:16]([CH3:18])=[CH2:17].C1(C)C=CC=CC=1>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)C1C(O)=C(C(C)(C)C)C=C(C)C=1.O>[C:15]([O:14][CH2:13][C:2]1([CH2:11][OH:12])[CH:1]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]1[CH2:4]3)[CH2:8]2)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: OCC1(CO)C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCC1(CO)C2CC3CC(C2)CC1C3
Yield: 33.4 %

Procedure:
A mixture of 100 g of 2,2-adamantane dimethanol, 48.2 g of methacrylic acid, 20 g of toluene, 25 g of acidic ion-exchange resin Amberlist-15, and 0.1 g of 2,2′-methylenebis(6-t-butyl-p-cresol) was heated at 120° C. for 6 hours while the water being formed was azeotroped off. After the reaction mixture resumed room temperature, it was filtered through Celite. The filtrate was concentrated in vacuum. 300 g of hexane was added to the concentrate for recrystallization. The crystals were recovered and dried in vacuum, obtaining 45.0 g (yield 33%) of the target compound. The spectral data of this compound were identical with those of the product in Synthesis Example 1-2.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[CH:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[OH:13])=[C:4](F)[CH:3]=1.[H-].[Na+]>>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][N:7]3[CH:11]=[CH:10][CH:9]=[C:8]3[CH:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:4]=2[CH:3]=1
Reactant: CN1CCC(C(O)c2cccn2Cc2ccc(Cl)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Product: CN1CCC(C2Oc3cc(Cl)ccc3Cn3cccc32)CC1
Temperature: 80 °C

Procedure:
A mixture of [1-(4-chloro-2-fluorobenzyl)-2-pyrryl]-[(1-methyl)piperidin-4-yl]methanol (0.65 g, 0.002 mole) and sodium hydride (50% in oil, 0.12 g, 0.0023 mole, washed once with hexane) in 25 ml 20% DMF/benzene was heated at 80° C. for seven hours.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:34])[CH:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:33][CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[S:9][CH:10]=1)C.[Li+].[OH-].O.Cl>C1COCC1.C(Cl)Cl>[CH:31]1([S:28]([C:25]2[CH:24]=[CH:23][C:22]([CH:13]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:12]([NH:11][C:8]3[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[N:7]=3)=[O:34])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH2:32][CH2:33]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(Oc2ccc(F)cc2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1csc(NC(=O)C(Oc2ccc(F)cc2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Reaction time: 2.5 h

Procedure:
{2-[2-(4-Cyclopropanesulfonylphenyl)-2-(4-fluorophenoxy)acetylamino]thiazol-4-yl}-acetic acid ethyl ester (obtained in example A54) was taken in THF, to it was added aqueous solution of LiOH and stirred for 1-4 h. After completion of the reaction, water and DCM was added and stirred for 5 min. The aqueous layer was acidified with 1 N HCl and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the title compound.
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6]>[Zn].C(O)(=O)C>[O:1]=[C:2]([C:8]1[C:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=12)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)/C=C/C(=O)c1c(-c2ccccc2)nn2ccccc12
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)c1c(-c2ccccc2)nn2ccccc12
Temperature: 100 °C
Yield: 45.4 %

Procedure:
A mixture of 4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)crotonic acid (3.61 g), zinc powder (5.0 g) and acetic acid (50 ml) was heated at 100° C. for 1.5 hours. The zinc powder was filtered off and washed with acetic acid. The filtrate and washings were combined and evaporated in vacuo. To the residue a saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added and extracted with ethyl acetate (50 ml×2). The combined extracts were washed with a saturated aqueous solution of sodium chloride (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give crystals of 4-oxo-4-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)butyric acid (1.65 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:20]([F:31])[CH:19]=1.CCOC(OC(OCC)=O)=O.CCCCCC.CCOC(C)=O>CN(C=O)C>[F:31][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([CH:24]=[CH2:25])[C:21]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:17][NH:16][C:13](=[O:15])[C:12]#[C:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=1
Reactant: CC(C)(C)c1ccc(C#CC(=O)O)cc1
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C=Cc1cc(CNC(=O)C#Cc2ccc(C(C)(C)C)cc2)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.8 %

