Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[CH2:9]([N:13]1[CH:17]=[CH:16][N:15]=[N:14]1)[CH2:10][C:11]#[CH:12].C(N(CC)CC)C.ClCCl>CN(C=O)C.[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)nn1
Reactant: C#CCCn1ccnn1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccc(C#CCCn2ccnn2)nn1
Reaction time: 6 h

Procedure:
3-Chloro-6-iodo-pyridazine (11.56 g, 48.1 mmol), 1-but-3-ynyl-1H-[1,2,3]triazole (6.99 g, 57.7 mmol) and triethyl amine (NEt3) (94 ml) are dissolved in DMF (188 ml) and copper iodide (CuI) (0.981 g, 5.15 mmol) is added under stirring. After passing a stream of argon through the mixture for 10 min tetrakis(triphenylphosphine)palladium(0) (2.836 g, 2.43 mmol) is added and stirring is continued for 6 h at r.t. Dichloromethane (300 ml) is added, the mixture is washed with 0.5N hydrochloric acid (HCl) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate) yielding 3-chloro-6-(4-[1,2,3]triazol-1-yl-but-1-ynyl)-pyridazine as a colorless solid. Yield 9.52 g (85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].[OH-].[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)c[nH]2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)cn2CCO[Si](C)(C)C(C)(C)C)CC1
Yield: 97.9 %

Procedure:
Combine 4-[4-(3,4-difluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (10.0 g; 0.028 mol; 1.0 equiv), (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (13.16 g; 0.055 mol; 2.0 equiv), powdered KOH (7.72 g; 0.14 mol; 5.0 equiv) in THF (100 mL) and stir at 40° C. for 16 h. Quench the reaction with water and extract with EA. Evaporate to give the title compound (14.3 g, crude). MS (ES+): m/z=522 (M+H)
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31]C=CC=2Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(CO)CC1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31]2)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3ccccc3)c2cc1F
Agent: OCC1CC1
Product: Fc1cc2nc(-c3cccnc3OCC3CC3)n(Cc3ccccc3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 1, from 1-benzyl-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 6, intermediate) and cyclopropyl-methanol (CAS Reg. No. 2516-33-8). Colorless powder (23%). MS (Turbo Spray): m/z=392.2 (M+H).
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[SH:37]C1N(C2N=C(N)NC(=O)C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.O.[C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)[C@@H](O)C1>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[C:27]2[SH:37])[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Nc1nc2c(nc(S)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)[C@]1(n2c(S)nc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for palmitoyl-2′-deoxyguanosine, substituting the appropriate amount of 8-mercaptoguanosine for 2′-deoxyguanosine monohydrate.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:12]3=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].O.[OH-].[Na+].C(=O)([O-])O.[Na+]>Br>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:12]3=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2cc(-c3ccc(OC)cc3)c3c(n2)CCCCCC3)CC1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCN1CCN(c2cc(-c3ccc(O)cc3)c3c(n2)CCCCCC3)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
2-(4-Ethyl-1-piperazinyl)-4-(4-methoxyphenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (1.3 g) is dissolved in 48% hydrobromic acid (10 ml) and the mixture is stirred at 120° C. for 2 hours. After cooling, water is added thereto and the mixture is neutralized with 1N aqueous sodium hydroxide solution and sodium hydrogen carbonate. The resulting precipitate is collected by filtration, washed with water, and recrystallized from methanol to give the desired product (0.6 g), m.p. 250°-253° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:10][C:11]([NH2:19])=[N:12][C:13]=2[C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][NH:26][CH3:27]>COCCOC>[CH3:25][N:26]([CH3:27])[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[N:10][C:11]([NH2:19])=[N:12][C:13]=2[C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: Nc1nc(-c2ccco2)c(-c2ccnc(F)c2)c(-c2ccco2)n1
Solvent: COCCOC
Product: CN(C)c1cc(-c2c(-c3ccco3)nc(N)nc2-c2ccco2)ccn1
Temperature: 70 °C
Reaction time: 11 h
Yield: 43 %

