Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH:10](O)[CH2:11][CH2:12][CH3:13])=[CH:8][N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>ClCCl>[Cl:27][CH:10]([C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=2)=[N:7][CH:8]=1)[CH2:11][CH2:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CCCC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Solvent: ClCCl
Product: CCCC(Cl)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
A solution of 392 mg (1.17 mmol) [rac]-1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butan-1-ol and 0.09 ml (1.22 mmol) thionylchloride in 4 ml dichloromethane were stirred at RT for 1 h. After concentration under reduced pressure 421 mg of pure [rac]-5-(1-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)C#CC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
To a solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate(7.46 g, 26.3 mmoles) in dichloromethane (350 mL) cooled in an ice-bath was added manganese dioxide (26.2 g, 301.3 mmol). The reaction mixture was stirred for 20 minutes and then was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 130 minutes and then was filtered twice through a pad of CELITE™. The filtrate was purified by flash chromatography on silica gel (195 g), eluting with dichloromethane, to afford 3.80 g (51%) of the title compound as a brownish-orange oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].C1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CCOCC>[CH2:36]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1cccn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A suspension of 10 g (65 mmol) of methyl pyrrol-2-ylglyoxylate in 100 ml of ether is added to a solution of 1.7 g (6.5 mmol) of 18-crown-6 with 7.3 g (65 mmol) of potassium tert-butylate in 100 ml of ether, stirring is carried out for 30 minutes and 11.1 g (65 mmol) of benzyl bromide in 50 ml of ether are then added dropwise. Stirring is carried out overnight at room temperature, the mixture is poured onto water and extracted with ether and the organic phase is dried and evaporated down. Chromatography over silica gel with hexane/ethyl acetate gives 6.7 g (42%) of the title compound as a reddish brown oi.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[C:11]([C:20]([F:21])([F:22])[F:23])[CH:12]=2)[C:17]([OH:19])=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (35.3 mL of a 0.31M stock solution, 10.9 mmol) cooled to −78° C. was treated with (4-fluoro-3-trifluoromethyl-phenyl)-acetic acid (1.11 g, 5.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.4 mL, 3:1). The resulting solution was stirred at −78° C. for 1 h. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.16 g, 5.52 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.2 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. This solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (3×100 mL) and diethyl ether (1×50 mL). The organics were dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate with acetic acid) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (1.28 g, 84.3%) as a white solid: mp 66-68° C.; El-HRMS m/e calcd for C15H16F4O2(MM 305.1165, found 305.1174.
Reaction SMILES: S([O-])(=O)(=O)C.ClCCl.[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([O:18][CH2:19][CH3:20])(=O)C>>[CH2:11]([C:10]1[CH2:13][CH:12]2[CH2:11][CH:10]([CH2:9][C:19](=[O:18])[CH2:20]2)[CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: CS(=O)(=O)[O-]
Solvent: ClCCl
Product: CCCCC1=CC2CC(=O)CC(C1)C2
Yield: 41 %

Procedure:
This reaction was performed in a manner similar to that described for the preparation of IIc, starting from mesylate IV (X=--CH2 --; R=n--C4H9) (13.6 g, 47.2 mmol), silica gel (14 g) and dichloromethane (140 ml). The residue obtained was subjected to column chromatography on silica gel (120 g) using hexane/ethyl acetate mixtures of increasing polarity as eluent. On elution with 95:5 hexane/ethyl acetate, the ketone IIe (3.7 g, 41% yield) was obtained. Continuing the elution with 90:10 hexane/ethyl acetate, alcohol V (X=--CH2 --; R=n--C4H9) (2.8 g, 28% yield) was obtained.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:8]([C:7]1[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=1)=[O:9]
Reactant: Clc1cccc(Cl)c1CC1CCCN1
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C(=O)N2CCCC2Cc2c(Cl)cccc2Cl)c(C(F)F)n1
Reaction time: 15 h
Yield: 78.8 %

