Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:10][N:11]([C:13]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:10][N:11]([C:13]3[CH2:18][CH:17]([CH3:19])[C:16](=[O:20])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-n2cc(-c3ccnc(N)c3)c(-c3ccc(F)cc3)n2)n[nH]c1=O
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: CC1CC(n2cc(-c3ccnc(N)c3)c(-c3ccc(F)cc3)n2)=NNC1=O
Yield: 50.9 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 100 mg (0.28 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,6-dihydro-5-methyl-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 32-2) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 51.9 mg of the title compound as a white powder. (Yield: 51%)
Reaction SMILES: Cl.C([O:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:14](=[O:26])[N:13]([CH3:27])[CH:12]=1)=[O:10])=C.CCO.[OH-].[Na+]>CCOC(C)=O.C1COCC1>[OH:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[F:25])=[CH:15][C:14](=[O:26])[N:13]([CH3:27])[CH:12]=1)=[O:10]
Reactant: C=COCCONC(=O)c1cn(C)c(=O)cc1Nc1ccc(Br)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NOCCO)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
1 N HCl solution (0.36 mL) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (0.077 g, 0.181 mmol) in a 1:1 mixture of EtOH:THF (6 mL). After 1 hour, the pH of the reaction mixture was adjusted to 5 to 7 with 2 N NaOH solution. The reaction mixture was diluted with EtOAc, washed with water, dried (MgSO4) and concentrated. Trituration with diethyl ether yielded 55 mg (76%) clean desired product as a white solid. MS APCI (−) m/z 398, 400 (M−, Br pattern) detected; 1H NMR (400 mHz, DMSO-d6) δ 11.65 (s, 1H), 9.41 (s, 1H), 8.13 (s, 1H), 7.68 (d, 1H), 7.43 (m, 3H), 4.74 (t, 1H), 3.91 (t, 2H), 3.62 (m, 2H), 3.36 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:3]1.[H-].[Na+].[CH3:19][O:20][C:21](=[O:30])[CH:22](Br)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:19][O:20][C:21](=[O:30])[CH:22]([N:7]1[C:2](=[O:1])[CH:3]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[N:6]1)[CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: N#Cc1ccccc1Oc1cn[nH]c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(Oc2ccccc2C#N)cc1=O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
A solution of 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (13.4 g, 62.9 mmol) in tetrahydrofuran (300 mL) cooled to −10° C. under nitrogen was treated with a 60% suspension of sodium hydride in mineral oil (3.5 g, 88.1 mmol). The reaction was stirred at −10° C. for 10 min and then warmed to 25° C. where it stirred for an additional 40 min. After this time, the reaction was treated with 2-bromo-3-cyclopentylpropionic acid methyl ester (Intermediate 10, 17.7 g, 75.5 mmol). The reaction was warmed to 50° C. for 18 h. After this time, the reaction was partitioned between water and methylene chloride. The aqueous layer was back extracted with methylene chloride. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography afforded 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (14.7 g, 63%) as a pale yellow solid; ESI-MS 368 [M+H+]; HPLC: >92% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.69-7.79 (m, 2H), 7.41-7.46 (m, 1H), 7.28-7.31 (m, 1H), 5.97 (s, 1H), 5.52-5.57 (m, 1H), 3.73 (s, 3H), 2.28-2.37 (m, 1H), 2.04-2.15 (m, 1H), 1.48-1.81 (m, 7H), 1.11-1.28 (m, 2H).
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)CC1.[Si]([O:44][CH2:45][CH2:46][N:47]([CH:77]1[CH2:81][CH2:80][CH2:79][CH2:78]1)[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49])(C(C)(C)C)(C)C>>[CH:77]1([N:47]([CH2:46][CH2:45][OH:44])[C:48]([C:50]2[C:55]([O:56][CH2:57][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]3([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[CH2:70][CH2:69][CH2:68][CH2:67]3)[N:51]=2)=[O:49])[CH2:78][CH2:79][CH2:80][CH2:81]1
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CCCC1
Agent: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCCC1
Yield: 89.5 %

