Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=[C:7]([NH:17][C:18](=[O:29])[NH:19][C:20]2[S:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[N:6]=1.[H-].[Na+].[CH3:34][O:35][CH2:36]Br.O>CN(C)C=O>[CH3:34][O:35][CH2:36][N:17]([C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:30])[F:31])[CH:10]=[C:9]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:8]=1)[C:18](=[O:29])[NH:19][C:20]1[S:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=1
Reactant: COCBr
Reactant: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)Nc1ccc(C(F)(F)F)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCN(C(=O)Nc1ccc(C(F)(F)F)s1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reaction time: 2.5 h

Procedure:
To a solution of 3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (1) (150 mg, 0.31 mmol) in anhydrous dimethyl formamide (DMF, 1.5 mL) at ambient temperature was added NaH (6.6 mg, 0.28 mmol, 60% dispersion in mineral oil). After stirring 20 minutes a solution of bromomethyl methyl ether (35 mg, 0.28 mmol) in anhydrous DMF (0.5 mL) was added. After 2.5 h the reaction was judged complete by TLC analysis. To the reaction was carefully added H2O (2 mL). The reaction was extracted with EtOAc (10 mL). The EtOAc solution was washed with H2O (3×7 mL) followed by brine (7 mL). The organics were dried (Na2SO4), filtered and evaporated to give crude product. The crude material was purified by silica gel chromatography (0 to 8% EtOAc in pet ether) to afford 3-(methoxymethyl)-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-(5-(trifluoromethyl)thiophen-2-yl)urea (4) as an off white solid (18 mg, 11%), mp 118-119° C.; 1H NMR (400 MHz, Acetone-d6) δ 11.84 (s, 1H), 7.41-7.28 (m, 1H), 6.66 (dd, J=4.1, 0.9 Hz, 1H), 6.18 (s, 1H), 5.54 (s, 2H), 5.02 (q, J=8.6 Hz, 4H), 3.27 (s, 3H); ESIMS m/z 527 ([M−H]+).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]3[O:40][CH2:39]3)[C:33]([O:35]C)=[O:34])(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([NH:31][CH:32]([CH2:37][CH:38]([OH:40])[CH2:39][S:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]4)=[CH:4][CH:3]=3)[C:33]([OH:35])=[O:34])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: Cc1cc(=O)oc2cc(S)ccc12
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3ccc4c(C)cc(=O)oc4c3)C(=O)O)cc2)cc1

Procedure:
Example 49 is prepared from 7-mercapto-4-methylcoumarin and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2([O:10]CCO2)[CH2:5][CH2:4]1)#[CH:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17](I)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>C(#N)C.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.[Cu]I>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([C:2]#[C:1][CH:3]2[CH2:4][CH2:5][C:6](=[O:10])[CH2:11][CH2:12]2)[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: C#CC1CCC2(CC1)OCCO2
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(C#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.9 grams (0.022 mole) of 8-ethynyl-1,4-dioxaspiro[4.5]decane, 10.5 grams (0.031 mole) of 3,5-di(trifluoromethyl)phenyl iodide (prepared in Step A of this Example), 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(I) iodide in 100 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is then stirred for about 2 hours with 150 mL of aqueous 1N hydrochloric acid. After this time the mixture is extracted with three 100 mL portions of ethyl acetate. The combined extracts are washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 4-[3,5-di(trifluoromethyl)phenylethynyl]cyclohexanone.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[N:11]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([NH2:15])[CH:12]=[N:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCn1cc(N)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask tert. butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate (7.88 g, 30.75 mmol), Pd/C (10%, 788 mg) and MeOH (130 mL, degassed) was added. The flask was evacuated and backfilled with H2 and the reaction mixture was stirred under H2-atmosphere at rt for 18 h. The reaction mixture was filtered over celite, washed with MeOH and the solvent was removed under reduced pressure to yield tert-butyl(2-(4-amino-1H-pyrazol-1-yl)ethyl)carbamate as a purple oil which was used in the next step without further purification. LC-MS conditions B: tR=0.35 min, [M+H]+=227.49.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([CH:17]=[O:18])=[C:15]3[N:10]([CH:11]=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([Mg]Br)#[CH:20]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([CH:17]([OH:18])[C:19]#[CH:20])=[C:15]3[N:10]([CH:11]=[N:12][CH:13]=[CH:14]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(-c2cccc(Cl)c2)nn2cnccc12
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2cccc(Cl)c2)nn2cnccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of 2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidine-3-carbaldehyde (1.5 g, 5.82 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesium bromide (17 mL, 0.5 M in tetrahydrofuran, 8.73 mmol). The reaction mixture was stirred 4 hours at room temperature then quenched with water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes:ethyl acetate) provided 1-[2-(3-chlorophenyl)pyrazolo[1.5-c]pyrimidin-3-yl]-2-propyn-1-ol (1.41 g, 85%). Rf 0.17 (2:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 9.27 (s, 1H), 7.93–7.90 (m, 2H), 7.83 (s, 1H), 7.73 (d, 1H), 7.50–7.41 (m, 2H), 5.78 (s, 1H), 2.99 (br, 1H), 2.71 (s, 1H); MS m/z 284 (M+1).
Reaction SMILES: [CH2:1]=O.[NH2:3][O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1>CO>[Si:12]([O:11][CH2:10][C@H:9]1[O:8][C@@H:7]([N:19]2[CH:27]=[C:25]([CH3:26])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6][C@@H:5]1[O:4][N:3]=[CH2:1])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:13])[CH3:14]
Reactant: Cc1cn([C@H]2C[C@H](ON)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: C=O
Solvent: CO
Product: C=NO[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 6 h
Yield: 95 %