Procedure:
In an autoclave, 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg, 0.621 mmol) was suspended in 1,2-dimethoxyethane (10 ml) and then a 50% dimethylamine aqueous solution (5 ml) was added thereto, followed by stirring at 70° C. After 11 hours, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and brine, dried over anhydrous sodium sulfate and then the filtrate was concentrated. The resulting solid was suspended in ethanol, collected by filtration and washed with ethanol, to give the title compound (92 mg, 43%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12](Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].[O-:18][C:19]#[N:20].[K+]>C(O)C.O>[OH:18][C:19]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[N:20]=1
Reactant: CC(C)(C)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1nc(O)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
6.3 g (0.02 mol) of 2,2-dimethylpropionyl chloride 2,4,6-trichlorophenylhydrazone was dissolved in 50 ml of ethanol. Then, a solution of 3.2 g (0.04 mol) of potassium cyanate in 30 ml of water, was dropwise added thereto under stirring at room temperature. After completion of the dropwise addition, stirring was continued at the same temperature for further 0.5 hour. The precipitated crystals were collected by filtration and washed with n-hexane to obtain 6.1 g (yield: 95.3%) of 5-hydroxy-3-(tert-butyl)-1-(2,4,6-trichlorophenyl)-1H-1,2,4-triazole as white powder having a melting point of from 272° to 274° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH3:17])=[O:15])[CH:6]=[C:7]2[C:12]=1[NH:11][CH:10]=[CH:9][C:8]2=O.P(Br)(Br)[Br:19]>CN(C)C=O>[Br:19][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([C:14]([O:16][CH3:17])=[O:15])[CH:6]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1cc(OC)c2[nH]ccc(=O)c2c1
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c2nccc(Br)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 8-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylate (14 g, 60.03 mmol, 1.00 equip), and N,N-dimethylformamide (200 mL). To the resulting mixture was then added PBr3 (17.8 g, 65.76 mmol, 1.10 equip) dropwise with stirring. The resulting solution was stirred for 3 h at 25° C. The reaction was then quenched by the addition of water (1000 mL). The pH value of the solution was adjusted to 8-9 with sodium bicarbonate. The solids were collected by filtration to yield methyl 4-bromo-8-methoxyquinoline-6-carboxylate as a yellow solid. LCMS (ES, m/z) 296 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6](Br)[CH:5]=1.B(O)(O)[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][C:8]1[CH:9]=[C:4]([C:3]([O:2][CH3:1])=[O:12])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1

Procedure:
To a stirred solution of 3-bromo-5-hydroxy-benzoic acid methyl ester (4.09 g, 17.7 mmol) and p-tolylboronic acid (2.86 g, 21 mmol) in toluene (36 mL) was added cesium carbonate (7.14 g, 22 mmol) in water (3.6 mL) at room temperature. The mixture was purged with nitrogen, and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.906 mmol) was added. The reaction mixture was subjected to microwave irradiation at 110° C. for 1 hour. After cooling, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified by flash chromatography to afford the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[C:12]([OH:21])=[CH:11]1)[CH3:9].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:21][C:12]1[C:13](=[O:20])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]([CH2:8][CH3:9])[CH:11]=1)(=[O:25])=[O:24]
Reactant: CCn1cc(O)c(=O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(OS(C)(=O)=O)c(=O)c2ccccc21

Procedure:
Triethylamine (5.6 ml) was added to a stirred suspension of 1-ethyl-3-hydroxy-4-quinolone (3.74 g) and methanesulphonyl chloride (2.3 ml) in dichloromethane (80 ml) and the resultant solution was stirred for 90 minutes. The solution was washed with water (50 ml) and dried over magnesium sulphate. The solvent was removed by distillation and the residue crystallised from industrial methylated spirit (10 ml) to give the novel compound 1-ethyl-4-oxo-1,4-dihydro-quinol-3-yl methanesulphonate, m.p. 141°-143°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[N:13]([N:15]=[CH:16][CH:17]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=[O:26])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:20].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:20][C:19](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:12]2[N:13]([N:15]=[CH:16][CH:17]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Brc1cc(OCc2ccccc2)cn2nccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)cn2nccc12
Temperature: 95 °C
Reaction time: 2 h

