Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)[CH:16]=[CH:15][C:14]=2[CH3:25])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:29][CH2:28]C1.C([Li])CCC.CN(C=O)C>CCOC(C)=O>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)[CH:16]=[CH:15][C:14]=2[CH3:25])=[CH:11][C:12]=1[CH:28]=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)s1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc(C=O)c(C(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In 150 mL round-bottom flask equipped with a stir bar, under N2, was added N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide (1.2 g, 3.4 mmol) followed by anhydrous THF (100 mL). The solution was cooled down to −78° C. and butyllithium, (2.2 ml, 30 mmol) was added dropwise over 5 min. The mixture was stirred at −78° C. for 0.5 hrs and was added DMF (0.780 ml, 10 mmol). The mixture was stirred at −78° C. for 0.5 hr, quenched with saturated solution of NH4Cl and then allowed to warm up to room temperature. The reaction then diluted with EtOAc (100 ml) and the layers were separated and the aqueous layer was extracted with EtOAc (3×50 ml) and the combined organic solution was washed with brine, water and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide (1.01 g). MS (ES+): 385 (M+H)+
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[F:43])(=[O:35])=[O:34])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][N:19]4S(C3C=CC=CC=3)(=O)=O)=[N:12][CH:11]=2)[CH2:3]1.[OH-].[Na+]>C(O)(C)C>[CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[O:14][C:13]([C:15]3[CH:23]=[C:22]([C:24]4[CH:25]=[C:26]([NH:32][S:33]([C:36]5[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=5[F:43])(=[O:34])=[O:35])[C:27]([O:30][CH3:31])=[N:28][CH:29]=4)[CH:21]=[C:20]4[C:16]=3[CH:17]=[N:18][NH:19]4)=[N:12][CH:11]=2)[CH2:3]1
Reactant: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (105 mg, 0.140 mmol) was suspended in isopropanol (2 ml) and 2M sodium hydroxide (aq) (0.699 ml, 1.399 mmol) added. The reaction mixture was stirred at RT for 2 h, the solvent removed under a stream of nitrogen and the residue dissolved in water (1 ml) and acidified to pH-6 by the addition of 2M hydrogen chloride (aq)(a black precipitate formed). The suspension was extracted with dichloromethane (3×2 ml) and the combined organics dried to give a brown solid. This was combined with the black precipitate which remained insoluble in the extraction, dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (20 mg).
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[OH:21][CH2:22][CH2:23]N>>[O:21]1[CH2:22][CH2:23][N:2]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:17][N:16]=[C:15]([CH3:18])[CH:14]=2)=[CH:19][CH:20]=1
Reactant: Cc1cc(CCCCCOc2ccc(C#N)cc2)on1
Reactant: NCCO
Product: Cc1cc(CCCCCOc2ccc(C3=NCCO3)cc2)on1
Yield: 68 %

Procedure:
5-{5-[4-(4,5-Dihydro-2-oxazolyl)phenoxy]pentyl}-3-methylisoxazole [IX; R=CH3, R1, R2, R3, R4, R5 and R6 =H, Y=(CH2)5, oxazole at 4-position] was prepared by conversion of 5-[5-(4-cyanophenoxy)pentyl]-3-methylisoxazole to the corresponding ethyl imino-ester hydrochloride (m.p. 120°-121° C.) and reaction of the latter with 2-hydroxyethylamine in accordance with the procedure of Example 1, part (c). The product was obtained in 68% yield as a colorless solid, m.p. 87°-88° C.; monomethanesulfonate salt, m.p. 124°-125° C. The free base was obtained as a colorless solid, m.p. 102°-103.5° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]1[C:9]2[N:10]([N:20]=[N:21][N:22]=2)[C:11]([CH3:19])=[CH:12][C:13]=1[NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=O)[CH3:2].Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]2[CH:12]=[C:11]([CH3:19])[N:10]3[N:20]=[N:21][N:22]=[C:9]3[C:8]=2[N:7]=1)[CH3:2]
Reactant: CCOCC(=O)Nc1c(NCC(C)C)cc(C)n2nnnc12
Agent: Cl
Solvent: c1ccncc1
