Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1.C1(N=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:20][N:3]([CH3:2])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:6][CH:7]([CH2:10][C:11]([NH:3][CH2:4][CH2:5][C:6]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:29][CH:28]=2)=[O:13])[CH2:8][CH2:9]1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(4-dimethylamino-4-phenylcyclohexyl)acetic acid hydrochloride (298 mg, 1.0 mmol) in dry dimethylformamide under argon. The clear solution was cooled in an ice-bath and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added. The reaction mixture was stirred at RT for 3 d and worked up by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). The mixture was diluted with water, 5 M sodium hydroxide solution (4 ml, 20 mmol) was added and the mixture was stored at 5° C. for 16 h. The crude product thereby precipitated out as a beige-coloured substance (400 mg). After purification by chromatography on silica gel with methanol, the product was obtained as a beige-coloured solid in a yield of 35% (144 mg) and with an m.p.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:18]O>>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To an ice cold solution of 3-bromo-5-nitro-benzoic acid (D5) (2.5 g, 10 mmol, 1 equiv) in MeOH (25 ml) was added SOCl2 (1 ml, 15 mmol, 1.5 equiv) dropwise. The resulting solution was allowed to warm to room temperature and was then stirred at 60° C. for 3 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in AcOEt and the organic layer was washed with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-nitro-benzoic acid methyl ester (D11) (2.6 g, 100%) as a yellow solid. RT=3.22 min
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[NH:9][C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=O)C.C([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[CH:40]=1)C1C=CC=CC=1>>[C:13]12([CH2:12][CH2:11][C:10]3[NH:9][C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])=[N:7][C:6]=3[C:4]([NH:45][C:41]3[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=3)[C:38]([OH:37])=[O:46])=[O:3])[CH2:14][CH:15]3[CH2:16][CH:17]([CH2:18][CH:19]([CH2:21]3)[CH2:20]1)[CH2:22]2
Reactant: CCOC(=O)c1nc(-c2ccccc2F)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Product: O=C(O)c1cccc(NC(=O)c2nc(-c3ccccc3F)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-Adamantan-1-yl-2,3-dioxo-pentanoic acid ethyl ester monohydrate (Example 44) was reacted with 2-fluorobenzaldehyde according to the procedure of Example 20, step b to produce 5-(2-adamantan-1-yl-ethyl)-2-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester. The ester was hydrolyzed according to the procedure of Example 20, step c and the resulting 5-(2-adamantan-1-yl-ethyl)-2-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid was reacted with 3-amino-benzoic acid benzyl ester using essentially the same procedure as in Example 20, step d. Deprotection was carried out according to the procedure of Example 20, step e to afford the title compound as a colourless foam.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])C>OS(O)(=O)=O>[CH:4](=[O:3])[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCC#CC(OCC)OCC
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCC#CC=O

Procedure:
A mixture of 2-pentadecynal diethyl acetal (4g) and 10% aqueous H2SO4 (60 ml) was refluxed with efficient stirring, for one hour. An additional 40 ml dilute H2SO4 was added at this stage and the mixture heated for another two hours. After cooling, the reaction mixture was extracted with CH2Cl2, the extract dried (Na2SO4) and evaporated in vacuo to provide a yellow oil. Yield: 2.9 g.
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([NH:32]C(OC(C)(C)C)=O)[CH2:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[N:21]=3)[CH:18]=2)=[CH:11][C:10]([CH3:46])=[N:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:46][C:10]1[CH:11]=[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([C:28]5([NH2:32])[CH2:29][CH2:30][CH2:31]5)=[CH:26][CH:27]=4)[N:21]=3)[CH:18]=2)[NH:8][N:9]=1
Reactant: Cc1cc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3c2)n(C(=O)OC(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2ccc3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)n3c2)[nH]n1
Reaction time: 2 h
Yield: 18.7 %

Procedure:
The crude product from Step 1 (79 mg) was dissolved in DCM/MeOH (2 mL/1 mL) and treated with HCl (4 M soln in dioxane, 0.96 mL). The reaction was stirred for 2 hours before it was poured onto ice, made alkaline with dilute aqueous sodium hydroxide solution (2M) and extracted with DCM. The organic phase was washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound (10 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([CH3:18])=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:20].[OH-].[Na+]>>[CH3:18][C:12]1[C:11]([O:10][C:4]2[C:5]([C:8]([NH2:9])=[O:20])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:16][CH:15]=[C:14]([CH3:17])[N:13]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(Oc2cc(Br)cnc2C#N)c(C)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Oc2cc(Br)cnc2C(N)=O)c(C)n1
Temperature: 25 °C
Yield: 92 %

