Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2].[CH2:14]=O.[OH-].[Na+]>[OH-].[Na+].C(O)(=O)C>[C:9]([O:8][C:6](=[O:7])[C:5](=[CH2:14])[C:4]([O:3][CH2:1][CH3:2])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=C(C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
This compound employed as the starting material in example 7 is prepared as follows: 10% NaOH (2 drops) is added to malonic acid tert-butyl ethyl ester (20 g). Aqueous 40% formaldehyde (15 ml) is then added very slowly thereto while keeping the temperature of the reaction mixture ≤5° C. and the pH at about 8.5 by means of 10% NaOH. The reaction mixture is then stirred at room temperature for 24 hours. The resulting reaction mixture is acidified by the addition of few drops of glacial acetic acid and charged, together with Cu(CH3COO)2, into a suitable distilling apparatus.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](O)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:29][O:30][C:31](=[O:40])[CH:32]([CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)[NH2:33].P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>O1CCCC1>[CH3:29][O:30][C:31](=[O:40])[CH:32]([CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)[NH:33][C:24](=[O:25])[C@H:12]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)C(N)Cc1cscn1
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
2.90 g (8.30 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine and 2.15 g (8.30 mmole) of 3-(4-thiazolyl)-DL-alanine methyl ester dihydrochloride were suspended in 30 ml of anhydrous tetrahydrofuran. Whilst ice cooling, 1.51 ml (9.95 mmole) of diethyl phosphorocyanidate and 3.82 ml (27.4 mmole) of triethylamine were added dropwise under a nitrogen gas stream, and the mixture was stirred overnight at room temperature. The reaction product was condensed by evaporation under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and then dried over anhydrous magnesium sulfate. The dried product was condensed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 10:1 by volume mixture of chloroform and methanol, to yield 2.62 g (61%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(4-thiazolyl)-DL-alanine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4][N:3]=1>ClC1C=CC=CC=1>[Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[S:4][N:3]=1
Reactant: O=C(O)c1c(Cl)nsc1-c1ccccc1
Solvent: Clc1ccccc1
Product: OCc1c(Cl)nsc1-c1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Into a 25-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-chloro-5-phenyl-1,2-thiazole-4-carboxylic acid (500 mg, 1.88 mmol, 1.00 equiv, 90%), chlorobenzene (2 mL), BH3 (3.1 mL, 3.00 equiv) at 0° C. The resulting solution was stirred for 12 h at 50° C. in an oil bath. The reaction was then quenched by the addition of 10 mL of sodium bicarbonate/H2O. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 80 mg (18%) of (3-chloro-5-phenyl-1,2-thiazol-4-yl)methanol as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([F:17])=[C:6](/[C:8](=[N:10]/[S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])[CH:7]=1.Br[C:20]([F:27])([F:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21](=[O:22])[C:20]([F:27])([F:26])[C@@:8]([C:6]1[CH:7]=[C:2]([Br:1])[C:3]([F:18])=[CH:4][C:5]=1[F:17])([NH:10][S@@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH3:25]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C/C(=N\S(=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Product: CCOC(=O)C(F)(F)[C@](C)(N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F

Procedure:
Starting from 2-methyl-propane-2-sulfinic acid [1-(5-bromo-2,4-difluoro-phenyl)-eth-(E)-ylidene]-amide (intermediate A2E) and ethyl 2-bromo-2,2-difluoroacetate, the product (R)-3-(5-bromo-2,4-difluoro-phenyl)-2,2-difluoro-3-((R)-2-methyl-propane-2-sulfinylamino)-butyric acid ethyl ester was obtained as an orange oil. MS (ISP): m/z=462.1 [M+H]+ and 464.1 [M+2+H]−.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:30]=[CH:29][C:15]([NH:16][C:17](=[O:28])[C:18]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])=[CH:14][CH:13]=1)=O)(C)(C)C.Cl.O1CCOCC1>>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:30]=[CH:29][C:15]([NH:16][C:17](=[O:28])[C:18]2[C:19]([O:26][CH3:27])=[CH:20][CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:14][CH:13]=1
Reactant: COc1cccc(OC)c1C(=O)Nc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(OC)c1C(=O)Nc1ccc(OCCN)cc1
Yield: 83.3 %