Product: CCOCc1nc2c(cc(C)n3nnnc23)n1CC(C)C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of 2-ethoxy-N-{7-[(2-methylpropyl)amino]-5-methyltetraazolo[1,5-a]pyridin-8-yl}acetamide (10.9 g, 35.6 mmol) and pyridine hydrochloride (10 g) in pyridine (100 mL) was heated at reflux under a nitrogen atmosphere for five days. An analysis by high-performance liquid chromatography indicated the presence of 16% starting material, and an additional 10 g of pyridine hydrochloride was added. After a total of seven days, the reaction was complete, and the solvent was removed under reduced pressure. The resulting black oil was dissolved in ethyl acetate (500 mL), and the solution was washed with water (3×200 mL), dried over magnesium sulfate, filtered, and concentrated to 200 mL. Needles began to form in the solution, which was placed in a freezer for two hours. The crystals were then filtered and washed with cold ethyl acetate to yield 6.85 g of 8-(ethoxymethyl)-7-(2-methylpropyl)-5-methyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine as light brown needles, m.p. 158–160° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][CH3:12].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=2)=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1cc(B(O)O)ccc1F
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cc(-c2nn(C(C)C)c3ncnc(N)c23)ccc1F
Temperature: 80 °C
Yield: 44.2 %

Procedure:
A solution of 4-fluoro-3-methoxyphenylboronic acid (61 mg, 0.36 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (90 mg, 0.30 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA62 (40 mg, 44% yield). ESI-MS (M+H)+ m/z calcd 302, found 302.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([O:24][CH3:25])[CH:20]=[CH:21][C:22]=1Br)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:35][CH3:36])(=[O:34])[C:27]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)CC>[C:26]([C:27](=[CH:28][C:22]1[CH:21]=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=1[CH2:16][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:29][C:30]([O:32][CH3:33])=[O:31])([O:35][CH3:36])=[O:34]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: COc1ccc(Br)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(=Cc1ccc(OC)cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A 500 mL flask was charged with 3-bis(tert-butoxycarbonyl)aminomethyl-4-bromoanisole(15 g, 36 mmol), dimethyl itaconate (7.5 g, 47 mmol), tri-o-tolylphosphine (1 g, 3 mol), palladium acetate (0.4 g, 2 mmol), diisopropylethylamine (12.8 mL, 72 mmol), and propionitrile (150 mL). The mixture was purged with argon (several evacuation/argon flush cycles), then was heated to reflux under argon for 1 hr. The reaction was allowed to cool to RT, then was poured into ice-cold ethyl ether (500 mL). The resulting precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by chromatography on silica gel (10%-20% ethyl acetate in hexane) to give the title compound (11.8 g, 66%) as a pale yellow oil: 1H NMR (CDCl3) δ 7.94 (s, 1 H, 7.15 (d, J=8.1 Hz, 1 H), 6.77 (d, J=8.1 Hz, 1 H, 6.76 (s, 1 H, 4.73 (s, 2 H), 3.81 (s, 3 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 3.38 (s, 2 H), 1.45 (s, 18 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9](=O)[CH3:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.P(Cl)(Cl)(Cl)=O>>[CH3:10][CH:9]1[NH:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]12
Reactant: CC(=O)NCCn1cccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1NCCn2cccc21

Procedure:
The solid N-[2-(1H-pyrrol-1-yl)ethyl]acetamide (8 g, described in Example 1) is added cautiously in small portions into phosphorus oxychloride (45 ml) upon stirring. The mixture is refluxed for 60 min, and evaporated under reduced pressure (1 mm Hg). The residue is dissolved in 600 ml of methanol, filtered, and diluted with 60 ml of water. Sodium borohydride (8 g) is then added over 40 min at 25° C. The reaction mixture is stirred overnight, concentrated in vacuo, rendered basic with 10% ammonium hydroxide, and extracted with chloroform. The extracts are dried and evaporated to give a residue (5.79) of the title compound, nmr(CDCl3) δ 1.38(d), 1.90(s), 3.25(m), 3.80(d), 3.86(d), 4.05(q), 5.85(dd), 6.14(t) and 6.53(dd). A solution of the title compound in ethanol and a solution of an equimolar amount of maleic acid in ethanol are combined. The resulting solution is concentrated to obtain the maleate salt of the title compound: mp 137°-138° C., uv(MeOH) λmax 210 nm; ε=15000, and anal. calc'd. for C8H12N2.C4H4O4 : C, 57.13% H, 6.39% N, 11.11% and found: C, 57.16% H, 6.44% N, 10.86%.