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentyl-amide (288) (250 mg, 0.39 mmol). The product was obtained as an off-white sticky solid (180 mg, 87.83%).
Reaction SMILES: C([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[CH2:31]Cl)C1C=CC=CC=1.[CH3:33][NH:34][CH3:35]>O1CCCC1>[CH2:20]([C@@H:18]1[CH2:19][N:14]2[C:15]([C:16]3[NH:8][C:9]([CH2:31][N:34]([CH3:35])[CH3:33])=[N:10][C:11]=3[N:12]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:27])=[N:17]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CNC
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(CCl)n2Cc1ccccc1
Solvent: C1CCOC1
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(CN(C)C)nc21
Temperature: 70 °C
Yield: 14.3 %

Procedure:
Compound 42 (60 mg, 0.134 mmol) obtained in Example 42 was dissolved in tetrahydrofuran (3 mL), to the solution was added a 2 mol/L solution of dimethylamine (200 μL, 0.401 mmol, 3.1 equivalents) in tetrahydrofuran, and the mixture was stirred with heating at 70° C. for 5.5 hours. The reaction solution was concentrated and then directly purified by silica gel column chromatography (chloroform:methanol=99:1 to 97:3), and the title compound (7 mg, 19%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:35])[CH2:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=2O)=[O:26])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)C>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:23]1[O:35][C:32]2[C:27]([C:25](=[O:26])[CH:24]=1)=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CC(=O)c1ccc(O)cc1O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Solvent: CC(C)O
Product: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(O)ccc12

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (217.5 mL, 260 mmol) was added to a well-stirred solution of 2,4-dihydroxy acetophenone, 14 (9.88 g, 65 mmol) in tetrahydrofuran (150 mL) under nitrogen atmosphere at −78° C. for 30 min. The reaction mixture was stirred at −78° C. for 1 h and at −30° C. for 2 h. It was again cooled to −78° C. and a solution of ethyl-3,5-dibenzyloxy-benzoate 8 (23.5 g, 65 mmol) in tetrahydrofuran (100 mL) was added over a period of 30 min. It was further stirred at room temperature for overnight and poured into ice water containing hydrochloric acid. It was extracted with chloroform, dried over sodium sulphate, filtered and evaporated on rotavapor to afford 1-(3,5-bis-benzyloxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (16). The residue, 16 (37.8 g) was refluxed with Dowex-H+ (8 g) in 2-propanol (300 mL) for 3-4 h. 2-Propanol was evaporated on rotavapor, residue suspended in hot dimethyl formamide and filtered. The filtrate was concentrated under reduced pressure and the product was washed with cooled methanol (3*200 mL) to afford 22. Yield 23.8 g (81%); mp 248-249° C.; MS (FAB) 451 (M++1); IR (KBr) 3452, 1620; 1H NMR (200 MHz, DMSO-d6) δ 7.84 (d, J=8.7 Hz, 1H), 7.52-7.28 (m, 10H), 7.23 (d, J=1.9 Hz, 2H), 6.98 (d, J=2.0 Hz, 1H), 6.89 (s, 1H), 6.89 (dd, J=8.6 Hz, 2.1 Hz, 1H), 6.82 (s, 1H), 5.14 (s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH2:11][CH3:12])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCC(C#N)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C#N)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
A mixture of 2-(4-chlorophenyl)butanenitrile (6.2 g, 35 mmol) in 50 mL DMF stirred at 0° C., was treated with NaH (0.99 g, 41 mmol). The mixture was stirred at 0° C. for 30 minutes, and was treated with MeI (7.3 g, 52 mmol). The mixture was stirred at 0° C. to room temperature for 2 hours, and was carefully quenched with H2O, and neutralized with 10% HCl to pH=5. The mixture was extracted with ether (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10% EtOAc/hexane to give 6.5 g of the product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:14]1[CH:13]=[N:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[CH:15]=1)=[O:28]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)/C=C/c2ccc(F)cc2Cl)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.[NH2:16][C:17](=O)[C@@H:18]([NH:37][C:38]([C:40]1([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)=[O:39])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[CH2:34][N:33]([CH3:35])[C:32](=[O:36])[C:29]3=[N:30][CH:31]=2)=[CH:22][CH:21]=1>ClCCl>[C:17]([C@@H:18]([NH:37][C:38]([C:40]1([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:51])([CH3:50])[CH3:52])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)=[O:39])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[CH2:34][N:33]([CH3:35])[C:32](=[O:36])[C:29]3=[N:30][CH:31]=2)=[CH:22][CH:21]=1)#[N:16]
Reactant: CN1Cc2cc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCCCC4)C(N)=O)cc3)cnc2C1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CN1Cc2cc(-c3ccc(C[C@@H](C#N)NC(=O)C4(NC(=O)OC(C)(C)C)CCCCC4)cc3)cnc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
Burgess' reagent (348 mg) was added to (S)-tert-butyl 1-(1-amino-3-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 32, step (iii), 391 mg) in dichloromethane (25 mL) at 20° C. under nitrogen. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with methanol/ethyl acetate (10:90 to 40:60) to afford the sub-titled compound (360 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[O-:26][C:27]#[N:28].[K+]>C(O)(=O)C.O>[CH2:15]([C:12]1[C:13](=[O:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:27]([NH2:28])=[O:26])[CH:3]=2)[C:9]2[N:25]=[CH:24][CH:23]=[CH:22][C:10]=2[N:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of 4-(3-aminophenyl)-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (200 mg) in acetic acid (2 ml) and water (2 ml) was added solution of potassium cyanate (99 mg) in water (1 ml). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (4% methanol in chloroform) to afford 2-benzyl-3-oxo-4-(3-ureidophenyl)-3,4-dihydropyrido[2,3-b]pyrazine (78 mg) as solid.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]1=[O:19])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>O1CCCC1>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:3]([OH:20])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(OC)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution containing (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (1.82 g, 6.48 mmol) in tetrahydrofuran (15 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (8.4 mL, 1.0 M, 8.42 mmol). The mixture was stirred at 25° C. for 2 h then, acidified with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate and concentrated to afford (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid, (1.35 g, 75%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:18]([O:20]C)=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17][C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCc2onc(-c3ccc(Cl)cc3)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCc2onc(-c3ccc(Cl)cc3)c2CC1