Procedure:
4′-[2-(tert-Butoxycarbonylamino)ethoxy]-2,6-dimethoxybenzanilide (1.17 g) was added with 4N HCl/dioxane (5 ml) and mixed for 6 hours at room temperature. The reaction mixture was concentrated under vacuum and residue was dissolved into chloroform (50 ml). The solution was washed with 1N sodium hydroxide aqueous solution (10 ml) followed by saturated sodium chloride (20 ml). After concentration under vacuum to small volume, the solution was subjected to purification by silica-gel column chromatography (chloroform methanol=4:1) to obtain 4′-(2-aminoethoxy)-2,6-dimethoxybenzanilide (0.74 g) as white powder.
Reaction SMILES: [Na+].[Na+].[P:3]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[C:31]3[N:30]=[CH:29][N:28]=[C:26]([NH2:27])[C:25]=3[N:24]=[CH:23]2)[C@H:19]([OH:32])[C@@H:18]1[OH:33])([O:6][P:7]([O:10][P:11]([OH:14])([OH:13])=[O:12])([O-:9])=[O:8])(=[O:5])[O-:4]>O.[OH-].[Na+]>[P:3]([O:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[C:31]3[N:30]=[CH:29][N:28]=[C:26]([NH2:27])[C:25]=3[N:24]=[CH:23]2)[C@H:19]([OH:32])[C@@H:18]1[OH:33])([O:6][P:7]([O:10][P:11]([OH:13])([OH:14])=[O:12])([OH:9])=[O:8])(=[O:4])[OH:5]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)([O-])OP(=O)([O-])OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Two hundred milligrams of adenosine 5'-triphosphate disodium salt (ATP), and 7.4 milligrams of ethylenedinitrotetraacetate disodium salt (EDTA) were dissolved in water and the pH adjusted to 8.0 with IN NaOH. The solution was then adjusted to a final volume of 20.0 milliliters with water with a final concentration of ATP at 1.0% (w/v).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CS(C)=O.O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 160 °C
Reaction time: 2 h
Yield: 121.8 %

Procedure:
In 120 mL of dimethyl sulfoxide were suspended 54.54 g (168 mmol) of 4-(diphenylmethoxy)-1-piperidinepropaneamine, 30.00 g (112.2 mmol) of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate and 11.82 g (112.2 mmol) of sodium carbonate, heated to 160° C. and stirred for 2 hours. After cooling to room temperature, 300 mL of ethyl acetate and 300 mL of water were added and separated into two layers. The organic layer was washed twice with 150 mL of water and concentrated under reduced pressure. The residue was subjected to alumina chromatography to be eluted with ethyl acetate. The desired fraction was collected and concentrated to provide 75.96 g of the crude title compound. HPLC purity area percentage 70.5%, Yield 85%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35]C)[CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[I-].[Na+].S1(CCCC1)(=O)=O.O>CC(C)=O.CCCCCCC.C1(C)C=CC=CC=1>[C:37]1([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=4)=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COc1cccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4cccc(OC)c4)cc3)cc2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: Oc1cccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4cccc(O)c4)cc3)cc2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
N,N'-diphenyl-N,N'-bis(3-hydroxyphenyl)-[1,1'-biphenyl]-4,4'-diamine was prepared, for example, from the N,N'-di(3-methoxyphenyl)-N,N'-diphenyl-[1,1-biphenyl]-4,4'-diamine by placing into a two liter three-necked round bottom flask, equipped with a mechanical stirrer and an argon gas inlet, 137.5 gms N,N'-diphenyl-N,N'-bis(3-methoxy phenyl)-[1,1'-biphenyl]-4,4'-diamine (0.25 moles), 223.5 gms anhydrons sodium iodide (1.5 moles) and 500 millileters warm sulfolane (distilled). The contents of the flask were heated to 120° C. then cooled to 60° C. Five millileters of D.I. water was added dropwise, followed by 190.5 millileters of trimethyl(chlorosilane (1.5 moles)). The contents were allowed to reflux for six hours. HPLC analysis was utilized to determine when the reaction was complete. The contents of the flask were poured into a 3 liter Erlenmeyer flask containing 1.5 liter of deionized water. The water layer was decanted and the dark oily residue taken up into 500 milliliters methanol. The methanol solution was extracted with two 400 milliliter portions of hexane to remove the hexamethyldisiloxane by-products. The methanol solution was roto-evaported to remove the solvents. The residue was taken up into 500 milliliters of acetone and then precipitated into 1.5 liters deionized water. The off-white solid was filtered and then washed with deionized water and dried in vacuo. The crude N,N'-diphenyl-N,N'-bis(3-hydroxyphenyl)-[1,1'-biphenyl]-4,4'-diamine was placed into a two liter round-bottom flask containing a magnetic stirrer and one liter toluene. Fifty gms. Florisil® (Florisil is a registered trademark of Floridin Co.) was added to the flask and allowed to stir for two hours. The dark Florisil® was filtered off, leaving a pale yelow toluene solution. The toluene was rotoevaporated to yield a pale yellow viscous oil. The oily product was dissolved in 400 milliliters acetone then diluted with 400 milliliters heptane and allowed to crystallize. The colorless crystals were filtered. Additional product was obtained by roto-evaporating the acetone from the filtrate. Yield was 85 percent, m.p. 113°-17° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14]C1C=CC(S)=CC=1.ICCC>>[Cl:14][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)c1ccc(F)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCCI
Product: CCCS(=O)(=O)c1ccc(Cl)cc1
Yield: 82 %