Procedure:
To 5-bromo-3-(2,6-dimethylpyridin-3-yloxy)picolinonitrile (25 g, 82 mmol) was added concentrated sulfuric acid (25 ml) and the mixture stirred at ambient temperature over night. The mixture was poured onto ice (500 ml) and the aqueous mixture neutralized using 50% NaOH. A solid formed at pH 7. The solid was collected and dried in vacuo to afford 3-(2,6-dimethylpyridin-3-yloxy)-5-bromopicolinamide (24.2 g, 92%).
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[N+:18]=[N-:19])(C)(C)C.[CH2:21](Br)[C:22]#[CH:23]>CCCCCC.CN(C=O)C>[N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]([CH2:23][C:22]#[CH:21])[C:8](=[O:20])[OH:7])=[N+:18]=[N-:19]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCN(Cc1ccccc1N=[N+]=[N-])C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium hydride (5.0 mg, 0.120 mmol, 60% suspension in mineral oil) was washed with hexane (2 mL) in a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of (2-azido-benzyl)-carbamic acid tert-butyl ester (20 mg, 0.08 mmol) in dry DMF (1 mL) at 0° C. The reaction mixture was stirred at this temperature for 30 min. Propargyl bromide (0.021 mL, 0.24 mmol) was added and the reaction mixture was stirred at r.t. for 2 h. After the completion of reaction as confirmed by TLC, crude product was extracted with ethylacetate (10 mL). The organic layer was washed with water (2×5 mL). Organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (silica gel; 1:9 EtOAc:Pet.Ether) to afford (2-azido-benzyl)-prop-2-ynyl-carbamic acid ten-butyl ester (20 mg, 87%) as a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:17]([CH:20]=1)[C:18]#[N:19]>C1(C)C(C)=CC=CC=1.CS(C)=O.[Pd]>[C:18]([C:17]1[CH:20]=[C:13]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:14]=[CH:15][C:16]=1[O:21][CH2:22][CH:23]([CH3:25])[CH3:24])#[N:19]
Reactant: CCOC(=O)c1scnc1C
Reactant: CC(C)COc1ccc(Br)cc1C#N
Agent: [Pd]
Solvent: CS(C)=O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 140 °C
Reaction time: 24 h

Procedure:
To a test tube-type reaction vessel (60 mL) were added ethyl 4-methylthiazole-5-carboxylate (2.14 g, 12.5 mmol), 5-bromo-2-isobutoxybenzonitrile (2.54 g, 10.0 mmol) obtained in the Reference Example 1 and xylene (7.6 mL). After adding compounds listed in the Table 9 as a palladium compound (0.025 mmol), a ligand (0.10 mmol), a base (21.0 mmol), a carboxylic acid (0.10 mmol), and an additive (1.0 mmol), the reaction vessel was filled with nitrogen gas and sealed air-tight. The reaction mixture was heated to 140° C. and stirred for 24 hours. After the completion of the reaction, a part of the reaction solution was diluted with xylene and DMSO and the resulting solution was analyzed by HPLC measurement. The total HPLC area % of the compound A to D and TM (TM means target compound) was adjusted to 100%, the calculated yield of the subject material was calculated from each HPLC area %. Calculation of the yield from the HPLC area % of the subject material was carried out by applying corresponding numbers in the following calculation formula. Yield (%) of TM=total amount of TM (mol)/[{total amount of A (mol)+total amount of C (mol)×2+total amount of TM (mol)}]×100 Total amount of each compound (mol)=HPLC area value (mAU) of each compound/HPLC area value (mAU/mol) per mol of each compound
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:10]2([O:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][CH3:17]>>[CH2:1]([N:8]1[CH2:14][CH2:13][C:10]([CH2:11][N:16]([CH3:17])[CH3:15])([OH:12])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: c1ccc(CN2CCC3(CO3)C2)cc1
Product: CN(C)CC1(O)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
9.6 g (50 mmol) of 5-benzyl-5-aza-1-oxaspiro[2,4]heptane are added dropwise to 50 ml of dimethylamine solution (50%) and the mixture is stirred overnight at room temperature. The batch is then concentrated and the residue is distilled.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7](OC)([C:9]2[S:10][C:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:12]([CH3:14])[CH:13]=2)[C@H:6]([OH:27])[C@@H:5]([OH:28])[C@@H:4]1[OH:29].C([SiH](CC)CC)C.B(F)(F)F>C(Cl)Cl.C(#N)C>[OH:1][CH2:2][C@@H:3]1[C@@H:4]([OH:29])[C@H:5]([OH:28])[C@@H:6]([OH:27])[C@H:7]([C:9]2[S:10][C:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:12]([CH3:14])[CH:13]=2)[O:8]1
Reactant: CCCc1ccc(Cc2sc(C3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc2C)cc1
Temperature: -45 °C
Yield: 37 %

