Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1.[C:20](=[N:33][C:34]1[CH:35]=[C:36]([CH:43]=[C:44]([O:46][CH3:47])[N:45]=1)[C:37](N(OC)C)=[O:38])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOCC>[C:20](=[N:33][C:34]1[CH:35]=[C:36]([C:37]([C:7]2[C:15]3[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=2)=[O:38])[CH:43]=[C:44]([O:46][CH3:47])[N:45]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Reactant: COc1cc(C(=O)N(C)OC)cc(N=C(c2ccccc2)c2ccccc2)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(Cl)c23)cc(N=C(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
n-BuLi (9.40 mL, 2.5 M in Hexane, 23.3 mmol) was added dropwise to a solution of 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (6.25 g, 22.2 mmol) in Et2O (190 mL) at −78° C. and stirred for 1 h. 2-(Benzhydrylidene-amino)-6,N-dimethoxy-N-methyl-isonicotinamide (10.0 g, 26.6 mmol) was added to the reaction mixture slowly and stirred for 3h, warmed to room temperature, and quenched with saturated aqueous NH4Cl (200 mL). The aqueous layer was extracted with EtOAc (3×200 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide a crude solid. Purification by flash column chromatography (ethyl acetate/hexanes 1:1) afforded the title compound as a yellow solid (7.31 mg, 63%). MS: 511.3 (MH+); HPLC Rf: 3.1 min. (HPLC method 3); HPLC purity: 100%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:16](O)[CH2:17][CH3:18]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:16][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCCO
Solvent: O=S(Cl)Cl
Product: CCCOC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), n-propanol (40 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours, then evaporated in vacuo. The residue was extracted with ethyl acetate (200 mL), washed with 10% Na2CO3, then water dried (MgSO4), and evaporated in vacuo to give n-propyl 4-hydroxyphenylacetate as an oil. A solution of n-propyl 4-hydroxyphenylacetate (5.8 g, 0.03 mol) in epichlorohydrin (50 mL) was refluxed in the presence of DBU (2 mL, 0.014 mol) for 2 hours. After the excess epichlorohydrin was removed, the residue was refluxed with isopropylamine (20 mL, 0.23 mol) in n-propanol (50 mL), for 4 hours, then was evaporated in vacuo. The residue was crystallized from n-hexane to yield 3.8 g (41%) of n-propyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, melting at 61°-62° C. and having the structural formula: ##STR28##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)Oc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC(C)(C)C)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-tert-butoxy-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4](P(OCC)(OCC)=O)[CH2:5][CH:6]([CH3:8])[CH3:7].[H-].[Na+].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([CH:20]=[C:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([O:2][CH3:1])=[O:17])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(OCC)C(CC(C)C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccccc1)CC(C)C
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirred solution of 4-Methyl-2-(diethylphosphono) pentanoic acid methyl ester (25.72 g, 96.3 mmole) in dry tetrahydrofuran (250 ml) under nitrogen was added sodium hydride (4.2 g, 60% dispersion in oil) portionwise. After stirring for 30 min. at room temperature benzaldehyde (11.22 g, 96.3 mmole) was slowly added and the reaction mixture was then stirred for a further hour at room temperature. Volatiles were then removed in vacuo and the residue was dissolved in ethyl acetate, washed with saturated aqueous ammonium chloride solution (250 ml×2), dried (sodium sulphate), filtered and evaporated in vacuo to an oil. Distillation under reduced pressure gave the title compound as an oil (16.6 g, 79%); (Found: C, 75.83; H, 8.38. C14H18O2 +0.2H2O requires: C, 75.78; H, 8.36%); δ(CDCl3) 0.87 and 0.95 (together 6H, each d, each J=7 Hz, (CH3)2CH); 1.90 (1H, m, (CH3)2CH); 2.34 and 2.52 (together 2H, each d, each J=8 Hz, CH2CH(CH3 )2); 3.82 (3H, s, OCH3); 7.70 and 7.2-7.42 (together 6H, s, m, C6H5, vinyl CH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:27][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(NC(=O)[C@H](COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)c1
Reactant: c1c[nH]cn1
Product: CCOC(=O)c1cccc(NC(=O)[C@H](Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The procedure described in Example 79 was repeated, except that (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-methanesulfonyloxypropanamide (100 mg) was reacted with imidazole to obtain the desired (S)-2-(4-chlorobenzenesulfonylamino)-N-(3-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (19.9 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3](=[N:7][C@H](C1C=CC=CC=1)C)[C:4]([NH2:6])=[O:5]>CO.[Pd]>[NH2:7][C@H:3]([C:4]([NH2:6])=[O:5])[C:2]([CH3:17])([CH3:16])[CH3:1]