Procedure:
At a temperature of 0° C., a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.97 g; 5.0 mmol) in dichloromethane (5 ml) was added dropwise to a stirred suspension of 2-(2,6-dichloro-benzyl)-pyrrolidine (1.20 g; 5.0 mmol), which was prepared as described in example P17, and triethylamine (1.5 g; 15.0 mmol) in dichloromethane (15 ml). The ice bath was removed and reaction mixture was allowed stirring for 15 hours. The reaction mixture was washed with 2M NaOH (20 ml), 2M HCl (20 ml) and saturated NaCl (20 ml) and then dried over Na2SO4. After removal of the solvent, the residue (1.9 g oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 3:7). 1.53 g (78.8% of theory) of [2-(2,6-dichloro-benzyl)-pyrrolidin-1-yl]-(3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanone was obtained in form of an oil.
Reaction SMILES: C([Li])CCC.[C:6]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].[B:20](OC)([O:23]C)[O:21]C.[Cl-].[NH4+]>C1COCC1>[B:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([NH:10][C:6]([CH3:9])([CH3:7])[CH3:8])(=[O:13])=[O:12])([OH:23])[OH:21]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 22 °C
Reaction time: 1 h

Procedure:
27 ml of n-butyllithium (15% solution in n-hexane) are added dropwise at −5° C. to a solution of 4.29 g of N-tert-butylbenzenesulfonamide in 25 ml of THF under argon. The mixture is stirred at 22° C. for 1 h, re-cooled to −5° C., and 2.8 g of trimethyl borate are slowly added dropwise. The mixture is stirred at 22° C. for 3 h, before 100 ml of aqueous ammonium chloride solution is added dropwise. The phases are separated, and the aqueous phase is extracted a further twice with MTB ether. The combined organic phases are dried over magnesium sulfate. Filtered and evaporated to dryness in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([CH2:29]Cl)=[O:28]>>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([CH2:29][N:14]1[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[N:11]([CH2:29][C:27]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[C:10](=[O:21])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]1=[O:16])=[O:28]
Reactant: O=C(CCl)c1cccs1
Reactant: CC(C)(C)OC(=O)NC1C(=O)Nc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NC1C(=O)N(CC(=O)c2cccs2)c2ccccc2N(CC(=O)c2cccs2)C1=O

Procedure:
Compound 14g is prepared in a manner similar to that used for preparation of Compound 14 h using previously prepared Compound 13 and 2-thienylcarbonylmethyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[CH:20]=[N:19][CH:18]=[C:17]([NH:21][C:22]3[N:23](C(OC(C)(C)C)=O)[N:24]=[C:25]([C:27]4[C:28]([O:34][CH3:35])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[CH:26]=3)[N:16]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:35][O:34][C:28]1[C:27]([C:25]2[CH:26]=[C:22]([NH:21][C:17]3[CH:18]=[N:19][CH:20]=[C:15]([O:14][C@@H:10]4[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]4)[N:16]=3)[NH:23][N:24]=2)=[CH:32][CH:31]=[C:30]([CH3:33])[N:29]=1
Reactant: COc1nc(C)ccc1-c1cc(Nc2cncc(O[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)n2)n(C(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(C)ccc1-c1cc(Nc2cncc(O[C@@H]3CCCNC3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-3-{6-[2-tert-butoxycarbonyl-5-(2-methoxy-6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylamino]-pyrazin-2-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (13.0 g, 22.3 mmol) in dichloromethane (150 mL) is added a solution of trifluoroacetic acid (12.4 mL, 167 mmol) dichloromethane (20 mL) over a period of 5 min at 0° C. The reaction is allowed to warm to room temperature and stirred for 3 h. The reaction is diluted with dichloromethane (1000 mL), followed by addition of saturated sodium bicarbonate solution (250 mL) and then stirred for 4 h. The organic portion is separated and dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting material is crystallized from isopropanol to obtain the desired product. Yield=7.2 g (85%). 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.71 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.97 (s, 1H), 7.46)(s, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.91 (s, 1H), 4.94-4.86 (m, 1H), 3.97 (s, 3H), 3.20-3.13 (m, 1H), 2.83-2.75 (m, 1H), 2.57 (dd, J=12.0, 84 Hz, 1H), 2.53-2.45 (m obscured, 1H), 2.42 (s, 3H), 2.15-2.05 (m, 1H), 1.71-1.63 (m, 1H), 1.60-1.49 (m, 1H), 1.49-1.40 (m, 1H); ES/MS m/z 382.5 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17])[CH:12]=O.N1CCCCC1>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[S:3])[NH:1]2)[CH:14]=[C:15]([Cl:18])[C:16]=1[OH:17]
Reactant: O=Cc1cc(O)c(O)c(Cl)c1
Reactant: O=C1CNC(=S)N1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1NC(=S)NC1=Cc1cc(O)c(O)c(Cl)c1
Temperature: 100 °C