Procedure:
2.5 of methyl 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-6-carboxylate in 20 ml of methanol were treated with 1.5 g of potassium hydroxide in 2 ml water at 20° C. for 16 hours. After removing the methanol by evaporation, the residue was taken up in water. The aqueous-alkaline solution was washed with diethyl ether, acidified with 2N hydrochloric acid and extracted with diethyl ether. After drying over magnesium sulfate and evaporation, there were obtained 1.8 g of 3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-6-carboxylic acid of melting point 144°-145° C. after recrystallization from ethyl acetate/hexane.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][CH:18]([O:28]CC1C=CC=CC=1)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]>C(O)C.[Pd]>[CH3:1][S:2]([CH:5]([CH2:15][CH2:16][CH2:17][CH:18]([OH:28])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(COc1ccc(F)cc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Yield: 90.9 %

Procedure:
The hydrogenolysis of 8-methylsulfonyl-12-benzyloxy-13-(4-fluorophenoxy)tridecanoic acid (1.237 g., 2.43 mmoles) in absolute ethanol (100 ml.) in the presence of 10% palladium on charcoal (0.2 g.) is carried out at 25° C. in an atmospheric-pressure hydrogenator. After hydrogen uptake stops, the catalyst is filtered off and the solvent is evaporated in vacuo to leave the title compound as a colorless oil (0.927 g., 2.21 mmoles, 91%). ir (neat) 2.8~4.0, 5.81, 6.22, 6.65, 6.86, 7.80, 8.30, 8.95, 10.46, 12.04, 13.18μ; pmr (CDCl3)δ1.1-3.0 (22H, m, containing a methyl singlet at 2.82δ), 3.6-4.2 (3H, m), 6.2-6.7 (2H, m), 6.7-7.2 (4H, m).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH2:35])[N:28]=3)=[C:21]([F:42])[CH:20]=1.O>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:1][CH2:35]2)[N:28]=3)=[C:21]([F:42])[CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1

