Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:29])[C:25]([O:27]C)=[O:26])=[CH:20][C:19]=3[Cl:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:29])[C:25]([OH:27])=[O:26])=[CH:20][C:19]=3[Cl:30])=[CH:16][CH:17]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)C(C)c1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(C(C)C(=O)O)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Powdered potassium hydroxide (331 mg, 5.90 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)propanoate (Intermediate 8-1; 834 mg, 1.97 mmol) in tert-butanol (20 mL) at 45° C. The resulting solution was stirred at 45° C. for 30 minutes. 2M HCl (6 mL) was added and the mixture was evaporated to remove the organic solvent. The suspension was collected by filtration, washed with water and dried under vacuum to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing the desired compound were evaporated to dryness to afford racemic 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)propanoic acid (603 mg, 74.8%) as a white solid. This was purified by preparative chiral-HPLC on a OJ column, eluting isocratically with 30% EtOH in isohexane (acidified with AcOH) as eluent. The fractions containing the desired compound were evaporated to dryness to afford:
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@H:10]([O:11][CH2:12][CH:13]=[CH2:14])[C@@H:9]([O:15][CH2:16][CH:17]=[CH2:18])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH3:35])=[CH:29][CH:28]=3)[CH:20]=2)[N:7]([CH3:36])[C@@H:6]1[CH2:37][O:38][CH2:39][CH:40]=[CH2:41])[CH:2]=[CH2:3]>C1COCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([O:15]/[CH:16]=[CH:17]/[CH3:18])[C@@H:10]([O:11]/[CH:12]=[CH:13]/[CH3:14])[C@H:5]([O:4]/[CH:1]=[CH:2]/[CH3:3])[C@@H:6]([CH2:37][O:38]/[CH:39]=[CH:40]/[CH3:41])[N:7]2[CH3:36])=[CH:20][C:21]=1[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH3:35])=[CH:31][CH:32]=1
Reactant: C=CCOC[C@@H]1[C@@H](OCC=C)[C@H](OCC=C)[C@@H](OCC=C)[C@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)N1C
Solvent: C1CCOC1
Product: C/C=C/OC[C@@H]1[C@@H](O/C=C/C)[C@H](O/C=C/C)[C@@H](O/C=C/C)[C@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)N1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 0.1 %

Procedure:
Ir(COD)[PCH3Ph2]PF6 (27 mg, 30 mol %) in THF (1 ml) was stirred under an atmosphere of H2 until the color changed from red to pale yellow (˜5 minutes). Compound from Step A (62 mg, 0.11 mol) in THF (1.5 ml) was then added and the mixture stirred at room temperature for 45 minutes and then concentrated. Purification by silica gel chromatography (20% EtOAc/hexanes) afforded (2S,3S,4R,5R,6R)-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-1-methyl-3,4,5-tris-[((E)-propenyl)oxy]-6-[((E)-propenyl)oxymethyl]-piperidine (62 mg, 0.11 mmol, 100%) as a colorless oil. MS (ES+) [M+H]+=582.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][Cl:27].[OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.C(O)C>C(O)C.CC(C)=O>[ClH:27].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 85.9 %

Procedure:
A mixture of 30.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one, 17.8 g of 2-(dimethylamino)ethyl chloride hydrochloride, 13.7 g of 96% potassium hydroxide, 60 g of sodium sulfate and 300 ml of acetone is stirred at 50° C. for 7 hours. After the reaction is completed, the mixture is filtered to remove inorganic materials and the filtrate is condensed. The residue is dissolved in ethanol. After cooling the solution, 10% HCl/ethanol is added thereto. The crystalline precipitates are collected by filtration and then dried. 35.1 g of cis-(+)-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepine-4(5H)-one hydrochloride are thereby obtained. Yield: 86.2%
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Product: COC(=O)c1c(CNC(=O)c2ccc(OC)cc2)c(=O)c2ccc(OC)cc2n1-c1ccccc1

Procedure:
3-[(4-methoxy-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester was prepared starting from intermediate K and 4-methoxybenzoyl chloride. MS calcd. for C27H24N2O6 [(M+H)+] 473.2, obsd. 473.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9]COC)=[CH:4][C:3]=1[CH2:13][O:14]COC.FC1C=CC2[B:26](O)[O:25]CC=2C=1>>[OH:25][B:26]1[C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=2[CH2:13][O:14]1
Reactant: OB1OCc2cc(F)ccc21
Reactant: COCOCc1ccc(Br)c(COCOC)c1
Product: OCc1ccc2c(c1)COB2O

