Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:19]1(=[O:26])[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]1>C1COCC1>[OH:25][C:22]1([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:19](=[O:26])[CH:20]=[CH:21]1
Reactant: O=C1C=CC(=O)C=C1
Reactant: C#Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C=CC(O)(C#Cc2ccccc2)C=C1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A suspension of potassium bis(trimethylsilyl)amide (1.95 g, 0.0098 mole) in 20 mL of dry THF was treated with phenylacetylene (0.92 g, 0.009 mole). A flocculant white precipitate formed immediately. Benzoquinone (0.97 g, 0.009 mole) was dissolved in dry THF (10 mL) and cooled to -78° C. The potassium phenylacetylide generated above was added dropwise over a period of about 10 min. The reaction was stirred an additional 10 min, quenched by adding saturated ammonium chloride solution (20 mL) and allowed to warm to RT. The mixture was diluted with saturated ammonium chloride solution, extracted with ether and filtered to remove a flocculant dark brown precipitate. The phases were separated and the aqueous phase extracted with additional ether. The combined ether extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flask chromatography on silica gel using 4:1 hexane/EtOAc as the eluent and the fractions containing the title product were combined and concentrated in vacuo to yield 0.27 g (14%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(=O)OCC>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:11]=[C:10]([S:12]([F:17])([F:16])([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(S(F)(F)(F)(F)F)cc1Cl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(F)(F)(F)(F)F)cc1Oc1ccc(F)cc1
Temperature: 120 °C
Yield: 32 %

Procedure:
300 mg of methyl 2-chloro-4-pentafluorosulfanylbenzoate, 113 mg of 4-fluorophenol and 659 mg of Cs2CO3 were dissolved in 1.5 ml of DMF (anhydrous) and stirred at 120° C. The mixture was then allowed to cool and was diluted with 10 ml of EA and washed 3 times with 5 ml of water each time. Drying over MgSO4 was followed by removal of the solvent in vacuo. 120 mg of an amorphous solid were obtained and were chromatographed on reversed phase silica gel:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
4-Benzyloxybenzoic acid chloride and an optically active 1,1,1-trifluoro-2-alkanol were allowed to react to give 1,1,1-trifluoro-2-alkyl 4-benzyloxybenzoate, which was subjected to hydrogenolysis to give 1,1,1-trifluoro-2-alkyl 4-hydroxybenzoate. An alkyl bromide and 2-hydroxynaphthalene-6-carboxylic acid methyl ester were allowed to react in the presence of potassium carbonate in a solvent such as dimethylformamide and then subjected to hydrolysis with an aqueous sodium hydroxide. The hydrolyzed product was allowed to react with 1,1,1-trifluoro-2-alkyl 4-hydroxybenzoate in the presence of dicyclohexylcarbodiimide to give 6-alkyloxynaphthalene-2-carboxylic acid 4-(1,1,1-trifluoro-2-alkyloxycarbonyl)phenyl ester. ##STR17## (B) 4-Hydroxybiphenyl-4'-carboxylic acid was dissolved in methanol and heated under refluxing in the presence of concentrated sulfuric acid to give 4-hydroxy-biphenyl-4'-carboxylic acid methyl ester. Then the ester and benzyl bromide were dissolved in a solvent such as DMF and the solution was allowed to react in the presence of anhydrous potassium carbonate to give 4-benzyloxybiphenyl-4'-carboxylic acid methyl ester. The compound obtained was subjected to hydrolysis with an aqueous sodium hydroxide solution to give 4-benzyloxy-biphenyl-4'-carboxylic acid. The compound was further allowed to react with thionyl chloride to give 4-benzyloxy-biphenyl-4'-carboxylic acid chloride.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C(C(O)=O)[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14].CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:1]([C:2]([Cl:4])=[O:3])[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1[nH]c(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Reaction time: 8 h

Procedure:
Oxalyl chloride (0.430 mL, 4.91 mmol) was added to a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-2-carboxylic acid (0.500 g, 2.45 mmol) in DCM (50 mL). DMF (9.51 μl, 0.123 mmol) was added to the reaction mixture and the resulting suspension was stirred overnight. The solvent was evaporated to afford the title compound as a crude product (0.804 g) which was used with no further purification. 1H NMR (400 MHz, CDCl3) δ ppm 11.02 (s, 1H), 7.11 (d, 1H), 3.97 (s, 3H).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([O:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:28])=[CH:15][N:14]=1>>[C:1]([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:17][C:16]([Br:28])=[CH:15][N:14]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Oc2cc(Br)cnc2N)cc1
Reactant: O=C(N=C=S)c1ccccc1
Product: N#Cc1ccc(Oc2cc(Br)cnc2NC(=S)NC(=O)c2ccccc2)cc1