Procedure:
A solution containing 1.16 g of thiohydantoin, 1.72 g of 3,4-dihydroxy-5-chlorobenzaldehyde and 0.2 ml of piperidine in 20 ml of acetic acid was heated for 4 h at 100° C. The product was filtered and washed with ether. Yield 1.0 g, mp 303-304° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)n1
Product: Cc1cccc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 62.9 %

Procedure:
6 mg of 5-(4-chlorophenyl)-6-methyl-4-(6-methyl-2-pyridyl)-2H-pyrida zin-3-one and 2 g of phosphorus oxychloride were mixed. The mixture was stirred for 4 hours on an oil bath of 130° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 4 mg of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(6-methyl-2-pyridyl)pyridazine (hereinafter, described as compound (4) of the present invention.).
Reaction SMILES: [F:1]C1C(F)=C(F)C(F)=C(F)C=1F.C(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]2[N:24]=[C:25]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:26]([C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[C:19]2[CH:18]=1>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CC(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([F:1])[N:20]2[N:24]=[C:25]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:26]([C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:28])=[C:19]2[CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cc(Cl)cc12
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [C-]#N
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(F)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing tetrabutylammoniumcyanide and THF (0.912 mL, 1.0 M) was added a solution containing hexafluorobenzene and THF (0.760 mL, 0.2 M) at −35° C. (caution, exothermic). The solution was removed from cooling and maintained at ambient temperature for 150 min. The solution thus obtained was cooled to 0° C. (ice bath) and added dropwise with stirring to a pre-cooled solution (−50° C., dry ice, acetone) containing tert-butyl 5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate and THF (0.608 mL, 0.38 M). The solution thus obtained was removed from cooling and allowed to proceed for 18 h. The solution was poured into water (25 mL). The aqueous portion was then extracted with ethyl acetate (2×25 mL). The organic portions were combined, then washed with water (3×20 mL), then washed with brine (25 mL), then dried over MgSO4, filtered and concentrated. The residue thus obtained was purified on silica gel (0-20% ethyl acetate/hexanes, 25 min gradient) to afford tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65-7.76 (m, 3H), 7.11-7.20 (m, 2H), 6.64 (dd, J=4.77, 2.01 Hz, 1H), 3.27 (s, 3H), 1.12 (s, 9H). LCMS retention time: 2.743 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 422 (MH+).
Reaction SMILES: C([C:4]1[CH:5]=[N:6][N:7]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][N:11]=2)[C:8]=1[OH:9])(O)=O>Cl>[OH:9][C:8]1[N:7]([C:10]2[CH:15]=[C:14]([CH:13]=[CH:12][N:11]=2)[C:16]([OH:18])=[O:17])[N:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccnc(-n2ncc(C(=O)O)c2O)c1
Agent: Cl
Product: O=C(O)c1ccnc(-n2nccc2O)c1
Yield: 16.5 %

Procedure:
A solution of 2-(4-carboxy-5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carboxylic acid (1.7 g, 6.8 mmol) in conc. HCl (50 mL) was heated at 90° C. for 2 h. The reaction mixture was cooled, extracted with EtOAc (200 mL), and washed with water and brine. The organic phase was dried, concentrated, and recrystallized from EtOH to afford the title compound (230 mg, 47%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 4.86 (1H, s), 7.68 (1H, s), 7.80 (1H, d, J=5.2 Hz), 8.60 (1H, d, J=1.6 Hz), 8.73 (1H, br). [M+H] Calc'd for C9H7N3O3, 206; Found, 206.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][C@@H:11]([OH:13])[CH2:10][N:9]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[CH:5]=[CH:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]([O:50]C(/N=N/C(OC(C)C)=O)=O)C.C(O)(=O)C>C1COCC1>[C:48]([O:13][C@@H:11]1[CH2:10][N:9]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:12]1)(=[O:50])[CH3:47]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CCOC(=O)c1cnn2ccc(N3C[C@H](O)C[C@@H]3c3cccc(F)c3)nc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2ccc(N3C[C@@H](OC(C)=O)C[C@@H]3c3cccc(F)c3)nc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.8 %

Procedure:
To a mixture of ethyl 5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 41, Step E, 260 mg, 0.702 mmol) and PPh3 (460 mg, 1.75 mmol) in THF (10.0 mL) was added DIAD (276 μL, 1.40 mmol) followed by acetic acid (80.4 μL, 1.40 mmol). The reaction was stirred at ambient temperature for 48 hours and then concentrated. The residue was purified by reverse phase column chromatography (0-70% acetonitrile/water) to afford ethyl 5-((2R,4S)-4-acetoxy-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (228 mg, 79% yield). MS (apci) m/z=413.0 (M+H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:13](Cl)=[O:14].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:13]([C:12]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:10]([Cl:9])[CH:11]=2)=[O:14])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 3,4-dichlorobenzoyl chloride (2.095 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 8 hours. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate to obtain 270 mg of the title compound (yield: 10%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2nnn(C)n2)ccc1OC
Temperature: 25 °C