Procedure:
This compound was made from 18h in the same manner as compound 19b: mp 124-128° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.53 (d, 2H), 4.94 (s, 2H), 5.24 (t, 1H), 7.26 (d, 1H), 7.33 (s, 1H), 7.64 (d, 1H), 9.08 (s, 1H); ESI-MS m/z 163 (M−H)−; HPLC purity 100%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1)[C:11]#[N:12].[OH-:27].[Na+]>S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:18]=[C:17]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[N:14]=1)[C:11]([NH2:12])=[O:27]
Reactant: [OH-]
Reactant: CC(C)(C)c1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccccc3S2)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)c1cc(C(F)(F)F)nc(C(C(N)=O)=C2Nc3ccccc3S2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[Benzothiazol-2(3H)-ylidene]-2-[4-tert-butyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile (150 mg, 0.39 mmol) was dissolved in concentrated sulfuric acid (1.5 mL) and stirred at room temperature overnight. The mixture was cooled to 0° C., poured over ice, and neutralized with 50% aqueous sodium hydroxide. The product was partially extracted into chloroform, and dried to a brown solid (57 mg), which was purified by reverse phase preparative HPLC to give 2-[benzothiazol-2(3H)-ylidene]-2-[4-tert-butyl-6-(trifluoromethyl)pyrimidin-2-yl]acetamide (13 mg) as a yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:33][C@H:34]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)[CH2:35][C@:36]([CH2:41][OH:42])([CH3:40])[C:37]([OH:39])=[O:38]>CCN(C(C)C)C(C)C.CN(C=O)C>[C:47]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:46]=[CH:45][C:44]([CH2:43][C@@H:34]([NH:33][C:6]([C:4]2[NH:3][N:2]=[N:1][CH:5]=2)=[O:8])[CH2:35][C@:36]([CH2:41][OH:42])([CH3:40])[C:37]([OH:39])=[O:38])=[CH:49][CH:48]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: O=C(O)c1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (130 mg, 1.2 mmol, 1.2 eq.) and HATU (400 mg, 1.1 mmol, 1.1 eq.) were dissolved in DIPEA (167 μL) and the resulting mixture was stirred for 5 minutes at room temperature in DMF (0.2 mL). DIPEA (3 eq.) and (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid (300 mg, 957 μmol, 1.0 eq.) dissolved in DMF (0.2 mL) was added, and the resulting mixture was stirred for 15 minutes. The reaction was quenched with AcOH and the product was purified by preparative HPLC then lyophilized to yield the title compound (120 mg, 95% purity). MS m/z [M+H]+ calc'd for C22H24N4O4, 409.18. found 409.4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:2].[Br:21]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[C:10]([CH2:11][Br:21])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:2]
Reactant: CCOC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 83.1 %

Procedure:
2-(tert-Butyl-dimethyl-silanyloxy)-6-methyl-benzoic acid ethyl ester (7.6 g, 25.8 mmol), N-bromosuccinimide (4.82 g, 27.1 mmol) and azobis(cyclohexanecarbonitrile) (0.32 g, 1.3 mmol) were dissolved in tetrachlormethane (130 ml). The solution was stirred at room temperature for 60 hours. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel column using a gradient of 1-2% ethyl acetate/hexane as eluent, which afforded 8.0 g (83%) of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]([CH3:38])([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:35](=[CH:36][CH:37]=1)[C:16]1=[N:17][O:18][C:19]([C:20]3[CH:21]=[N:22][N:23]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:24]=3[C:25]([F:28])([F:27])[F:26])=[C:15]1[CH2:14][CH2:13]2)[C:3](OCC)=[O:4].[BH4-].[Na+].C(OCC)(=O)C.[Cl-].[NH4+]>C(O)C.O>[NH2:1][C:2]([CH3:38])([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:35](=[CH:36][CH:37]=1)[C:16]1=[N:17][O:18][C:19]([C:20]3[CH:21]=[N:22][N:23]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:24]=3[C:25]([F:28])([F:27])[F:26])=[C:15]1[CH2:14][CH2:13]2)[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)(N)CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(N)(CO)CCc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Yield: 43.1 %

Procedure:
To a stirred solution of ethyl 2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 50D, 80 mg, 0.153 mmol) in ethanol (1 mL) was added sodium borohydride (30 mg, 0.793 mmol) at room temperature. The reaction mixture was stirred at room temperature for 19 hr before ethyl acetate (4 mL) and water (2 ml) were added followed by the addition of saturated aqueous ammonium chloride solution (3 mL). The aqueous layer was separated and extracted with ethyl acetate (3×2 mL). The combined ethyl acetate solutions were dried over sodium sulfate and concentrated under reduced pressure to give a white solid. The solid was triturated with ethyl acetate to give 2-amino-2-methyl-4-(3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butan-1-ol (32 mg, 0.066 mmol, 43.5% yield) as a white solid.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][NH2:13]>O>[CH3:12][N:13]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:6]
Reactant: CN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: CN1C(=O)c2ccccc2C1=O