Procedure:
Following the general method as outlined in Intermediate 105, starting from 4-chlorothiophenol (Aldrich) and 1-iodopropane, the title compound was obtained as an oil which solidified upon standing in 82% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:28])[N:17]2[CH3:29])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:21]([N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH3:30])[C:4]([OH:36])=[O:3])=[CH:8][CH:9]=2)[N:17]([CH3:29])[C:18]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccccc3)C(=O)N2C)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccccc3)C(=O)N2C)cc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionic acid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, and concentrated. The residue is diluted with 1N HCl, extracted with CH2Cl2, dried, concentrated, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.33-7.22 (m, 5H), 7.07 (d, 2H, J=8.6 Hz), 6.71 (d, 2H, J=8.6 Hz), 4.39, 4.35 (ABq, 2H, J=15.3 Hz), 3.94 (t, 2H, J=5.7 Hz), 3.69-3.62 (m, 1H), 3.58-3.52 (m, 1H), 3.50-3.44 (m, 1H), 3.40 (t, 1H, J=9.1 Hz), 3.04-3.01 (m, 1H), 3.02, 2.94 (ABq, 2H, J=13.9 Hz), 2.85 (s, 3H), 2.25-2.18 (m, 1H), 1.92-1.85 (m, 1H), 1.62-1.54 (m, 1H), 1.46 (s, 3H), 1.42-1.32 (m, 2H), 0.92 (t, 3H, J=7.2 Hz). MS [EI+] 469 (M+H)+, [EI−] 467 (M−H)+.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:53]([O:60][C:61]([N:63]1[CH2:67][CH:66]([C:68]2[C:76]3[C:71](=[CH:72][C:73]([F:77])=[CH:74][CH:75]=3)[NH:70][CH:69]=2)[CH:65]2[NH:78][CH2:79][CH2:80][CH:64]12)=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:53]([O:60][C:61]([N:63]1[CH2:67][CH:66]([C:68]2[C:76]3[C:71](=[CH:72][C:73]([F:77])=[CH:74][CH:75]=3)[NH:70][CH:69]=2)[CH:65]2[N:78]([C:10](=[O:12])[CH:2]([NH:1][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:3]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:9])[CH2:79][CH2:80][CH:64]12)=[O:62])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(OCc1ccccc1)N1CC(c2c[nH]c3cc(F)ccc23)C2NCCC21
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(OC(C)(C)C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution containing Boc-Thr(tBu)-OH (138 mg, 0.5 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (190 mg, 0.5 mmol) and DIPEA (111 mg, 0.8 mmol) were added followed by the addition of crude 42 (195 mg, 0.5 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 336 mg of crude 43 as an amber-colored foam which was used without further purification. Mass spectrum, m/z [637.3] (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[F:17])(=[O:3])[NH2:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:15])([CH3:16])[C:12]([O:14][CH3:18])=[O:13])=[CH:6][C:5]=1[F:17])(=[O:3])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Nc1ccc(C(N)=O)c(F)c1)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C)Nc1ccc(C(N)=O)c(F)c1
Temperature: 57.5 °C

Procedure:
A solution of 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoic acid and K2CO3 (1.5 equivalents) in DMF (10 fold) was stirred at RT for 10 min. MeI (1.5 equivalents) was added and the reaction mixture was heated at 55-60° C. for 2 h. The solvent was removed under reduced pressure and the reaction mixture was poured in water, extracted with ethyl acetate (100 mL×2), dried over Na2SO4, concentrated and purified by column chromatography. 1H NMR (CDCl3, Freebase): δ (ppm) 7.9 (t, 1H), 6.5 (bs, 1H), 6.4 (d, 1H), 6.2 (d, 1H), 5.6 (bs, 1H), 4.6 (bs, 1H), 3.75 (s, 3H), 1.6 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:28])=[CH:17]/[C:18]2[NH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CI.[C:31]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:28])=[CH:17]/[C:18]2[N:19]([CH3:31])[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)[nH]1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1cnc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)n1C
Reaction time: 24 h
Yield: 53.8 %