Procedure:
To a solution of potassium tert-butoxide (4.02 g, 35.8 mmol) in 100 mL DMSO under nitrogen was added trimethyl sulfoxonium iodide (7.89 g, 35.8 mmol) in 4 portions over about 20 minutes. 2-(4-(1,3-Dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[5,4-b]pyridine (10.0 g, 23.9 mmol) was suspended in 150 mL THF and filtered through a glass frit, rinsing with 25 mL THF. The filtrate was added to the reaction dropwise very slowly from an addition funnel over 1.5-2 h. The resulting orange reaction was allowed to stir 30 min, at which point the THF was removed in vacuo, resulting in a precipitate. Water and ice was added slowly with stirring (approximately 400 mL total). The solid was isolated by filtration rinsing with water and MeOH. The solid was dried in vacuo to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a light orange solid. MS (ESI) m/z: Calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: Br[C:2]1[N:40]=[C:5]2[N:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([C:29]5[N:33]=[C:32]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=6)[NH:31][N:30]=5)[CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:41][NH2:42]>>[CH3:41][NH:42][C:2]1[N:40]=[C:5]2[N:6]=[C:7]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([C:29]5[N:33]=[C:32]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=6)[NH:31][N:30]=5)[CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Brc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Reactant: CN
Product: CNc1nc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cn2n1
Temperature: 110 °C

Procedure:
150 mg 2-bromo-6-phenyl-5-(4-{[4-(5-pyridin-2-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (prepared as described under example 52) is dissolved in 8 ml of a methylamine solution (2M in THF). The reaction mixture is heated under microwave irradiation to 110° C. for 8 hours. The solvent is evaporated and the residue is purified by RP HPLC (water, 10 mM NH4COOH, pH 3.7/ACN) to yield the desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.[CH2:20](O)[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:20][CH3:21])=[O:17])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (0.18 mgs, 0.67 mmol) was dissolved in dry THF (7 mls). To this solution was added ethanol (0.037 mls, 0.81 mmol) and resin bound triphenylphosphine (0.93 g, 2.014 mmol, 2.16 mmol/g). This mixture was gentyl stirred at room temperature for 20 minutes. Diisopropylazidodicarboxylate (0.34 mls, 1.68 mmol) was then added and the mixture was stirred at room temperature for one hour, then filtered, and the resin rinsed several times with EtOAc. The filtrate was concentrated and the resulting material was purified by Flash 40 Biotage (40M cartridge, 30% EtOAc/Hexanes) to give 137 mgs (70%) of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate as an orange oil.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[S:13](N3C=CC=C3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1.S(Cl)([Cl:28])(=O)=O>>[Cl:28][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:21]=[CH:22][C:23]2[O:24][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=S(=O)(c1ccsc1CCc1ccc2c(c1)OCO2)n1cccc1
Product: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Yield: 42 %

Procedure:
3-Chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene was prepared in the same manner as described in the Example 15E using N-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole by conducting basic hydrolysis (iso-propanol and potassium hydroxide) of the sulfonamide to the potassium sulfonate (93%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 42% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].Br[C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>CN(C)C=O.[Cu]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[CH:28]=[CH:27][C:17]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:10][C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)=[CH:22][CH:21]=3)=[O:19])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(Oc2ccc(C(=O)c3ccc(Oc4ccc(C(C)C)cc4)cc3)cc2)cc1

Procedure:
To a solution of 4-isopropylphenol (20.4 g.) in 30 ml of dimethylformamide was added slowly a slurry of sodium hydride, 60% in mineral oil (6.0 g.) in 150 ml of dimethylformamide. When the reaction was complete, 8.5 g. of 4,4'-dibromobenzophenone and 1.0 g. dendritic copper powder were added and the reaction mixture heated to reflux and held at reflux for 24 hours. The solvent was removed under vacuum and the residue poured into ice-water. The crude product was recrystallized from ethanol to give the desired compound, mp 104-105° C. Structure was confirmed by IR, NMR, C-13 NMR and MS.