Procedure:
Prepared according to the method of Example 7, step C from benzoyl isothiocyanate and 4-(2-amino-5-bromopyridin-3-yloxy)benzonitrile.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].S(Cl)([Cl:15])=O>CN(C)C=O>[N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
13.7 g of p-aminobenzoic acid was dispersed in a solution of 100 cc of water and 30 cc of 30% hydrochloric acid in an ordinary manner and the dispersion was cooled with ice. A solution of 8.3 g of sodium nitrite in 50 cc of water was added dropwise to the dispersion to effect the diazotization reaction. A solution of 10.1 g of sodium azide in 70 cc of water was added dropwise to the mixture, stirred for about one hour, filtered and vacuum-dried to obtain p-azidobenzoic acid. 5.4 g of the thus obtained p-azidobenzoic acid was dissolved in 10 cc of dimethylformamide and 25 g of thionyl chloride was added dropwise to the solution. The mixture was stirred for about one hour and the product was added dropwise to ice-water. After filtration followed by washing with water and vacuum drying, p-azidobenzoyl chloride was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[NH2:37][CH2:38][CH2:39][OH:40]>C(#N)C>[OH:40][CH2:39][CH2:38][N:37]1[C:32](=[O:33])[C:4]2[CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[NH:6][C:7](=[O:19])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[C:3]=2[CH2:2]1
Reactant: NCCO
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Solvent: CC#N
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)N(CCO)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(rac)-Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulfonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (200 mg, 0.34 mmol; Example 13A) was dissolved in acetonitrile (5 ml), 2-aminoethanol (62.5 mg, 1.02 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was then purified directly by preparative HPLC (column: Kromasil C18, 125 mm×20 mm, 5 μm, 100 Å; mobile phase A: water with 0.01% formic acid, mobile phase B: acetonitrile; gradient: 0 min 10% B→2 min 10% B→9 min 90% B→12 min 90% B→12.1 min 10% B→15 min 10% B; flow rate: 0.35 ml/min; UV detection: 254 nm). This gave 98 mg (54% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]2=O)[C:8]([F:23])=[CH:7][C:6]=1[Cl:24].P(Cl)(Cl)([Cl:29])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:26])[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]=[C:12]2[Cl:29])[C:8]([F:23])=[CH:7][C:6]=1[Cl:24]
Reactant: CON(C)C(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1.98 g of N-methoxy-N-methyl-2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzamide, 1.5 ml of phosphorus oxychloride and 1.2 ml of pyridine in 10 ml of toluene is stirred at 80° C. for 3.5 hours. The mixture is then treated with 50 ml of ice-water and extracted three times with 80 ml of ethyl acetate each time. The combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and treated with 200 ml of n-hexane, and the mixture is filtered through 20 g of silica gel. The mixture is then concentrated and the product is left to crystallize out. In this manner there is obtained N-methoxy-N-methyl-2-chloro-5-[2-chloro-4-oxo-6-trifluoromethyl-3(4H)-pyrimidinyl]-4-fluorobenzamide, m.p. 183° C.;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].[CH:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=1.CN1CCOCC1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])/[CH:5]=[CH:6]/[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: OCCc1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CCOC(=O)/C=C/OCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
The reaction was performed in standard glassware under an atmosphere of N2. To 100 ml of diethylether were added 9.8 g (0.1 mol) of propiolic acid ethyl ester, 12.2 g (0.1 mol) phenylethanol and 10.1 g (0.1 mol) of N-methylmorpholine. This solution was kept without stirring at room temperature for 24 hours. The mixture was evaporated under vacuum and the residue purified by bulb to bulb distillation (bp: 70-75° C., 0.006 mbar) to yield 15.7 g (88%) of an oil.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[N:10][C:11]=1[Cl:12].[OH-].[Na+]>O1CCOCC1.O>[Cl:5][C:6]1[CH:7]=[C:8]([O:13][CH:2]([F:4])[F:3])[CH:9]=[N:10][C:11]=1[Cl:12]
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1cnc(Cl)c(Cl)c1