Procedure:
Ethyl (E)-2-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-5-imidazolecarboxylate (Compound 5, 25 mg, 0.066 mmol) was dissolved in acetone (3 mL) at room temperature and treated with methyl iodide (0.025 mL) and K2CO3 (100 mg). The suspension was stirred for 24 hours, filtered through Celite and concentrated under reduced pressure. The residue was treated with water (5 mL) and the organic material was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate=5:1) to give the title compound as a light yellow solid (14 mg, 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=1.[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][CH2:26][C:25]2[CH:32]=[C:33]([NH:36][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[O:11][CH2:12][C:13]#[N:14])[C:5]([Cl:19])=[CH:4][N:3]=3)[CH:34]=[CH:35][C:24]1=2)(=[O:22])[CH3:21]
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)ccc21

Procedure:
Title compound was prepared from [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile and Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one in an analogous manner to Example 1221d. (120° C., 40 min). Title compound isolated (70 mg, 47%) as an off-white solid. MP 233-234, LCMS 492.27 (M+H), HPLC purity 98%, 1H-NMR (CDCl3, 400 MHz) δ 8.27 (d, 7.9 Hz, 1H), 8.15 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.30-7.21 (m, 2H), 7.18-7.09 (m, 3H), 6.08 (bt, J=5.1 Hz, 1H), 4.93 (s, 2H), 4.88-4.82 (m, 1H), 4.39-4.33 (m, 1H), 3.83-3.78 (m, 1H), 3.82-3.75 (m, 1H), 3.08-3.02 (m, 1H), 2.81-2.74 (m, 1H), 2.64-2.59 (m, 1H), 1.83 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]([CH3:15])=[CH:11][C:12](Cl)=[O:13].C(N(CC)CC)C>C(OC(C)C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12](=[O:13])[CH:11]=[C:10]([CH3:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)=CC(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)Oc1ccc(F)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of the 4-fluorophenol (25.3 g) and dimethylacryloyl chloride (25.9 g) in diisopropyl ether (500 mL) cooled in an ice bath was added triethylamine (35 mL) dropwise over a period of 20 minutes. After 1 hour, the reaction mixture was washed with water and brine, dried over sodium sulfate, and the organic solvent was evaporated in vacuo to give crude ester. Distillation under vacuum gave dimethylacrylate 4-fluorophenyl ester (38.20 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:5]=[C:4]([NH:13]C(=O)C)[CH:3]=1.[OH-].[K+].[CH3:19][CH2:20]O.O>>[C:20]1([CH3:19])[CH:4]=[CH:3][CH:2]=[CH:1][C:1]=1[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[N:5]=[C:4]([NH2:13])[CH:3]=1
Reactant: CC(=O)Nc1cc(C)n(C2CCCCO2)n1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccccc1-c1cc(N)nn1C1CCCCO1

Procedure:
Crude N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)acetamide (28.86 mmol) was dissolved in EtOH/H2O (2:3, 100 mL) together with potassium hydroxide (11 g, 202 mmol) and was refluxed for 16 hrs. The reaction mixture was concentrated and then extracted with CHCl3. The combined organic layers were washed with brine and dried over Na2SO4. Solvent evaporation and purification by silica gel column chromatography (PE-EtOAc, 7:3 to 3:7) gave 5-tolyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-amine (2.99 g regioisomer A and 4.39 g regioisomer B, 99% over 4 steps).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.[F:24][C:25]1([F:43])[CH2:30][CH2:29][N:28]([C:31](OC2C=CC([N+]([O-])=O)=CC=2)=[O:32])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>>[F:24][C:25]1([F:43])[CH2:30][CH2:29][N:28]([C:31]([N:6]2[CH2:5][CH2:4][N:3]([C:8]3[N:9]=[N:10][C:11]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:12]4[CH:17]=[CH:16][N:15]=[CH:14][C:13]=34)[C@H:2]([CH3:1])[CH2:7]2)=[O:32])[CH2:27][CH2:26]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(F)(F)CC1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H]1CN(C(=O)N2CCC(F)(F)CC2)CCN1c1nnc(-c2ccccc2)c2ccncc12
Temperature: 80 °C

Procedure:
To a 10 mL round bottomed flask was added (R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[3,4-d]pyridazine 16 (110 mg, 360 μmol), 4-nitrophenyl 4,4-difluoropiperidin-1-carboxylate (124 mg, 432 μmol), and potassium carbonate (100 mg, 720 μmol). The reaction was heated to 80° C. overnight. After cooling to room temperature, the solvent was removed under vacuum, and the residue was redissolved in ethyl acetate and washed with water (10 mL), followed by NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography afforded (R)-(4,4-difluoropiperidin-1-yl)(3-methyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl)methanone 42. MS 452.2 (calc'd) 453.3 (M+H, found).