Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.[CH2:9]([C:13]1[C:17]([CH2:18][CH2:19][C:20]2[S:21][C:22]([C:26](O)=[O:27])=[C:23]([CH3:25])[N:24]=2)=[C:16]([CH3:29])[O:15][N:14]=1)[CH2:10][CH2:11][CH3:12]>O1CCOCC1.C1(C)C=CC=CC=1>[CH:1]([NH:4][C:26]([C:22]1[S:21][C:20]([CH2:19][CH2:18][C:17]2[C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:14][O:15][C:16]=2[CH3:29])=[N:24][C:23]=1[CH3:25])=[O:27])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC(C)C)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a stirred solution of isopropylamine (77 mg, 1.3 mmol) in dioxane (3 mL) under argon and at room temperature was added trimethylaluminium (0.65 mL of a 2M solution in toluene, 1.3 mmol). After 1 h, a solution of 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (100 mg, 0.32 mmol) in dioxane (4 mL) was added and the reaction mixture heated at 90° C. overnight. The reaction mixture was then cooled, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with Seignette's salt solution then dried, filtered, and concentrated. Purification by chromatography (silica, 0 to 5% methanol in dichloromethane) gave the title compound (50 mg, 44%) as a light yellow oil. MS: m/e=350.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])[NH2:5].[CH3:16][S:17](Cl)(=[O:19])=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:17]([CH3:16])(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccncc1-c1ccc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1ccc(NS(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 3.4 %

Procedure:
To a solution of Intermediate 27 (0.102 g, 0.466 mmol) and methanesulfonyl chloride (0.043 mL, 0.560 mmol) in DMF (3.26 mL) was added sodium hydride (0.037 g, 0.933 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 3 days, then quenched with saturated aqueous NH4Cl solution and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue, which was further dried under high vacuum. The crude material was dissolved in CH2Cl2 and purified by silica gel chromatography using an ISCO machine (12 g column, 30 mL/min, 0-10% MeOH in CH2Cl2 over 25 min, tr=14 min) to afford the title compound (5.1 mg, 0.016 mmol, 3.54% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:64])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[CH:34][C:33]=2[C:44]2[CH:49]=[C:48]([C:50](=[O:63])[NH:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=3)[CH:47]=[CH:46][N:45]=2)[N:25]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC2C=CC([N+]([O-])=O)=CC=2)=[O:12])[CH2:7][CH2:6]1.[CH3:65][O:66][CH2:67][CH2:68][NH2:69].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:65][O:66][CH2:67][CH2:68][NH:69][C:11]([N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:64])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]4)=[CH:34][C:33]=3[C:44]3[CH:49]=[C:48]([C:50](=[O:63])[NH:51][CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([C:59]([F:60])([F:62])[F:61])[CH:54]=4)[CH:47]=[CH:46][N:45]=3)[N:25]=2)[CH2:10][CH2:9]1)=[O:12]
Reactant: COCCN
Reactant: CN(CCN1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCNC(=O)N1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-nitrophenyl 4-(2-(methyl((6-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)pyridin-2-yl)methyl)-amino)ethyl)piperazine-1-carboxylate (100 mg, 0.11 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 2-methoxyethanamine (10 mg, 0.13 mmol, 1.00 equiv), and N,N-diisopropylethylamine (45 mg, 0.35 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The mixture was concentrated under vacuum. The crude product (0.1 g) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 23.2 mg (18%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.76 (s, 1H), 9.54-9.52 (m, 1H), 9.05-9.03 (m, 1H), 8.48-8.45 (m, 1H), 8.26 (m, 1H), 8.14-8.12 (m, 2H), 7.88-7.86 (m, 1H), 7.79-7.24 (m, 7H), 6.71 (m, 1H), 4.65-4.63 (d, J=5.7 Hz, 2H), 4.09 (m, 3H), 3.69-3.01 (m, 23H), 1.71-1.59 (m, 6H). MS (ES, m/z): 816 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:13][CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CCCCCC>[Br:13][CH2:14][CH2:15][O:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:9][CH:8]=1
Reactant: OCCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FC(F)(F)Oc1ccc(OCCBr)cc1
Reaction time: 12 h
Yield: 103.7 %