Procedure:
Chlorodifluoromethane was passed at 50° C. into a mixture of 32.8 g (0.2 mol) of 5,6-dichloro-3-pyridinol in 200 ml of 1,4-dioxane and 40 g (1 mol) of sodium hydroxide in 100 ml of water until starting material was no longer present. The further procedure was then carried out as described in Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH:20]([CH3:25])[CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[OH-].[Na+].[CH2:35]1COCC1>CO>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([OH:26])[CH:20]([CH3:25])[CH2:21][C:22]([O:24][CH3:35])=[O:23])=[CH:15][CH:14]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CCCc1c(OCCCSc2ccc(C(O)C(C)CC(=O)O)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCSc2ccc(C(O)C(C)CC(=O)OC)cc2)ccc(C(C)=O)c1O
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To the 4-((3-(4-acetyl-3-hydroxy-2-propylphenoxy) propyl)thio)-beta-methyl-gamma-hydroxybenzene butanoic acid γlactone (8.84 g, 20 mM) described in EP 104,885 (Apr. 4, 1984) was added a mixture of 2N NaOH (12 ml, 24 mM), THF (50 ml) and MeOH (20 ml) and the mixture was stirred 12 hours under N2. The reaction mixture was evaporated to dryness and dissolved in water (75 ml) and cooled to 0° C.; 1N HCl was added drop wise until the PH was lower than 6 and the organic compound was extracted into EtOAc (200 ml). The organic layer was washed with brine (100 ml) and dried with Na2SO4. The solvent was removed in vacuo with no heating and the residue was dissolved in Et2O (100 ml) and cooled to 0° C. Diazomethane (in Et2O) was added in excess and the reaction mixture was evaporated to dryness with no heat and dried under high vacuum to yield the title compound as an oil slightly contaminated (by less than 10 percent of the starting lactone).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>O>[C:14]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)NN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)NNC(=O)C(C)(C)C
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of 40.8 g. (0.33 m.) of tert.-butylhydrazine hydrochloride in 300 ml. of distilled water was placed in a 500 ml. 4 neck, round bottom flask equipped with a high speed mechanical stirrer, a thermometer and a condenser, and cooled to 10° C. The solution was made basic by adding 24.3 g. (0.225 m.) of sodium carbonate and then 18.9 g. (0.15 m.) of pivaloyl chloride was added dropwise over 1 hour holding the temperature below 10° C. with an ice bath. The mixture was stirred for 3 hours and the white solid which formed was filtered off and dried. The product weight 16.5 g. after drying and had a melting range of 97°-105° C.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH:15]([OH:17])[CH3:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](=[O:17])[CH3:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c2cc(C(C)O)ccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCc1nn(C2CCCC2)c2cc(C(C)=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Into a 1-neck round-bottom flask was added 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanol (1.06 g, 4.10 mmol), pyridinium chlorochromate (1.77 g, 8.20 mmol) and 40 mL of methylene chloride. The reaction was stirred at room temperature for 1 hour, filtered through Celite, and rinsed with 200 mL of ethyl acetate. Approximately 20 g of silica gel were added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel eluting with 20% ethyl acetate in hexanes to yield 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanone (809 mg, 77%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:8].[CH3:29][O:30][C:31]1[CH:67]=[CH:66][C:34]([CH2:35][N:36]2[CH:40]([CH2:41][CH2:42]OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:39][N:38]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=3)[C:37]2=[O:65])=[CH:33][CH:32]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:42][CH2:41][CH:40]2[CH2:39][N:38]([CH2:54][C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:59][CH:60]=3)[C:37](=[O:65])[N:36]2[CH2:35][C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:67][CH:66]=2)=[CH:15][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccc(C(F)(F)F)cc3)CC2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Yield: 93.6 %

Procedure:
Cesium carbonate (2.49 g, 7.647 mmol) is added to a solution of 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.77 g, 5.88 mmol) and toluene-4-sulfonic acid 2-[3-(4-methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (3.64 g, 6.47 mmol) in DMF (40 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, then dried, concentrated, and purified by flash chromatography (acetone/hexanes gradient) to provide the title compound (3.80 g, 94%). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=7.8 Hz), 7.23-7.19 (m, 4H), 7.13 (d, 2H, J=8.4 Hz), 6.97 (t, 1H, J=7.8 Hz), 6.86 (d, 2H, J=8.4 Hz), 6.81 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=7.8 Hz), 4.66, 4.20 (ABq, 2H, J=14.9 Hz), 4.47, 4.43 (ABq, 2H, J=15.5 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.89-3.85 (m, 2H), 3.80 (s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 1H, J=9.1 Hz), 3.26, 3.08 (ABq, 2H, J=13.6 Hz), 3.00 (t, 1H, J=9.1 Hz), 2.20-2.14 (m, 1H), 1.87-1.78 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 691 (M+H)+. Rf=0.46 in 50% acetone in hexanes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]1[C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:9]=2[NH:16][C:26]1=[O:28])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 204.9 %