Procedure:
A solution of HCHO (20% aqueous, 1 ml) was added dropwise to a stirred solution of 3'-O-amino-5'-O-(t-butyldimethylsilyl)thymidine (3, 7.42 g, 20 mmol) in dry MeOH (400 ml) at room temperature. After 6 h, another portion of HCHO (20% aqueous, 1.5 ml) was added and stirring continued for 16 h. The resulting solution was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel to give compound 10 (7.25 g, 95%) as clear foam. 1H NMR (CDCl3) δ0.1 [s, 3, (CH3)2 ], 0.9 [s, 9, (CH3)3 ], 1.9 (s, 3, CH3), 2.25-2.72 (m, 2, 2' CH2), 3.85-4.15 (2m, 3, 5' CH2, 4' H), 4.85 (m, 1, 3'H), 6.25 (dd, 1, 1'H), 6.5 and 6.95 (2d, 2, N=CH2), 7.43 (s, 1, (6H), 9.2 (br s, 1 NH).
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].[C:7](=O)([O-])[O-].[K+].[K+].BrC[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>CC(C)=O.ClCCl>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[CH2:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4])#[N:18]
Reactant: N#Cc1ccccc1CBr
Reactant: O=C([O-])[O-]
Reactant: CNS(C)(=O)=O
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(Cc1ccccc1C#N)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of N-methyl-methanesulfonamide (0.61 g, 5.6 mmol) and potassium carbonate (1.0 g, 7.6 mmol) in Acetone (10 mL) was added 2-bromomethyl-benzonitrile (1.0 g, 5.1 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (30 mL), filtered through a plug of diatomaceous earth and evaporated to a yellow waxy solid (1.2 g). N-(2-Cyano-benzyl)-N-methyl-methanesulfonamide was isolated as yellow waxy solid (1.2 g, 100%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.73-7.63 (m, 3H), 7.44 (t, J=7.5 Hz, 1H), 4.56 (s, 2H), 2.95 (s, 3H), 2.84 (s, 3H). MS=225 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[CH:13]1([C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14]1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[N:22]=2)[CH:7]=1
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: Nc1cccc(C2CCC2)n1
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1cccc(C2CCC2)n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 17.5 %

Procedure:
A heavy walled resealable tube was charged with methyl 4,6-dichloropyridazine-3-carboxylate (1.3 g, 6.28 mmol) and 6-cyclobutylpyridin-2-amine (931 mg, 6.28 mmol) in acetonitrile (6.00 mL). The tube was heated with stirring in an oil bath at 80° C. for 48 h. Solvent was evaporated under vacuum, the residue was dissolved in dichloromethane and then purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 10% over 20 min dichloromethane/acetone to give methyl 6-chloro-4-(6-cyclobutylpyridin-2-ylamino)pyridazine-3-carboxylate (350 mg, 17.5% yield) as a light yellow solid. 1H NMR (CHLOROFORM-d) δ: 10.62 (s, 1H), 9.49 (s, 1H), 7.59 (t, J=7.9 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 4.10 (s, 3H), 3.67 (quin, J=8.6 Hz, 1H), 2.24-2.58 (m, 4H), 1.85-2.22 (m, 2H); LC-MS 319.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[C:13]([F:21])([F:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[C:24]2[CH:31]=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:15]2)[C:13]([F:21])([F:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCNC2
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CC(F)(F)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 106.1 %