Reactant: C[C@H](N=C(C(N)=O)C(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[C@H](N)C(N)=O
Reaction time: 6.5 h
Yield: 78.7 %

Procedure:
A solution of 12.0 g (51.7 mmol) of (S)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide in 200 ml of methanol was hydrogenated in a low pressure hydrogenation apparatus in the presence of 2.0 g of 5 percent Pd/C at 40° C. and normal pressure for 6.5 hours. After cooling the catalyst was filtered off and the filtrate was evaporated to dryness: 6.7 g (99.5%) of white crystals containing 90.8% (S)-tert-leucinamide, 97.0% e.e. Recrystallization from 40 ml of cyclohexane yielded 5.3 g (78.5%) of (S)-tert-leucinamide as white crystals, m.p. 104°-105° C., [α]=-23.2 (c=1, CHCl3), 96.9% e.e.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=2)=[CH:12][CH:11]=1.CS(C1C=CC(N2C(C3C=CC(Br)=CC=3)=CC(C(F)(F)F)=N2)=CC=1)(=O)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Br)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1
Reactant: OB(O)c1ccco1
Agent: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Product: CCOC(=O)c1cc(-c2ccc(-c3ccco3)cc2)n(-c2ccc(S(C)(=O)=O)cc2)n1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of 2-thiophenboronic acid and Ethyl 5-(4-bromophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole-3-carboxylate prepared according to the procedure of EXAMPLE 63, step 1) instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][CH2:19][C@@H:20]1[CH2:24][CH2:23][C:22](=[O:25])[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C1([Se]Cl)C=CC=CC=1.OO>C1COCC1.CN1C(=O)N(C)CCC1>[Si:11]([O:18][CH2:19][C@@H:20]1[CH:24]=[CH:23][C:22](=[O:25])[N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl[Se]c1ccccc1
Agent: OO
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CC(C)(C)OC(=O)N1C(=O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of NaHMDS (35 mL, 35 mmol, 1.0M solution in THF) in THF (45 mL) at 0° C. was added DMPU (4.8 mL) and the reaction mixture was stirred 20 minutes. The reaction mixture was cooled to −78° C. and to it was added a solution of 4-2 (4.8 g, 14.6 mmol) in THF (20 mL) and the reaction was stirred an additional 30 minutes. At this time a solution of phenylselenenyl chloride (3.35 g, 17.5 mmol) in THF (15 mL) was added and the reaction was stirred at −78° C. for 2 h. The reaction quenched with saturated NH4Cl (200 mL) at −78° C. and the reaction mixture was warmed to ambient temperature. The reaction mixture was extracted with EtOAc (3×200 mL) and the combined organic phase was dried over magnesium sulfate and concentrated. The residue was resuspended in THF (100 mL) and cooled to 0° C. To the reaction mixture was added H2O2 (6.4 mL, 73 mmol, 35% solution in water). The reaction mixture was stirred 2 h and quenched with saturated NaHCO3 (200 mL). The reaction was extracted with EtOAc (3×200 mL) and the combined organic phase was dried over magnesium sulfate and concentrated. The residue was purified by normal phase silica gel chromatography (0 to 70% EtOAc in hexanes) to afford the product (4-3) as an off-white solid. ESI+ MS: [M-Boc+H]+ 228.3.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:16]=[C:15]([NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:14][N:13]=2)[C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.CO.[OH-].[Na+]>O1CCCC1>[CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:16]=[C:15]([NH:17][C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:14][N:13]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A solution of ethyl 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer)(11 g) in a mixture of tetrahydrofuran (72 ml), methanol (72 ml) and 2N sodium hydroxide (72 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and adjusted to pH 2 with 3N hydrochloric acid. The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated with petroleum ether to give 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (7.75 g) as a solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][N:18]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].CO[2H]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][N:18]([CH2:30][CH:31]3[CH2:32][CH2:33]3)[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3)c3ccc(F)c(C(=O)OC)c3)cc2)cc1
Agent: [2H]OC
Product: CCCCc1ccc(C#Cc2ccc(CN(CC3CC3)c3ccc(F)c(C(=O)O)c3)cc2)cc1

Procedure:
The title compound was prepared following procedure described in example 36, step c) from methyl 5-[{4-[(4-butylphenyl)ethynyl]benzyl}(cyclopropylmethyl)amino]-2-fluorobenzoate (200 mg; 0.43 mmol) and obtained quantitatively (200 mg) as a white powder. HPLC, Rt: 5.45 min (purity: 97.7%), LC/MS, M−(ESI): 454.1, 1H M (MeOD) δ: 7.24-7.42 (m, 5H), 7.22 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.7 Hz, 2H), 7.01 (d, J=7.9 Hz, 2H), 4.64 (s, 2H), 3.36 (d, J=6.4 Hz, 2H), 2.59 (t, J=7.9 Hz, 2H), 1.57 (m, 2H), 1.34 (m, 2H), 1.21 (m, 1H), 0.91 (t, J=7.3 Hz, 3H), 0.50 (m, 2H), 0.21 (m, 2H).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:21].CCOCC>CO>[ClH:21].[ClH:21].[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCOCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC1CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of tert-butyl N-[4-(morpholin-4-yl)cyclohexyl]carbamate (1.0 g, 3.52 mmol, 1.00 equiv) in methanol (5 mL) was added concentrated hydrochloric acid (1.5 mL) at 0° C. The resulting solution was stirred overnight at room temperature. To this mixture was slowly added ether (50 mL). The precipitates were collected by filtration and dried in an oven to give 4-(morpholin-4-yl)cyclohexan-1-amine dihydrochloride (500 mg, 55%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[F:10][C:11]([F:21])([F:20])[CH2:12][O:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([O:13][CH2:12][C:11]([F:20])([F:10])[F:21])[NH:18][N:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Nc1cc(OCC(F)(F)F)[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.00 g, 5.45 mmol) in THF (10 ml) at room temperature was added 5-(2,2,2-trifluoroethoxy)-1H-pyrazol-3-amine (986 mg, 5.45 mmol) and triethylamine (606 mg, 6.0 mmol) and the reaction mixture was stirred at 40° C. overnight. The suspension was filtered and washed with water and dried to give the desired product as a white solid. MS: 328 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][CH2:12][CH2:11]O2)=[CH:5][CH:4]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19]C=[CH:17][C:16]=1COCOC>>[B:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[C:17]2[CH:16]=[CH:15][CH:20]=[CH:19][C:11]=2[CH2:12][O:13]1
Reactant: COCOCc1ccccc1Br
Reactant: N#Cc1ccc(B2OCCO2)cc1
Product: N#Cc1ccc(B2OCc3ccccc32)cc1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(4-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)-benzene to afford white crystalline product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[O:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:16]([O:18]CC)=[CH2:17])CCC.O.CCOC(C)=O>CN(C=O)C.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>[O:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:16](=[O:18])[CH3:17])[CH:3]=2)[O:8][CH2:9]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cnc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2c(c1)OCO2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A round-bottomed flask was charged with 6-Bromo-[1,3]dioxolo[4,5-b]pyridine IM13 (1.74 g, 8.61 mmol) in DMF (25 ml) under N2 and tributyl(1-ethoxyvinyl)tin (3.65 ml, 10.8 mmol) was added. Tetrakistriphenylphosphinepalladium(0) (0.50 g, 0.43 mmol) was added and the solution was stirred at 65° C. overnight. The mixture was added to water and EtOAc and the phases were separated. The org phase was washed with brine, dried (MgSO4) filtered and was rotovaped. The residue was dissolved in THF (100 ml), and a mixture of water (15 ml) and conc. HCl (2.5 ml) was added and the solution was stirred at it 5 min. The solution was added to brine and sat NaHCO3 solution was added until the solution was slightly alkaline. The org Phase was extracted with EtOAc and the phases were separated. The org phase was washed with brine, dried (MgSO4) filtered and was rotovaped. The residue was redissolved in THF (10 ml) EtOAc (20 ml) and heptanes (20 ml). The mixture was concentrated until 25 ml remained and cooled in ice. A solid precipitated and was collected by filtration. Yield: 0.942 g (66%) of IM21. 1H-NMR (500 MHz, DMSO) δ 8.47 (s, 1H), 8.54 (s, 1H), 6.27 (s, 2H), 2.53 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1[CH2:28][O:27][CH2:26]C1.C([Li])CCC.ICOC>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([CH2:26][O:27][CH3:28])=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: C1CCOC1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: COCI
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(COC)cc3C)c(C)nc12
Temperature: 25 °C
Yield: 44 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and THF (3 mL) is added 1.34 M n-Bu-Li (0.50 mL, 0.80 mmol). After 30 minutes iodo-methoxy-methane (0.097 mL, 1.15 mmol) is added and the solution warmed to ambient temperature. After 1 hour the solution is diluted with EtOAc (40 mL) washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-20% EtOAc/hexane gradient) furnish the title compound (0.12 g, 0.34 mmol, 44%). 1H NMR (CDCl3), δ 0.87 (t, J=7.5 Hz, 6H), 1.72-1.90 (m, 4H), 2.09 (s, 3H), 2.45 (s, 3H), 2.49 (s, 3H), 3.28-3.37 (m, 1H), 3.44 (s, 3H), 4.61 (s, 2H), 6.65 (s, 1H), 6.93 (s, 1H). LC/MS (m/z): calcd. for C20H27N3OS (M+H)+: 358.3; found: 358.3.