Procedure:
To a suspension of 25.0 g (0.17 mol) of phthalic anhydride in 200 ml of water was added 30 g (0.38 mol) of a 40% aqueous solution of methylamine. The mixture was heated at reflux for four hours, after which approximately 50 ml of the aqueous amine was removed by distillation and the mixture allowed to cool. The resultant precipitate was collected by filtration to yield 10.3 g of N-methylphthalimide (cyclic imide (b)(4)).
Reaction SMILES: ClCC=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C.[NH:21]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:22][C:23]([O-:25])=[O:24]>>[NH:21]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CNCC(=O)[O-]
Agent: C=Cc1ccccc1C=C
Agent: ClCC=Cc1ccccc1
Product: O=C(O)CNCC(=O)O
Reaction time: 24 h

Procedure:
To a crosslinked copolymer of chloromethylstyrene-divinylbenzene (weight ratio of chloromethylstyrene to divinylbenzene: 80/20) was added ethyl iminodiacetate in an amount two times the molar amount of chloromethyl groups of the crosslinked copolymer of chloromethylstyrene-divinylbenzene, and reaction was allowed to proceed at 120° C. for 24 hours. The obtained solid product was filtered off using a glass filter and washed with acetone. Thus, there was obtained a granular iminodiacetic acid type chelating resin having a particle diameter of 74 to 147μ [100 to 200 mesh (Tyler)] (hereinafter referred to as "Adsorbent A"). The degree of coversion was 70%. The obtained chelating resin was packed in a glass-made column equipped with a stopcock for an outlet at the bottom thereof and a jacket and having an inside diameter of 10 mm and a length of 1000 mm. Then the temperature of the whole column was maintained at 50° C., and to the column at its top was supplied an aqueous ammonia having a pH value of 9.0, with the outlet opened by switching the stopcock. The supply of the aqueous ammonia was continued until the pH value of the solution flowing out of the outlet of the column reached 9.0. Thus, the chelating resin was equilibrated with the solution. Then 150 ml of an aqueous solution containing 15 mM each of lanthanum (III) chloride and neodymium (III) chloride and adjusted, by an aqueous hydrogen chloride solution, to have a pH value of 4.0 was supplied to the top of the column at a rate of 3.5 ml/min. Subsequently, a 0.1M aqueous hydrogen chloride solution was fed to the top of the column at a rate of 3.5 ml/min. It took 2 hours for the rear portion of the adsorption band to flow out of the column. During the supply of the 0.1M aqueous hydrogen chloride solution, the rear boundary of the adsorption band which was visible due to the purple neodymium ions present in the rear portion of the band was kept clear. The eluate from the bottom of the column was collected in 5-ml fractions. The concentration of the rare earth elements in each fraction was determined using X-ray fluorescent spectrometer VXQ-150 (an apparatus manufactured and sold by Shimadzu Corporation, Japan).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7](Cl)(=[O:9])=[O:8].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH3:22])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][N:21]([CH3:22])[S:7]([C:6]2[CH:5]=[C:4]([Cl:11])[S:3][C:2]=2[Cl:1])(=[O:9])=[O:8])=[CH:17][CH:18]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1cc(Cl)sc1Cl

Procedure:
From 2,5-dichlorothiophene-3-sulfonyl chloride (755 mg) and [2-(4-fluorophenyl)ethyl]methylamine (the compound of Preparation Example 14) (510 mg), the title compound (1.14 g) was obtained as a colorless oily matter, in the same way as Preparation Example 41.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]3[N:31]=[CH:32][C:33]([C:34]4[CH:35]=[N:36][C:37]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[CH:38][CH:39]=4)=[C:10]3[N:9]=2)[CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:54])C=1>C(Cl)Cl>[C:40]1([C:37]2[N:36]=[CH:35][C:34]([C:33]3[CH:32]=[N:31][N:11]4[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])=[CH:13][C:8]([CH:5]5[CH2:4][CH2:3][C:2]6([O:54][CH2:1]6)[CH2:7][CH2:6]5)=[N:9][C:10]=34)=[CH:39][CH:38]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC3(CC2)CO3)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.9 %

Procedure:
To a solution of 5-(4-methylenecyclohexyl)-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (455 mg, 0.709 mmol) in DCM (4 mL) at 0° C. was added a solution of m-CPBA (191 mg, 0.850 mmol) in DCM (3 mL). The resulting mixture was warmed to rt and stirred for 4 h. All the volatiles were removed under reduced pressure and the residue was purified by a SiO2 column (0-20% EtOAc/Hexanes, Rf=0.25 in 20% EtOAc) to afford 3-(6-phenylpyridin-3-yl)-5-(1-oxaspiro[2.5]octan-6-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a pale yellow oil (163 mg). HPLC-MS TR=3.32 min (UV 254 nm, 5 min method); mass calculated for formula C36H51N5O3Si2 657.4, observed LCMS m/z 658.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:15][NH2:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].CN(C)C(N(C)C)=N.C(OO)(=O)C>ClCCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[N+:15]=[N-:16]
Reactant: Cc1ccccc1C(=NN)c1ccccc1
Agent: CC(=O)OO
Agent: CN(C)C(=N)N(C)C
Agent: [I-]
Solvent: ClCCCl
Product: Cc1ccccc1C(=[N+]=[N-])c1ccccc1
Reaction time: 0.08 h