Procedure:
A mixture of (4-tert-Butylphenyl)propynoic acid (step 2 of Example 11, 0.16 mmol, 33.0 mg) and N-(4-aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (step 6 of Example 2, 0.19 mmol, 39.20 mg), DEPC (1.2 eq, 0.19 mmol, 29.13 μl), TEA (2 eq, 0.32 mmol, 44.60 μl) in DMF under an Ar atmosphere was stirred at room temperature for 12 h. Upon completion, as determined by TLC, the reaction solution was extracted by EtOAc (150 ml×3) and the organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated. After silica gel column chromatography (n-hexane/EtOAc=2:1), 3-(4-tert-butylphenyl)propynoic acid 3-fluoro-4-methanesulfonylamino-5-vinylbenzylamide (49.5 mg, 0.11 mmol, 72.25%) was isolated.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.C(O[C:15](=O)[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](=[O:28])N(OC)C)[CH2:19][CH2:18]1)(C)(C)C.[O:30]1[C:35]2[CH:36]=[CH:37][C:38](C=O)=[CH:39][C:34]=2[O:33][CH2:32][CH2:31]1>>[S:9]1[C:8]([C:23]([C@H:20]2[CH2:19][CH2:18][C@H:17]([NH:16][CH2:15][C:38]3[CH:37]=[CH:36][C:35]4[O:30][CH2:31][CH2:32][O:33][C:34]=4[CH:39]=3)[CH2:22][CH2:21]2)=[O:28])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: c1ccc2sccc2c1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: O=C(c1cc2ccccc2s1)[C@H]1CC[C@H](NCc2ccc3c(c2)OCCO3)CC1

Procedure:
Using thianaphthene (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.4 mmol) according to the same protocol as that described for example 1, steps 1.a to 1.c, the title compound was obtained as a colourless oil which solidified on standing (50 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH:24]=[CH:25][CH3:26])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1>C(OCC)(=O)C.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[Se:20][C:21]([CH2:24][CH2:25][CH3:26])=[CH:22][CH:23]=2)=[CH:15][CH:14]=1
Reactant: CC=Cc1ccc(-c2ccc(-c3ccc(OCCC)c(F)c3F)cc2)[se]1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCOc1ccc(-c2ccc(-c3ccc(CCC)[se]3)cc2)c(F)c1F

Procedure:
0.7 g (1.7 mmol) of 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)-5-propenyl-selenophene is hydrogenated in 30 ml of ethyl acetate/toluene (2:1), in the presence of Pd/C (5% of Pd) at atmospheric pressure and RT. The reaction soln. is filtered and concentrated to dryness. Recrystallisation from n-heptane/toluene (4:1) gives 2-(2′,3′-difluoro-4′-propoxybiphenyl-4-yl)-5-propylselenophene as a solid having an m.p. of 114° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][C:12](B(O)O)=[CH:11][C:10]=2[F:19])=[CH:5][CH:4]=1)[CH3:2].Br[C:21]1[S:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:21]3[S:22][C:23]([CH2:26][CH3:27])=[CH:24][CH:25]=3)=[CH:11][C:10]=2[F:19])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Br)s1
Reactant: CCc1ccc(-c2c(F)cc(B(O)O)cc2F)cc1
Product: CCc1ccc(-c2c(F)cc(-c3ccc(CC)s3)cc2F)cc1

Procedure:
The compound 2-(4′-ethyl-2,6-difluorobiphenyl-4-yl)-5-ethylthiophene (SUP-2-2) is prepared analogously to Example 1 from 4′-ethyl-2,6-difluoro-4-biphenylboronic acid and 2-bromo-5-ethylthiophene.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:21])[CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:20][N:12]([CH2:11][CH2:10][C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:21])[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CN(CCC(=O)Nc1cnn(C)c1N)C(=O)OC(C)(C)C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CCC(=O)Nc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of tert-butyl N-{3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxopropyl}-N-methylcarbamate (4.88 g) in N,N-dimethylformamide (50 ml) were added trityl chloride (6.86 g), triethylamine (6.86 ml) and 4-dimethylaminopyridine (80 mg) succesively. The mixture was stirred at room temperature overnight. To the resulting mixture was added ethyl acetate and washed with water (three times) and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give tert-butyl N-methyl-N-(3-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-3-oxopropyl)carbamate (4.20 g) as an amorphous solid.
Reaction SMILES: Cl[CH2:2][CH:3](Cl)[CH3:4].[CH2:6]([CH:8]1O[CH2:9]1)Cl.[CH3:11][C:12](=[CH:15][CH2:16]C)C=O>>[CH2:4]=[CH:3][CH2:2][CH2:6][CH2:8][CH2:9][CH2:11][CH2:12][CH2:15][CH3:16]
Reactant: CC(Cl)CCl
Reactant: CCC=C(C)C=O
Reactant: ClCC1CO1
Product: C=CCCCCCCCC