Procedure:
4-(Trifluoromethoxy)phenol (15 g), 2-bromoethanol (7.76 g) and triphenylphosphine (22.1 g) were dissolved in tetrahydrofuran (250 ml). Diethyl azodicarboxylate (13.3 ml) was added dropwise to the stirred mixture and stirring was continued for 12 hours. The mixture was concentrated in vacuo to give a yellow oil. The oil was diluted with hexane to precipitate the triphenylphosphine oxide by-product which was removed by filtration. The filtrate was concentrated and purified on silica using 10% ether in hexane as eluant to give the product (18.35 g). 1H NMR (250 MHz, CDCl3) δ 3.63 (2H, t, J 6.1 Hz), 4.30 (2H, t, J 6.2 Hz), 6.84-6.95 (2H, m), 7.12-7.17 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14].N1CCCCC1>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:16]1[NH:17][CH:18]=[CH:19][CH:20]=1)[CH3:14])#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)c1ccc[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(=C1C(=O)Nc2ccc(C#N)cc21)c1ccc[nH]1

Procedure:
To a suspension of 5-cyanoindolin-2-one (158 mg, 1 mmol) in ethanol (15 mL) was added 2-acetylpyrrole (95 mg, 1 mmol) and piperidine (0.1 mL). The reaction mixture was refluxed for 2 hours. A golden-colored product precipitated from the reaction mixture, which was filtered and washed with ethanol to afford 5-cyano-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (160 mg) 1H NMR (400 MHz, DMSO-d6) δ 2.80 (s, 3H), 6.40. (m, 1H), 7.04 (d, 1H), 7.20 (m, 1H), 7.42 (m, 1H), 7.60 (dd, 1H), 8.04 (s, 1H), 11.40 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C#N

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J29) (304 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (370 mg, 70%).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.CCN(CC)CC>ClCCCl>[CH3:2][C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)([CH3:4])[CH3:3]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)[Si](Oc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., tert-butyldiphenylchlorosilane (50 g) was added slowly to a solution of p-hydroxybenzaldehyde (22 g) and Et3N (42 mL) in 1,2-dichloroethane (400 mL) and the mixture was stirred at room temperature a few hours. After the usual work up, the product was purified by flash chromatography on silica using EtOAc:hexane 1:10 and was used as such for Step 2.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].NC1C=CC(C)=C(C(C2C=CC(NC3C=CC=C([Cl:53])C=3)=CC=2Cl)=O)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:53])[CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 461 (1.40 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:6 as the eluent to afford the title compound as yellow syrup.
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([OH:20])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH2:3])=[O:20]
Reactant: CCN(CC)c1ccccc1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1ccccn1
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 481.7 %

Procedure:
Diethylaniline (0.27 μL, 1.7 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (0.8 mg, 1.5 μmol, 1 equiv) in THF (0.15 mL) at 0° C. under an argon atmosphere and the solution was stirred for 10 min. Picolinic acid (0.24 mg, 2.0 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.38 mg, 2.0 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.25 mg, 1.8 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 17 h 45 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a yellow oil, which was purified by flash column chromatography (70% ethyl acetate-hexanes) to give the pyridine-2-carboxylic acid amide derivative (1.0 mg, 100%) as a white solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.[Cl:12][CH2:13][Si:14]([CH3:17])([CH3:16])Cl.Cl>O1CCCC1>[Cl:12][CH2:13][Si:14]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1)([CH3:17])[CH3:16]
Reactant: C[Si](C)(Cl)CCl
Reactant: CCOc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)CCl)cc1
Temperature: -78 °C
Yield: 23.1 %