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[O:7][C:8]1[C:16]2[O:15][C:14](=[O:17])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>CO>[OH:15][C:16]1[C:8]([O:7][C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH3:3])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]([OH:1])=[O:17]
Reactant: COc1ccccc1Oc1cccc2c1OC(=O)C2
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: COc1ccccc1Oc1cccc(CC(=O)O)c1O
Reaction time: 3 h
Yield: 71.9 %

Procedure:
A solution of potassium hydroxide (1.3 g) in methanol (30 ml) was added to a solution of 7-(2-methoxyphenoxy)-2,3-dihydrobenzofuran-2-one (1.3 g) in methanol (30 ml), and allowed to stand at room temperature for 3 hrs. Methanol was distilled off from the reaction mixture, and the residue was dissolved in water. The aqueous solution was acidified with conc. hydrochloric acid, and the precipitating crystals were collected by filtration, washed with water, dried and then recrystallized from a mixture of ethyl acetate and n-hexane to give 2-[2-hydroxy-3-(2-methoxyphenoxy)phenyl]acetic acid (1.0 g). mp 125°-126° C.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:14]=[C:13](F)[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7].O>C1COCC1>[F:3][C:4]1[CH:14]=[C:13]([NH:2][CH3:1])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NC)cc1F
Reaction time: 3 h

Procedure:
A solution of MeNH2 in THF (21.6 mL; 2 M; 43.3 mmol) was added dropwise to a solution of ethyl 2,4-difluoro-5-nitrobenzoate (5.0 g; 21.6 mmol) in THF (70 mL) at −5° C. The mixture was left over night at rt whereafter an additional portion of MeNH2 in THF (10.0 mL; 2 M; 21.6 mmol) was added at 0° C. After 3 h at rt, water was added and the mixture was concentrated. The resulting precipitate was filtered off and dried to give the sub-title compound. Yield: 5.0 g (96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.N1C=CC=C[CH:32]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Na+]>CN(C)C=O.O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[N:1]=[CH:32][N:12]([CH2:13][CH3:14])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cnc2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 504.4 mg (1.20 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of dimethylformamide were added 0.29 ml (3.60 mmol) of pyridine and 0.13 ml (1.49 mmol) of oxalyl chloride under ice-cooling, followed by overnight stirring at room temperature in an atmosphere of argon. Then, the resulting mixture was heated at 80° C. with stirring for 5 hours. The reaction mixture was allowed to cool to room temperature and then poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:21](Cl)=[O:22])([CH3:17])[CH3:16]>O1CCCC1>[C:9]([N:8]([CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[CH:19]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)NCc1ccncc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccncc2)C(C)=O)cc1C(C)(C)C
Yield: 8.8 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 0.90 g of product from Example 15, 0.316 g of washed 50% sodium hydride, 2.57 g of product from Example 33 and 25 ml of dry tetrahydrofuran. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 0.275 g of desired product as a yellow oil which crystallizes on standing.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cccc(N)c2)n1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
tert-Butyl (6-iodopyridin-2-yl)carbamate (1.50 g, 4.68 mmol), copper(I) iodide (68.0 mg, 0.36 mmol) and bis(triphenylphosphine)palladium(II) chloride (100 mg, 0.2 mmol) were stirred in tetrahydrofuran (14 mL) with triethylamine (0.70 mL, 5.0 mmol) under N2 at rt. 3-Ethynylaniline (0.47 mL, 4.5 mmol) was added and the mixture was heated at 60° C. overnight. The mixture was filtered, washed with EtOAc and concentrated under vacuum to give the desired product as a brown solid (1.23 g, 89%). LCMS for C14H12N3O2 ([M-(tBu)+H]+H)+: m/z=254.1.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:25]3[CH2:30][C@H:29]([CH3:31])[O:28][C@H:27]([CH3:32])[CH2:26]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[CH3:14].[CH3:33][NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:35]([N:34]([CH3:33])[C:8]1[CH:9]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:25]3[CH2:30][C@H:29]([CH3:31])[O:28][C@H:27]([CH3:32])[CH2:26]3)[N:17]=2)[CH:11]=[CH:12][C:13]=1[CH3:14])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CNCc1ccccc1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N3C[C@@H](C)O[C@@H](C)C3)n2)cc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(N(C)C)nc(N3C[C@@H](C)O[C@@H](C)C3)n2)cc1N(C)Cc1ccccc1