Procedure:
To (2-methylphenyl)phenyl ketone hydrazone (10.5 g, 0.05 moles) dissolved in 1,2-dichloroethane (50 ml) containing iodide (2 ml, 1% w/v solution) and 1,1,3,3-tetramethylguanidine (22.5 ml) was added peracetic acid solution (11.4 ml, 1.27 × 0.05 moles) at 0° over 30 minutes. After the addition the mixture was stirred for 5 minutes longer. The red solution was washed with water (5 × 200 ml), dried over sodium sulphate and made up to 250 ml in a volumetric flask. An aliquot (50 ml) treated with excess acetic acid yielded 221 ml gas corrected to NTP which corresponded to a 98.6% yield of diazoalkane. The compound was characterised by a major absorption at 2050 cm-1 and λmax 516 nm. A solid ester derivative was made by treating (5R, 6R, 1S, 3S)-2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid 1-oxide in chloroform with an aliquot of the diazoalkane solution. After gas evolution had ceased the slightly yellow solution was washed with 5% sodium bicarbonate solution, water, and the organic residue left after removal of the organic solvent crystallised from hot propan-2-ol. The solid was identified as (2-methylphenyl)phenylmethyl (5R, 6R, 3S, 1S)-2,2-dimethylpenam-6-phenylacetamidopenam-3-carboxylate 1-oxide by its n.m.r. spectrum and melting point and mixed melting point 140° - 145° with an authentic sample of the ester.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:7][CH:6]=1)=[O:4].C(O)(=O)C>CO>[OH:4][CH2:3][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(CSCCN2C(=O)c3ccccc3C2=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCSCc1ccc(CO)o1
Reaction time: 0.75 h

Procedure:
Sodium borohydride (165 mg) was added in portions over a period of 10 mins to a solution of 2-[2-[(5-formyl-2-furanylmethyl)thio]ethyl]-1H-isoindole-1,3(2H)-dione (5.0 g) in methanol (100 ml) at 0° C. After stirring for 45 mins, acetic acid (1 ml) was added and the mixture evaporated. Water (100 ml) was added and the solid that precipitated extracted into ethyl acetate (2×150 ml). The ethyl acetate extracts were dried (magnesium sulphate) and evaporated yielding an oil which solidified on trituration in light petroleum (b.p. 60°-80° C.). Crystallisation from methyl acetate-light petroleum (b.p. 60°-80° C.) afforded the title compound as a light, white solid (4.05 g) m.p. 82.5°-84° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[F:12][C:5]1[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:3][C:2]([NH:1][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1F
Product: COC(=O)c1cc(NCc2ccc(OC)cc2)cc(N2CCCC2=O)c1F

Procedure:
Methyl 2-fluoro-5-({[4-(methyloxy)phenyl]methyl}amino)-3-(2-oxo-1-pyrrolidinyl)benzoate (D154) was prepared from methyl 5-amino-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D150) in an analogous manner to the process described for Ester 35 (B35) using 4-(methyloxy)benzaldehyde instead of propionaldehyde. [M+H]+=373.4, RT=2.85 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[O:32]=[S:26]1(=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 67.3 %

Procedure:
Using (4-bromo-2-methylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (402 mg) described in Preparation Example 253 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (307 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=Cc1ccc(Oc2cccnc2)cc1
Yield: 44.1 %

Procedure:
A mixture of 25 g of 3-bromopyridine, 20 g of 4-hydroxybenzaldehyde, 60 g of potassium carbonate and 150 ml of hexamethylphosphoramide was heated at a temperature of 130° to 135° C. for 11 hours. After cooling, the mixture was poured into water and extracted with diethyl ether. The ether extract was washed with water and extracted with 10% hydrochloric acid. The aqueous layer was washed with diethyl ether, rendered alkaline with sodium hydroxide and extracted with diethyl ether. The ether extract was washed with water and dried over sodium sulfate. The solvent was distilled off and the resulting oily substance was purified by silica gel chromatography (eluted with diethyl ether) to obtain 13.9 g (45% yield) of 4-(3-pyridyloxy)benzaldehyde as a colorless oil having a boiling point of 135°-140° C./2-3 mmHg.