Procedure:
To a mixture of 5.1 g (0.21 mole) of powdered magnesium metal in 100 ml of dry tetrahydrofuran was added dropwise 40 g (0.20 mole) of ethyl 4-bromophenyl ether. Upon completion of addition this mixture was heated at reflux for one hour. In a second flask was placed 28.5 g (0.199 mole) of (chloromethyl)dimethylchlorosilane in 100 ml of tetrahydrofuran, and this flask was cooled to -78° C. The contents of the first flask were added dropwise to the second flask. The temperature of the reaction mixture was maintained at -78° C. for one hour after addition was complete, and it was then poured into 200 ml of 10% hydrochloric acid. The organic phase was washed once with 10% hydrochloric acid. The aqueous phase was extracted with diethyl ether, and these extracts were combined with the organic phase. After being dried, filtered, and having the solvent evaporated under reduced pressure, the residue was vacuum distilled, yielding 10.5 g of (chloromethyl)(4-ethoxyphenyl)dimethylsilane, b.p. 99°-110° C./0.12 mm of Hg. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:30][CH2:31][CH3:32])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.C([Li])(C)(C)C.[O:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[NH2:15][C:6]1[C:5]2=[N:4][N:3]([CH2:30][CH2:31][CH3:32])[C:2]([CH2:1][C:41]3([OH:44])[CH2:42][CH2:43][O:38][CH2:39][CH2:40]3)=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1C
Reactant: O=C1CCOCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCOCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution of di(tert-butyl) 1-methyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (1.32 g, 3.00 mmol) in anhydrous tetrahydrofuran (THF) (30 mL) was cooled to −78° C. under an argon atmosphere. tert-Butyllithium (4.4 mL of a 1.7 M solution in pentane) was added over a period of five minutes, and the resulting dark-colored solution was stirred at −78° C. for 30 minutes. Tetrahydro-4H-pyran-4-one (901 mg, 9.0 mmol) was added, and reaction mixture was stirred for 10 minutes. The −78° C. bath was replaced with a 0° C. bath, and then saturated aqueous ammonium chloride (30 mL) was added. The aqueous layer was separated and extracted three times with tert-butyl methyl ether, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.3 g) was purified by automated flash chromatography (eluting with ethyl acetate) and heated in refluxing 1 M hydrogen chloride in ethanol (50 mL) for one hour. The solution was allowed to cool to room temperature and then made basic with the addition of 2 M aqueous sodium carbonate. The resulting solution was extracted four times with chloroform, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue (1.2 g) was purified by automated flash chromatography and recrystallized from acetonitrile to provide 430 mg of 4-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]tetrahydro-2H-pyran-4-ol as a white solid, mp 209-211° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:20]([N:19]([CH2:22][CH3:23])[C:17](=[O:18])[C:16]1[CH:24]=[CH:25][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:14][CH:15]=1)[CH3:21]
Reactant: NCc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(CCCCOCCCCCCBr)cc1
Product: CCN(CC)C(=O)c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Yield: 76.5 %