Temperature: 110 °C
Yield: 36.2 %

Procedure:
Sodium tert-butoxide (60 mg, 0.63 mmol) was added to a solution of N4-(3-bromo-4-methylphenyl)-2-(cis-2,6-dimethylmorpholinyl)-N6,N6-dimethyl-4,6-pyrimidinediamine (50 mg, 0.12 mmol) and N-methyl(phenyl)methanamine (50 mg, 0.40 mmol) in tetrahydrofuran (2 mL). Tris(dibenzylidineacetone)dipalladium (1 mg, 0.001 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2 mg, 0.003 mmol) were added to this mixture and the resulting mixture was heated at 110° C. for 16 hours. The mixture was then cooled to room temperature, concentrated in vacuo, and purified by preparative thin-layer chromatography [eluent: hexane/EtOAc (3:1)], giving the desired product (20 mg, 36%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([C:27]2([O:33][CH2:34][CH3:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: CCOC1(c2ccc(I)cc2)CCOCC1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: CCOC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)CCOCC1
Yield: 68.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (60.4 mg) was reacted with tetrahydro-4-(4-iodophenyl)-4-ethoxy-2H-pyran (66.4 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-ethoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (68.9 mg). Column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1 cyclohexane/ethyl acetate=4/1) was used for purification.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH:24]1([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:1]([C:4]34[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]5[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]5[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]3)[CH2:6][CH2:5]4)=[O:2])=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(C2CCCCC2)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(C4CCCCC4)cc3)(CC1)CC2
Yield: 30 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-cyclohexylaniline (60.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-cyclohexylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (22.3 mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1.[CH:16]([N:29]1[CH2:32][C:31](=[O:33])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH:16]([N:29]1[CH2:32][C:31]([C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:7]=2)([OH:33])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1coc2ccccc12
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2cc3ccccc3o2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (2.23 mL, 5.58 mmol) was added dropwise to a solution of 3-bromobenzofuran (1.0 g, 5.08 mmol) in THF (35 mL) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. and then a solution of 1-benzhydrylazetidin-3-one (1.2 g, 5.08 mmol, as prepared in step 1 of example FAB270) in THF (10 mL) was added dropwise at the same temperature. The mixture was allowed to warm back to room temperature overnight. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel using petroleum ether/dichloromethane (50:50 to 0:100) as eluent. The title compound was obtained as a yellow solid (230 mg, 13%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([NH:26][C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:23])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: NN1CCOCC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Product: O=C(NN1CCOCC1)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 41 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (100 mg, 0.29 mmol) was converted, using 4-aminomorpholine instead of S-(+)-1-amino-2-propanol, to the title compound (57 mg, 41%), which was obtained as a white solid. MS: m/e=429.2 [M+H]+.