Procedure:
To a solution of crude (3R,4S,5S,6R)-6-(hydroxymethyl)-2-methoxy-2-(4-methyl-5-(4-propylbenzyl)thiophen-2-yl)tetrahydro-2H-pyran-3,4,5-triol (50) in DCM (11.8 mL) and ACN (11.8 mL) was added triethylsilane (0.786 mL, 4.90 mmol) followed by BF3 etherate (0.611 mL, 4.90 mmol) under nitrogen atmosphere at −60° C. The reaction temperature was maintained −60 to −30° C. for 2 hours. The reaction was quenched with a saturated NaHCO3 solution (20 mL), and then extracted with EtOAc (50 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by prep HPLC (C18) to provide the title compound 51 (391 mg, 0.996 mmol, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C1N2CCN(CC2)C1.[O:25]1[CH2:30][CH2:29][N:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[N:14][C:13]([O:16][C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:32])=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Reactant: O=C(Cl)N1CCOCC1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: Cc1c(Cl)cc(-c2ccc(OC(=O)N3CCOCC3)nn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
1.27 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 1.12 L g of triethylenediamine were suspended in 25 ml of acetonitrile, and then 1.5 g of morpholinocarbonyl chloride were added dropwise thereto. When the addition was complete, the mixture was stirred at room temperature for 30 minutes and then the white precipitate thus produced was removed by filtration. The filtrate was concentrated by evaporation under reduced pressure and then extracted with chloroform. The solvent was distilled under reduced pressure from the extract, giving a crude product which, after recrystallization from a mixture of benzene and hexene, gave 1.72 g (94%) of the desired Compound No. 10, melting at 155°-159° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 28 g of 4-nitrophenol, 36 g of ethyl 2-bromopropionate, 27.6 g of potassium carbonate and 500 ml of butanone was stirred and refluxed for 17 hours. The resulting mixture was diluted with 500 ml of water and extracted with ether. The extract was concentrated in a rotary evaporator and the residue was recrystallized from ether-hexane to give ethyl 2-(4-nitrophenoxy)propionate (1D), as a yellow solid, m.p.: 55-56° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1>C(O)C>[Cl:4][C:5]1[N:6]=[C:7]([N:2]([CH3:3])[CH3:1])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2sccc2n1
Solvent: CCO
Product: CN(C)c1nc(Cl)nc2ccsc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.4 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.77 g) in ethanol (30 mL) was added 2,4-dichlorothieno[3,2-d]pyrimidine (1.00 g) with ice cooling, and the mixture was stirred for 12 h while heating to room temperature. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine, then the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized with diethyl ether to obtain 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.90 g). (2) A mixture of 2-chloro-N,N-dimethylthieno[3,2-d]pyrimidin-4-amine (0.60 g), (S)-1-(3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (2.70 g), N,N-diisopropylethylamine (1.80 g), and ethylene glycol (18 mL) was heated at 110° C. for 20 h with stirring. The reaction mixture was diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, chloroform/methanol) and crystallized with diethyl ether to obtain white solid (S)-1-(3-(4-dimethylaminothieno[3,2-d]pyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1.[CH2:16](Br)[CH:17]=[CH2:18]>>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:18][CH:17]=[CH2:16])=[CH:10][C:9]=2[OH:15])=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: Oc1ccc(-c2ccc(Cl)nn2)c(O)c1
Product: C=CCOc1ccc(-c2ccc(Cl)nn2)c(O)c1

Procedure:
3-Chloro-6-(2,4-dihydroxyphenyl)pyridazine was reacted with allyl bromide under similar conditions to those described in Example 1(i), to give 3-chloro-6-(4-allyloxy-2-hydroxyphenyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[CH3:27][C:28]1([CH:31]=O)[CH2:30][CH2:29]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([C:16](=[CH:27][C:28]3([CH3:31])[CH2:30][CH2:29]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC1(C=O)CC1
Solvent: C1CCOC1
Product: COc1cn(C(=CC2(C)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: -20 °C
Reaction time: 3 h