Procedure:
Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol) methyl iodide (0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g, 3.33 mmol) were combined in acetone (8 mL) and heated at reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated. Flash chromatography on silica gel afforded 170 mg (21%). LC/MS (HPLC method 3): tR=2.01 min, 249.09 (MH)+
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([C:12]3[N:16](C4CCCCO4)[N:15]=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][NH:3]1.[Cl:23][C:24]1[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([F:37])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:23][C:24]1[C:32]([C:33]([F:35])([F:36])[F:34])=[C:31]([F:37])[CH:30]=[CH:29][C:25]=1[C:26]([N:3]1[CH2:4][CH2:5][C:6]2[C:11]([C:12]3[NH:16][N:15]=[CH:14][CH:13]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:2]1[CH3:1])=[O:27]
Reactant: CC1NCCc2c(-c3ccnn3C3CCCCO3)ncnc21
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CC[SiH](CC)CC
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1c2ncnc(-c3ccn[nH]3)c2CCN1C(=O)c1ccc(F)c(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of the product of Example 112, step g (60 mg, 0.20 mmol) in DCM (2 mL) was added 2-chloro-4-fluoro-3-(trifluoromethyl)benzoic acid (49 mg, 0.20 mmol), followed by EDCI (116 mg, 0.607 mmol), HOBt (19 mg, 0.14 mmol) and TEA (2.0 mL, 0.607 mmol). The reaction was stirred at room temperature overnight. The crude mixture was treated directly with TFA (0.8 mL) and triethylsilane (81 L, 0.20 mmol) and stirred for 3 h. The solvents were removed in vacuo and the residue was azeotroped with toluene (1×). Chromatography on SiO2 eluted with EtOAc/Hex afforded the desired product (59 mg, 66%). MS (ESI) mass calcd. C19H14ClF4N5O, 439.1. m/z found 440.1 [M+H]+. 1H NMR (500 MHz, MeOD): 9.08-8.87 (m, 1H), 7.92-7.68 (m, 2H), 7.57-7.44 (m, 1H), 7.10-6.92 (m, 1H), 5.71-5.63 (m, 1H), 3.68-3.33 (m, 3H), 3.19-3.08 (m, 1H), 1.77-1.56 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[C:7]3[OH:12])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cccc2c(O)cccc12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc3c(O)cccc23)cc1
Yield: 96 %

Procedure:
A solution of 1 mole 5-amino-1-naphthol in dry pyridine was stirred at 0°C and treated portionwise with 1 mole of p-toluenesulfonyl chloride. When analysis showed that the 5-amino-1-naphthol was consumed the reaction mixture was poured onto a sufficient quantity of aqueous hydrogen chloride to neutralize the excess pyridine and allow separation of the product as a fine powder which was filtered, washed with water, and recrystallized from ethanol to obtain (96% yield) analytically pure 5-p-toluenesulfonamido-1-naphthol having a melting point of 182°-194°C. Next, 2.58 g. (4.00 mmol) of 4-(m-aminophenylsulfonamido)-N-[4-(2,4-di-tert-pentylphenoxy)butyl]-1-hydroxy-2-naphthamide were dissolved in 10 ml. dry pyridine and treated with 50 ml. 5:1 acid and 10 ml. concentrated hydrochloric acid. The clear solution was cooled to 0°C. and treated with a solution of 284 mg. (4.00 mmol) sodium nitrite in 3 ml. of ice water. The resulting orange solution was added rapidly to a solution of 1.25 g. (4.00 mmol) of the above sulfonamidonaphthol dissolved in 8 ml. dry pyridine and 50 ml. 5:1 acid, and cooled to 5°C. The orange dye formed immediately. After 40 minutes at 5°-10°, the dye was precipitated by adding 300 ml. ice water and adjusting the pH to 2 with concentrated HCl. The orange powder obtained by filtration was washed with 8 liters of water and dried to give 3.31 g. Compound 12. This compound was tested in a manner similar to that of Example 12A and the released dye was found to have a λ max of 555 nm. The Dmax of transferred image was 0.97.