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]([OH:20])=O)[CH:13]=[CH:14][CH:15]=1)#[N:9].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]2=[O:41])=[C:31]([CH3:42])[CH:30]=1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]3=[O:41])=[C:31]([CH3:42])[CH:30]=2)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1cccc(NC(C(=O)O)c2ccccc2F)c1
Reactant: Cc1cc(N)ccc1N1CCCCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)C(Nc2cccc(C#N)c2)c2ccccc2F)ccc1N1CCCCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
225 μl (2.22 mmol) of 4-methylmorpholine are added to a solution of 600 mg (2.22 mmol) of (3-cyanophenylamino)-2-fluorophenylacetic acid, 453 mg (2.22 mmol) of 1-(4-amino-2-methylphenyl)piperidin-2-one, 426 mg (2.22 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 300 mg (2.22 mmol) of hydroxybenzotriazole hydrate (HOBt) in 1 ml of DMF, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is introduced into water, and the precipitate is filtered off, giving 2-(3-cyanophenylamino)-2-(2-fluorophenyl)-N-[3-methyl-4-(2-oxopiperidin-1-yl)phenyl]acetamide as a colourless solid; ESI 456.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][C:16]([CH2:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:17][CH:18]=2)=[C:9]([O:30][CH3:31])[CH:8]=1)(=O)=O.[NH:34]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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].O.O1CCOCC1>[CH3:31][O:30][C:9]1[CH:8]=[C:7]([C:37]2[CH:38]=[N:34][NH:35][CH:36]=2)[CH:12]=[CH:11][C:10]=1[C:13]1[N:14]=[N:15][C:16]([CH2:19][CH:20]2[CH2:25][C:24]([CH3:26])([CH3:27])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[CH:17][CH:18]=1
Reactant: OB(O)c1cn[nH]c1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1-c1ccc(CC2CC(C)(C)NC(C)(C)C2)nn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cn[nH]c2)ccc1-c1ccc(CC2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To a microwave vial was added 3-methoxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazin-3-yl)phenyl trifluoromethanesulfonate (160 mg, 0.33 mmol), 1H-pyrazol-4-ylboronic acid, (73.4 mg, 0.66 mmol), potassium phosphate (209 mg, 0.99 mmol), Pd2(dba)3 (30.1 mg, 0.03 mmol), and SPhos (26.9 mg, 0.06 mmol), followed by addition of 1,4-dioxane (2.6 mL)/H2O (0.7 mL). The vial was purged with N2 for 5 minutes and the reaction mixture was heated at 100° C. in the microwave for 1 h. The reaction mixture was concentrated in vacuo. The crude material was adjusted to pH 3 using 1 M HCl aqueous solution and loaded on an SCX column. The crude material was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions were concentrated to afford 3-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-6-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)pyridazine (133 mg) MS [M+H+]=406.2.
Reaction SMILES: Br[CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:5]=2[O:4][C:3]1([CH3:13])[CH3:12].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>CN(C)C=O>[C:14]([O:17][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Br:11])[C:5]=2[O:4][C:3]1([CH3:13])[CH3:12])(=[O:16])[CH3:15]
Reactant: CC1(C)Oc2c(Br)cccc2C1Br
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC1c2cccc(Br)c2OC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7.6 grams (0.025 mole) of 3,7-dibromo-2,3-dihydro-2,2-dimethylbenzofuran and 11.3 grams (0.115 mole) of powdered potassium acetate in 125 mL of dry N,N-dimethylformamide is stirred at ambient temperature for about 24 hours. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is poured into about 350 mL of water and the mixture is extracted with diethyl ether. The ether extract is concentrated under reduced pressure, yielding 3-acetoxy-7-bromo-2,3-dihydro-2,2-dimethylbenzofuran.