Procedure:
An optically-active compound of 3,3-difluoro-1,6-diaza-spiro[3.5]nonane-1-carboxylic acid benzyl ester 1 hydrochloride (11.2 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4.2 g), potassium carbonate (18.7 g) and water (104 ml), and the mixture was stirred for 16.5 hours with refluxing. The mixture was cooled to room temperature, and thereto were added ethyl acetate and water. The mixture was filtered, and the filtrate was separated and the resulting organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=3/1). The resulting residue was purified by silica gel column chromatography (eluent: chloroform/acetone=2/1) again to give the titled compound (12.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.O>[Cl:10][C:4]1[CH:3]=[C:2]([NH2:1])[CH:9]=[CH:8][C:5]=1[C:6]1[NH:13][N:12]=[N:11][N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nnn[nH]2)c(Cl)c1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-amino-2-chloro-benzonitrile (Aldrich, 765 mg, 5 mmol) in toluene (10 mL), sodium azide (423 mg, 6.5 mmol) and triethylamine hydrochloride (895 mg, 6.5 mmol) was added and the mixture was stirred vigorously at 115° C. overnight. The mixture was cooled and poured into water. The aqueous layer was adjusted to PH=5 by the addition of 6 N HCl and the solid formed was filtered and dried. 175 mg,
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9](O)=[C:6]([O:7]C)[CH:5]=1)=[O:3].C([O-])([O-])=[O:14].[K+].[K+].C(Br)C1C=CC=CC=1>CC#N>[CH3:1][C:2]([C:4]1[CH:12]=[CH:11][CH:9]=[C:6]([OH:7])[C:5]=1[OH:14])=[O:3]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: BrCc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cccc(O)c1O
Temperature: 25 °C
Yield: 70.3 %

Procedure:
To a solution of acetovanillone (33) (4.70 g, 28.3 mmol) in MeCN (60 mL) was added K2CO3 (8.05 g, 58.3 mmol) and KI (0.20 g, 1.2 mmol). The mixture was stirred under N2 atmosphere and benzyl bromide (34) (4.0 mL, 34 mmol) was added dropwise. The reaction mixture was reflux for 24 h and then cooled to 25° C., then resulting precipitate was filtered off. The filtrate was evaporated and purified by column chromatography (SiO2, n-hexane: CH2Cl2=1:2) to give 30. White solid; yield: 70.3%; mp 87-88° C.; 1H-NMR (CDCl3. 200 MHz): δ 2.51 (s, 3H), 3.91 (s, 3H), 5.20 (s, 2H), 6.86 (d, J=8.2 Hz, 1H), 7.21-7.55 (m, 7H); 13C-NMR (CDCl3, 50 MHz): δ 26.19, 56.05, 70.79, 110.53, 112.13, 123.07, 127.18, 128.10, 128.68, 130.72, 136.28, 149.49, 152.41, 196.80; Anal. calcd for C16H16O3: C, 74.98; H, 6.29. Found: C, 75.02; H, 6.25.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:15]=[C:14]([C:16]2[NH:24][C:23]3[C:22]4([CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH2:21][N:20](CC4C=CC(OC)=CC=4)[C:19](=[O:46])[C:18]=3[CH:17]=2)[CH:13]=[CH:12][N:11]=1>C(O)(C(F)(F)F)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:15]=[C:14]([C:16]2[NH:24][C:23]3[C:22]4([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH2:21][NH:20][C:19](=[O:46])[C:18]=3[CH:17]=2)[CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)c3[nH]c(-c4ccnc(-c5cc6ccccc6o5)n4)cc3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC2(CCNCC2)c2[nH]c(-c3ccnc(-c4cc5ccccc5o4)n3)cc21
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 95.7 %

Procedure:
A6 (3.60 g, 5.81 mmol) was dissolved in TFA (29.0 mL). The mixture was stirred at 140° C. for 40 min in the microwave. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The crude product was purified by Strong Cation Exchange (SCX) with MeOH as eluent, followed by rinsing with 0.7 N NH3 in MeOH to obtain the pure free base as yellow solid (2.22 g). 1H NMR (400 MHz, DMSO-D6, 300K): δ=1.64 (2H, d, J=12.8 Hz), 2.15 (2H, br dt, J=13.0 Hz), 2.71 (2H, t, J=11.9 Hz), 2.89 (2H, d, J=11.2 Hz), 3.46 (2H, s), 4.12 (1H, br s), 7.24 (1H, s), 7.35 (1H, t, J=7.4 Hz), 7.37 (1H, s), 7.46 (1H, t, J=7.4 Hz), 7.75 (1H, d, J=8.2 Hz), 7.81 (1H, d, J=5.6 Hz), 7.83 (1H, d, J=8.6 Hz), 8.09 (1H, s), 8.76 (1H, d, J=5.4 Hz), 11.78 (1H, br s); MS (ES) C23H21N5O2 requires: 399. found: 400.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[C:18](=O)[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[NH:11]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:18]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[N:11]=[C:12]2[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: COc1ccc(-n2[nH]c3c(c2=O)CCCC3)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-n2nc3c(c2Cl)CCCC3)c(F)c1
Yield: 10.8 %