Procedure:
To a chilled solution of (2-amino-4-cyanophenyl)-carbamic acid tert-butyl ester (2.1 g, 8.8 mmol) in CH2Cl2 (50 mL) and triethylamine (1.22 mL, 8.8 mmol) was added a solution of triphosgene (0.94 g, 3.2 mmol) in CH2Cl2 (50 mL) slowly. The reaction was stirred at room temperature for 3 hours, diluted with CH2Cl2, washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using a gradient from 30% to 60% ethyl acetate in n-heptane as eluent to afford 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (1.7 g, 75%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[CH2:18][O:19][CH2:20][C:21](O)=[O:22])=[C:12]([C:25]([O:27]C)=[O:26])[CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:21](=[O:22])[CH2:20][O:19][CH2:18][C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][C:12]=2[C:25]([OH:27])=[O:26])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1

Procedure:
Using the same method as in Example 1-(ii), 3-bromoaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester (yield: 81%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=O)[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30]C(=O)C(F)(F)F)[CH2:26][CH2:25]2)[CH:3]=1.[NH3:37]>CO>[NH2:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([O:23][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:37])=[O:21])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:29][CH2:28]1
Reactant: N
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](NC(=O)C(F)(F)F)CC3)c2c1C
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CC[C@H](N)CC3)c12

Procedure:
0.100 g methyl 4-(4-fluoro-2-(trans-4-(2,2,2-trifluoroacetamido)cyclohexyloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (cpd.15.1) and 2 ml 7 M ammonia in MeOH were stirred in a pressure tube overnight at 70° C. and 8 days at 90° C. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16][CH:17]=[C:18]([CH3:26])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:25])[CH2:23]O.P(Br)(Br)[Br:28]>C1COCC1>[Br:28][CH2:23][C:22]([CH3:25])=[CH:21][CH2:20][CH2:19][C:18]([CH3:26])=[CH:17][CH2:16][C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c(CC=C(C)CCC=C(C)CO)c(OC)c2ccccc12
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Product: COc1c(C)c(CC=C(C)CCC=C(C)CBr)c(OC)c2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 157.4 %

Procedure:
6.45 g (18.22 mmol) of 8-(1,4-dimethoxy-3-methyl-naphtalen-2-yl)-2,6-dimethyl-octa-2,6-dien-1-ol was dissolved in 45 ml of dry THF. At 0° C., 0.9 ml (2.59 g, 9.58 mmol) PBr3 was added drop wise via septum and syringe and the clear, colourless solution was stirred at 0° C. for 3 h. The reaction was quenched by addition of ice cold water. The layers were separated and the aqueous layer was extracted with ether. The combined organic extracts were washed with NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to give 2-(8-bromo-3,7-dimethyl-octa-2,6-dienyl)-1,4-dimethoxy-3-methyl-naphtalene as a colorless oil (6.29 g, 15.08 mmol, 83%). The crude product was used for the next step without further purification.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[Br:5][C:6]1[S:10][C:9](N)=[N:8][N:7]=1>O.Cl.[Cu]>[Br:5][C:6]1[S:10][C:9]([N+:1]([O-:3])=[O:2])=[N:8][N:7]=1
Reactant: Nc1nnc(Br)s1
Reactant: O=N[O-]
Agent: [Cu]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1nnc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
To a stirred solution of NaNO2 (116 g, 1.68 mol) in water (1200 mL) was added copper metal powder (72 g, 1.12 mol) and 1.2 mL conc. HCl. Thereafter, 5-bromo-1,3,4-thiadiazol-2-amine (100 g, 0.56 mol) was warmed to dissolve in 4 M aq. HCl (120 mL) and added potionwise. The mixture was stirred at r.t. for 3 hrs. The precipitated yellow solid was filtered and washed with water. The solid was dissolved in ether, filtered and the filtrate concentrated in vacuo to give 2-bromo-5-nitro-[1,3,4]thiadiazole (57 g, 88% purity in HPLC, 48% yield).