Procedure:
Column 2 separates the lighter boiling 1,2-dichloropropane, residual epichlorohydrin, and 2-methyl-2-pentenal in the overheads and obtains 1-decene and DCP at the bottom. Stream details for Column 2 are shown in Table 5.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH:11]([CH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][NH:9][C:10](=[O:31])[CH:11]([CH2:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)NOCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)NO)cc1

Procedure:
N-benzyloxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-phenyl- propionamide (1.25 g, 2.85 mmol) is dissolved in 45 mL of ethanol. To this is added 0.36 g of palladium hydroxide on carbon (Pearlman's catalyst), and the suspension is placed in a shaker under 15 psi of hydrogen for 2.25 hours. The catalyst is filtered off, washing with ethanol, and the ethanol solution is concentrated in vacuo to afford, after evaporation from methylene chloride, 0.875 g of the title compound as a white solid.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([C:15]([NH:17][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[C:28]([F:37])[CH:27]=2)[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[N+:38]([O-])=O)C1C=CC=CC=1.[H][H].CCOC(C)=O>C1COCC1.[Pd]>[NH2:38][C:10]1[CH:11]=[CH:12][C:13]([C:15]([NH:17][C@@H:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[C:28]([F:37])[CH:27]=2)[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:16])=[N:14][C:9]=1[OH:8]
Reactant: [H][H]
Reactant: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)nc1O

Procedure:
To a stirred mixture of (S)-6-(benzyloxy)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-nitropicolinamide (800 mg, 0.0014 mol) in THF (8 mL), was added 10% Pd/C (800 mg, Aldrich). The reaction mixture was stirred under hydrogen atmosphere in the form of hydrogen bladder (˜20-22 PSI) for 12 h at room temperature. After completion of the reaction (monitored by TLC, 100% EtOAc), the reaction mixture was filtered through Celite® brand filter agent, the filtrate dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 11.00 (s, 1H), 9.13 (d, J=6 Hz, 1H), 8.46 (d, J=4 Hz, 1H), 7.79 (t, J=9.2 Hz, 1H), 7.57-7.46 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 7.08 (br. s., 1H), 6.62 (d, J=7.6 Hz, 1H), 6.40 (br. s., 1H), 5.83 (br. s., 2H). MS (ESI, positive ion) m/z: 440.9 (M+H).
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH2:14])=[NH:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:18](=[C:20]([C:26]#[N:27])[C:21](OCC)=[O:22])[OH:19].[Na].O>C(O)C.C(O)(=O)C>[NH2:27][C:26]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:10]=2)[NH:14][C:21](=[O:22])[C:20]=1[N:18]=[O:19]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: N=C(N)c1cccc(Cc2ccccc2)c1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nc(-c2cccc(Cc3ccccc3)c2)[nH]c(=O)c1N=O
Reaction time: 5 h
Yield: 78.3 %

Procedure:
3-Benzylbenzamidine hydrochloride (12.3 g.) and ethyl α-oximinocyanoacetate (7.1 g.) were added to a solution of sodium (4.6 g.) in anhydrous ethanol (60 ml.). The mixture was heated under reflux with stirring for 5 hours and then allowed to stand at room temperature overnight. The mixture was poured into water (600 ml.), acidified to pH 5 with glacial acetic acid and chilled for 3 hours. The solid obtained was filtered off and washed with water to give 4-amino-2-(3-benzylphenyl)-5-nitrosopyrimid-6-one (11.95 g.), m.p. 145°-148° C. (with decomposition).