Procedure:
6-(benzyloxy)-4-bromopyrazolo[1,5-a]pyridine (150 mg, 0.495 mmol), tert-butyl carbamate (116 mg, 0.990 mmol), tris(dibenzylideneacetone)dipalladium (0) (45.3 mg, 0.049 mmol), Xantphos (57.3 mg, 0.099 mmol), and cesium carbonate (484 mg, 1.48 mmol) were suspended in 1,4-dioxane (5 mL). The mixture was sparged with argon for 10 minutes then heated to 95° C. After 2 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to afford tert-butyl [6-(benzyloxy)pyrazolo[1,5-a]pyridin-4-yl]carbamate contaminated with tert-butyl carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[OH:21][CH2:22][CH2:23][NH2:24]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:24][CH2:23][CH2:22][OH:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCCO
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCCO)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-hydroxylethylamine (17.6 mg, 0.12 mmol). The title compound was obtained as a solid (7.8 mg, 17.0% yield). MS m/z: 347.80, 349.80 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O1CCOCC1.[OH-].[Na+]>[C:14]([NH:1][CH:2]([P:10]([OH:12])[OH:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: NC(CC1CCCCC1)P(O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NC(CC1CCCCC1)P(O)O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 7.00 g (0.037 moles) of 1-amino-2-cyclohexylethylphosphonous acid in 105 ml of dioxane and 40 ml of 1N NaOH was cooled to 0° C. in an ice bath and stirred vigorously while 10.50 ml (12.53 g; 0.073 moles) of benzyl chloroformate and 80 ml of 1N NaOH were added rapidly and simultaneously over a period of approximately 1 minute. The pH was adjusted to the 8-9 range using 1N NaOH (hydrion paper) added in small increments. The reaction mixture was allowed to come to room temperature, and vigorous stirring was continued for 48 hours. The dioxane was removed in vacuo and the aqueous washed with 100 ml of ether. The ether layer was discarded and the aqueous solution acidified using 1N KHSO4 to approximately pH=1-2 (hydrion paper). The solution was extracted with 5×100 ml of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to afford N-CBZ-1-amino-2-cyclohexylethylphosphonous acid as a white solid.
Reaction SMILES: C1(S([CH:10]2[CH:20]([C:21]3[C:26]([CH3:27])=[C:25]([Br:28])[CH:24]=[CH:23][N:22]=3)[NH:19][C:12]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:11]2)(=O)=O)C=CC=CC=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1>[Br:28][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([C:20]2[CH2:10][CH2:11][C:12]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[N:19]=2)[C:26]=1[CH3:27]
Reactant: Cc1c(Br)ccnc1C1NC2(CCN(C)C2=O)CC1S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1c(Br)ccnc1C1=NC2(CC1)CCN(C)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To an ice cooled solution of 7-(benzenesulfonyl)-8-(4-bromo-3-methyl-2-pyridyl)-3-methyl-3,9-diazaspiro[4.4]nonan-4-one (which may be prepared as described in Description 8) (3500 mg, 7.54 mmol) in THF (5 mL) was added potassium tert-butoxide (1691 mg, 15.07 mmol) and the reaction was stirred for 1 hour. Additional KOtBu (1.7 g, 15.1 mmol) was added and the reaction was stirred at 00° C. for 1 hour, and allowed to warm to room temperature overnight. The reaction was quenched by addition of acetic acid (3.45 mL, 60.3 mmol), concentrated in vacuo and loaded onto a silica column (100 g SNAP). Elution using EtOAc gave 2-(4-bromo-3-methyl-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (1410 mg, 4.3762 mmol, 58.063% yield) as a pale yellow crystalline solid;
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:6][C@@H:7]([C:16]([N:18]2[CH:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)=[O:24])[CH2:21][CH:20]=[N:19]2)=[O:17])[CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccc(F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ccc(F)cn1
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (323 mg, 0.72 mmol) in 1,4-dioxane (5.0 mL) was added 4.0 M hydrochloric acid in 1,4-dioxane (9.0 mL, 36 mmol) at room temperature. The reaction mixture was stirred for 4 hours. After this time, the solvent was removed by reduced pressure to afford the crude product, (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (283 mg, 100%), which was used directly in the next step. MS: 491 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25]
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 50 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 37 mg (yield 60%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]2)[C:3]1=[O:13].[CH3:15][Li]>>[CH3:15][C:3]1([OH:13])[C:4]2([CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]2)[CH2:5][CH2:6][CH2:7][C:2]1([CH3:14])[CH3:1]
Reactant: [Li]C
Reactant: CC1(C)CCCC2(CC=CCC2)C1=O
Product: CC1(C)CCCC2(CC=CCC2)C1(C)O
Yield: 98 %