Procedure:
4-[4-[(6-Bromohexyl)oxy]butyl]-N,N-diethybenzamide (6.0 g) and benzylamine (9.36 g) were stirred under nitrogen at 120° for 30 mins. Excess benzylamine was removed by distillation under reduced pressure. The residual solid was dissolved in ethyl acetate (100 ml) and washed with 8% aqueous sodium bicarbonate (100 ml). The ethyl acetate solution was dried and evaporated to give a yellow oil which was purified by FCC eluting System B (95:5:1) to give the title compound as a yellow oil (4.88 g), t.l.c. (System B 95:5:1) Rf 0.15.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([C:19]#[N:20])=[CH:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:21].[Na+]>O1CCCC1.[Ag]=O>[C:19]([C:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:12][N:8]([C:6]2[O:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][CH:5]=2)[CH:9]=1)#[N:20]
Reactant: [OH-]
Reactant: N#Cc1cn(-c2ccc(C=O)o2)cc1-c1ccccc1
Agent: O=[Ag]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cn(-c2ccc(C(=O)O)o2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(5-formylfuran-2-yl)-4-phenyl-1H-pyrrole-3-carbonitrile (0.14 g) in tetrahydrofuran (4 mL) were added silver oxide (0.15 g) and sodium hydroxide aqueous solution (2 mol/L, 0.4 mL), and this mixture was stirred at room temperature for 6 hours. The insoluble material was removed by filtration, and this filtrate was concentrated. To this residue were added water (15 mL) and hydrochloric acid (2 mol/L, 2 mL), this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This residue was purified by column chromatography on silica gel (eluent: methanol/dichloromethane=1/10−1/5) to give the title compound (0.040 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[N:6][CH:7]=1.[F:21][C:22]1([F:36])[CH2:24][C@@H:23]1[CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1>>[F:21][C:22]1([F:36])[CH2:24][C@@H:23]1[CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([O:20][C:3]2[C:2]([NH:1][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][C:27]([O:26][CH2:25][C@H:23]4[CH2:24][C:22]4([F:36])[F:21])=[CH:28][CH:29]=3)=[CH:7][N:6]=[C:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:19])[CH3:11])[CH:4]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(OC[C@H]2CC2(F)F)cc1
Reactant: C[C@@H](COc1cc(O)c(N)cn1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1cc(OC(=O)c2ccc(OC[C@H]3CC3(F)F)cc2)c(NC(=O)c2ccc(OC[C@H]3CC3(F)F)cc2)cn1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((5-amino-4-hydroxypyridin-2-yl)oxy)propan-2-yl)carbamate and 4-(((1R)-2,2-difluorocyclopropyl)methoxy)benzoic acid, and in the same manner as in Step D of Example 83, the title compound was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.OC1C=CC=CN=1.C[O:27][C:28]([C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=1)=O>COC(C1N(C)C=CN=1)=O>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:28]([C:30]3[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: COC(=O)c1nccn1C
Agent: Oc1ccccn1
Product: Cn1ccnc1C(=O)NC1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A melt of 3-[2-(4-amino-1-piperidyl)ethyl]indole (1.0 g, 4.11 mmol), 2-hydroxypyridine (0.3 g, 3.16 mmol) and 2-methoxycarbonyl-1-methyl-1H-imidazole (0.57 g, 4.07 mmol) was heated at 160° C. for 3 hours under N2. More 2-methoxycarbonyl-1-methyl-1H-imidazole (5 drops) was added and heating continued for a further 11/2 hours. The mixture was cooled and chromatographed on silica (100-200 aktiv) eluting with absolute ethanol. The title compound was isolated as a brown glass (0.97 g,).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>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>[CH2:31]([O:30][C:28]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:29])[CH3:32]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc2ncccc2cc1Cn1nnc2ncc(Br)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Temperature: 100 °C

Procedure:
A mixture of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-7-fluoro-quinoline (2.0 g, 5.57 mmol), Pd(Ph3P)4 (0.64 g, 0.56 mmol) and tributyl(1-ethoxyvinyl)stannane (4.02 g, 11.14 mmol) in DMF (50 mL) was purged with nitrogen and then heated at 100° C. for 7 h. After removal of the solvent under reduced pressure, the residue was diluted with DCM, washed sequentially with aqueous KF and water, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with gradient (DCM:MeOH=50:1) to give the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.15 (d, 1H), 7.83 (d, 1H), 7.54 (m, 1H), 6.22 (s, 2H), 5.50 (d, 1H), 4.73 (d, 1H), 4.02 (q, 2H), 1.40 (t, 3H). LCMS (method E): [MH]+=351, tR=5.42 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:43])[CH:28]([CH:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:43])[CH:28]([CH:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:17])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1
Reactant: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)ccc1C(=O)O
Product: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1C(=O)c1ccc(-c2ccccc2)cc1CNC(=O)OC(C)(C)C
Yield: 80 %

Procedure:
3-(tert-Butyloxycarbonylaminomethyl)biphenyl-4-carboxylic acid (1.15 g, 3.5 mmol) and 3-(3-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester (0.91 g, 3.5 mmol) are coupled as described in EXAMPLE 1B to give the title compound (1.22 g, 2.8 mmol). 1H NMR (CDCl3, 300 MHz) □ 7.63-7.25(m, 12H), 4.85-4.70(two m, 1H), 4.48(m, 1H), 4.38(br.s, 2H), 3.80-3.71(m, 1H), 3.68, 3.62(two s, 3H), 3.63-3.40(m, 2H), 3.21-3.10(m, 1H), 2.90-2.78(m, 1H), 2.20-2.05(m, 1H), 2.02-1.65(m, 3H), 1.45(s, 9H).