Procedure:
At −78° C., 1.87 ml (1.87 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) were added dropwise to a solution of 500 mg (1.33 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 10 ml of THF, and the mixture was stirred for another 10 min 488 mg (5.80 mmol) of 1-methylcyclopropanecarbaldehyde were then added, and after a further 10 min the mixture was warmed to −20° C. After 3 h at −20° C., the reaction was terminated by addition of 30 ml of saturated aqueous ammonium chloride solution and the reaction mixture was extracted three times with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little dichloromethane and purified by flash chromatography (24 g silica cartridge, 35 ml/min, cyclohexane/ethyl acetate gradient). Yield: 257 mg (44% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(NC(=NC(C)C)O[C:26]([CH3:29])([CH3:28])[CH3:27])(C)C>C(Cl)Cl>[C:26]([O:15][C:14](=[O:16])[C@H:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH:17]([CH3:19])[CH3:18])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid (30 g, 104.4 mmol), [prepared as described in Example 2, step 1 above], in methylene chloride was added N,N′-diisopropyl-O-tert-butylisourea [can be prepared by the procedure described in Lon J. Mathias, Synthesis, 561-576, (1979)] (75 mL, 3.5 M solution) via additional funnel over 45 min. The reaction mixture was maintained at 0° C. for 2 h, and then allowed to warm to room temperature overnight. Purification by flash chromatography on a silica gel column using (10-20%) ethyl acetate/hexanes as the eluant gave of 2(R)-(4-methoxybenzenesulfonylamino)-3-methylbutyric acid tert-butyl ester (18 g) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CO[CH:16](OC)[CH2:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]=[CH:17][N:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:9]2=[O:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(CNc1ccc(Oc2ccccc2)cc1)OC
Solvent: ClC(Cl)Cl
Product: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(F)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4-Fluoro-3-nitrophenyl isocyanate (0.45 ml) was added to a solution of (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (750 mg) in chloroform (10 ml). The reaction was shaken at 70° C. for 2 hours. A second portion of 4-fluoro-3-nitrophenyl isocyanate (0.45 ml) was added. After 16 hours at 70° C., volatiles were removed and TFA.(10 ml) was added. After shaking for 16 hours, volatiles were removed and the residue was purified by chromatography on silica gel (eluent: dichloromethane/hexane 8:1). The product with the molecular weight of 391.36 (C21 H14FN3O4); MS (ESI): 392 ([M+H]+), was obtained in this way.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].O[C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[C:21]([O:23]CC)=[O:22]>>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:13][O:14][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([OH:23])=[O:22])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(CO)CC1
Reactant: CCOC(=O)c1cccc(O)c1
Product: CC(C)(C)[Si](C)(C)OC1CCC(COc2cccc(C(=O)O)c2)CC1

Procedure:
Prepared from [4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-methanol and ethyl 3-hydroxybenzoate by a method similar to Example 1.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1.C([O:18][C:19](=[O:30])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([Cl:29])[CH:23]=1)C>>[Cl:29][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]([OH:30])=[O:18])[CH:27]=[CH:26][C:25]=1[O:28][CH2:2][C:3]1[C:4]([S:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(CCl)c(SC2CCCC2)n1
Reactant: CCOC(=O)CCc1ccc(O)c(Cl)c1
Product: Cc1ccc(COc2ccc(CCC(=O)O)cc2Cl)c(SC2CCCC2)n1
Yield: 49.3 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-6-methyl-pyridine (35 mg, 0.15 mmol) obtained in Step C of Preparation Example 36 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (36 mg, 0.17 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 58%).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([S-:11])#[N:10].[Na+]>C(O)C>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: CC(=O)C(Cl)CCCl
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)C(CCCl)SC#N
Yield: 86.7 %

Procedure:
A solution of 7.8 g (0.05 moles) of 3,5-dichloro-2-pentanone with 4.15 g (0.051 moles) of sodium rhodanide in 50 cm3 of ethanol is boiled for 2 hours under stirring. Then the procedure described in Example 1 is followed. 7.7 g (87%) of 3-thiocyanato-5-chloro-2-pentanone are obtained, which is identical in all respect with the product of