Procedure:
2,2-Dimethylspiro[5,5]undec-8-en-1-one was treated with methyllithium according to the general procedure (example 2, procedure 5) to give 1,2,2-trimethylspiro[5,5]undec-8-en-1-ol in 98% yield. The crude product was purified by bulb-to-bulb distillation (B.p.=140-150° C./0.032 mbar).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.BrC1C([NH:32][NH2:33])=NC(C)=CC=1C1C=CC(Cl)=CC=1>>[Br:1][C:2]1[C:3]([CH3:16])=[N:4][C:5]([NH:32][NH2:33])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Cc1nc(Cl)cc(-c2ccc(Cl)cc2)c1Br
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(NN)n1
Product: Cc1nc(NN)cc(-c2ccc(Cl)cc2)c1Br
Yield: 92 %

Procedure:
The title compound (200 mg, 92% yield) as a white solid was prepared from 3-bromo-6-chloro-4-(4-chlorophenyl)-2-methylpyridine (220 mg, 0.7 mmol) by procedures analogous to those used for the preparation of 3-bromo-4-(4-chlorophenyl)-2-hydrazinyl-6-methylpyridine. HPLC/MS: retention time=2.87 min, [M+H]+=312.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:21]=3[CH:31]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:32]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH2:27][CH3:28])([CH2:29][CH3:30])[C:21]=3[CH:31]=2)=[O:32])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(NC(C)=O)cc3)cc21
Reactant: OO
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(NC(C)=O)cc3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamidophenylmercapto)-butoxy]-4,4-diethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:26])[C:22](OC)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:26])([CH3:27])[CH2:22][OH:23])=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH2:28][CH3:29])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Cc2ccc(C(C)(C)C(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Solvent: C1CCOC1
Product: CCc1cc(Cc2ccc(C(C)(C)CO)cc2)nc(-c2cccc(Cl)c2)n1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 35.9 %

Procedure:
A 25-mL round bottom flask was charged with methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoate (0.259 g, 0.57 mmol) and THF (6 mL) at rt. Borane-dimethylsulfide complex (0.158 mL, 1.67 mmol) was added and the resulting solution was stirred at 55° C. for 2.5 h. LCMS analysis indicated only partial reduction. Borane-dimethylsulfide complex (0.100 mL, 1.05 mmol) was added and the resulting solution was stirred at 55° C. for a further 19 h until the starting material was consumed (monitored by LCMS analysis). The reaction was quenched with methanol then treated with 2N aqueous HCl (0.1 mL) and concentrated under reduced pressure. The residue was diluted with methanol and then concentrated under reduced pressure. The residue absorbed onto silica (2 g) then purified by column chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as the eluent to afford the title compound (0.078 g, 36%) as a colorless oil. MW=380.91. 1H NMR (DMSO-d6, 500 MHz) δ 8.38-8.34 (m, 2H), 7.61-7.54 (m, 2H), 7.33-7.26 (m, 5H), 4.60 (t, J=5.5 Hz, 1H), 4.07 (s, 2H), 3.38 (d, J=5.5 Hz, 2H), 2.78 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H), 1.18 (s, 6H); APCI MS m/z 381 [M+H]+.