Procedure:
The 4.32 g residue from Step B was mixed at ambient temperature with 5.37 g (0.035 mole) of phosphorus oxychloride until complete dissolution occurred. At this point the reaction mixture was heated at reflux under nitrogen for one hour. The phosphorus oxychloride was evaporated from the reaction mixture under reduced pressure, leaving a residue weighing 1.50 g. This residue, together with a similar residue weighing 0.30 g from an earlier experiment, was then was placed on a silica gel column and eluted with hexane/ethyl acetate (4:1). After the product-containing fractions were combined and the solvents evaporated under reduced pressure, 0.50 g of 3-chloro-2-(2-fluoro-4-methoxyphenyl)-4,5,6,7-tetrahydroindazole was isolated. The NMR was consistent with the proposed structure.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>C(#N)C>[CH3:32][O:33][C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([C:2]1[N:1]([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:4][N:3]=1)=[O:37]
Reactant: COc1ccccc1C(=O)Cl
Reactant: Clc1ccc(C(CCOC2CCCCO2)Cn2ccnc2)cc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1C(=O)c1nccn1CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-(Imidazol-1-yl)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (0.86 g) (see Preparation 30) and triethylamine (1.3 ml) were dissolved in acetonitrile (15 ml), under a nitrogen atmosphere, the solution cooled in an ice-bath and 2-methoxybenzoyl chloride (1.4 ml) added, dropwise. The mixture was allowed to warm to room temperature slowly and then stirred for 2 days. The acetonitrile was removed under reduced pressure and the residue dissolved in dichloromethane (20 ml) and washed sequentially with water and brine. The organic phase was then dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with 97:3, by volume, dichloromethane:methanol to give 1-[2-(2-methoxybenzoyl)imidazol- 1-yl]-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butane (1.1 g) as an oil and as a mixture of diastereomers.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].Cl>O1CCCC1>[CH2:20]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCCC(C(=O)OCC)C(=O)OCC
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
To 120 ml of dry tetrahydrofuran (THF) was added 4.9 g of 60% sodium hydride, and 29.5 g of diethyl malonate was added dropwise with stirring under ice-cooling. After addition, stirring was continued for 15 minutes, and then 10 g of 6-bromo-1-hexen was added to the mixture and heated to reflux for 21 hours. The reaction solution was cooled, poured into ice-cold water, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=20:1) to provide 14.5 g of the objective compound as yellowish oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].C[O:29][C:30](=[O:39])[CH:31](Br)[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([CH2:32][CH:31]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][C:17]([F:26])([F:27])[F:16])[CH:6]=[N:5]2)[C:30]([OH:29])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2OC(F)(F)F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-trifluoromethoxy-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethoxy-phenoxy)-6H-pyridazin-1-yl]-propionic acid as a white solid (14.11 g, 83% for the final step); LC-MS: 413.0 [M+1]+, tR=5.39 min. Purity on HPLC: 97.5% (214 nm), 97.9% (254 nm), tR=8.94 min. 1H NMR (300 MHz, CDCl3): δ 9.90 (s, 1H, broad), 7.89 (d, 1H, J=2.7 Hz), 7.40˜7.33 (m, 3H), 7.24 (s, 1H), 5.96 (d, 1H, J=2.4 Hz), 5.53 (dd, 1H, J1=10.2 Hz J2=4.5 Hz), 2.86˜2.38 (m, 1H), 2.29˜2.07 (m, 1H), 1.79˜1.49 (m, 7H), 1.20˜1.08 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36]([O:38]C)=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.CO.O.[OH-].[Na+]>C1COCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)O
Temperature: 80 °C
Yield: 83 %

Procedure:
To a suspension of methyl N-{[3′-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)biphenyl-4-yl]sulfonyl}valinate obtained in Reference Example 95 (0.250 g, 0.456 mmol) in THF (3 mL)-methanol (3 mL)-water (3 mL) was added 4N aqueous sodium hydroxide solution (0.399 mL, 1.60 mmol) at room temperature, and the mixture was stirred under heating at 80° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, and concentrated under reduced pressure, and the residue was diluted with water. The mixture was acidified with 1N hydrochloric acid, and partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol to give the title compound as a white powder (0.202 g, 83%).
Reaction SMILES: [S:1]([CH2:5][CH2:6][O:7][C:8](=[O:12])[C:9](C)=[CH2:10])([OH:4])(=[O:3])=[O:2].[K]>>[S:1]([CH2:5][CH2:6][O:7][C:8](=[O:12])[CH:9]=[CH2:10])([OH:4])(=[O:3])=[O:2]
Reactant: C=C(C)C(=O)OCCS(=O)(=O)O
Agent: [K]
Product: C=CC(=O)OCCS(=O)(=O)O

Procedure:
2-sulfoethylmethacrylate, potassium salt