Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][CH:25]([CH3:34])[C:26]([O:28][C@H:29]([CH3:33])[C@H:30](O)[CH3:31])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][C:19](=[O:21])[O:20][C:16]=2[CH:15]=1)[C:10]([O:12][C@H:30]([CH3:31])[C@H:29]([O:28][C:26](=[O:27])[CH:25]([CH3:34])[CH3:24])[CH3:33])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc2oc(=O)oc2c1)C(=O)O
Reactant: CC(C)C(=O)O[C@H](C)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc2oc(=O)oc2c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a mixture of (2S)-2-[(tert-butoxy)carbonylamino]-3-(2-oxobenzo[3,4-d]1,3-dioxolen-5-yl)propanoic acid (16) (5.86 g, 18.1 mmol) and (1R,2R)-2-hydroxy-1-methylpropyl 2-methylpropanoate (15) (4.15 g, 21.84 mmol) in anhydrous dichloromethane (40 mL), a solution of dicyclohexylcarbodiimide (5.62 g, 27.3 mmol) in anhydrous dichloromethane (10 mL) was added dropwise at 0° C. To the solution, a catalytic amount of 4-(dimethylamino)pyridine was added. The resulting mixture was stirred at 0° C. for 30 min, then at room temperature for 2 hours. TLC indicated a completed reaction. The side product, dicyclohexylurea, was removed by filtration. The filtrate was diluted with dichloromethane (100 mL) and washed with 10% citric acid and water. The organic layer was collected, dried over MgSO4, and concentrated to provide the title compound (17) (6.4 g, 76% yield). MS (ESI) m/z 465.9 (M+H)+.
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[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:34]([O:35][CH3:36])=[CH:33][C:24]2[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[CH:22]=1.Cl.COCCO.C(=O)([O-])[O-]>O1CCOCC1.CCOC(C)=O>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:34]([O:35][CH3:36])=[CH:33][C:24]3[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)c(OC)cc21
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.4 mmol), and 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (104 mg, 0.444 mmol), 4 M of Hydrogen chloride in 1,4-Dioxane (100 uL), 2-Methoxyethanol (4.5 mL, 57 mmol;) were charged into Radley tube. Heat 110° C. for about 3 hours, cooled to room temperature. The mixture was treated with excess MP-carbonate and stirred 30 min. Filtration followed by concentration gave a yellow film. Treatment with EtOAc and sonication provided an off-white solid. This material was stripped onto Celite and purified on ISCO column (40 g SiO2, gradient 50% EtOAc hexane to 100% EtOAc to 5% MeOH/EtOAc) gave 2-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (42.06 mg, 20%). MP: 232-233° C. 1H-NMR (dmso, 400 MHz) δ 11.56 (s, 1H), 8.74 (d, J=4.5 Hz, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 7.73 (d J=7.8 Hz, 1H), 7.67 (s, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.05 (s, 1H) 3.85-3.80 (broad m, 2H), 3.83 (s, 3H), 2.80 (d, J=4.2 Hz, 3H), 2.50-2.49 (m, 2H), 2.12-2.10 (m, 2H), 2.10-1.99 (m, 2H), 1.01 (t, J=7.0 Hz, 3H); LC/MS: 495.37 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([F:11])[CH:4]=1)#[N:2].[CH3:12][NH:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:13]([CH3:12])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CNCCC(=O)OC(C)(C)C
Product: CN(CCC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1F

Procedure:
The title compound was prepared following the general procedure 10, starting from 4-cyano-2-fluorobenzyl bromide (Fluorochem, 2.0 g, 9.3 mmol) and tert-butyl N-methyl-beta-alaninate (1.8 g, 11.2 mmol, prepared as described in Biorg. Med. Chem. (11) 2003, 3083-3099). It was isolated as a yellow oil (2.4 g, 87%). 1H NMR (CDCl3, 300 MHz) δ 7.82 (dd, J=10.0, 1.6 Hz, 1H), 7.69 (dd, J=7.8, 1.6 Hz, 1H), 7.60 (m, 1H), 3.58 (s, 2H), 2.61 (t, J=6.9 Hz, 2H), 2.38 (t, J=6.9 Hz, 2H), 2.14 (s, 3H), 1.38 (s, 9H). LC/MS (Method B): 293.0 (M+H)+. HPLC (Method A) Rt 2.44 min (Purity: 88.5%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCCCC2)c1
Yield: 88.6 %

Procedure:
In 150 ml of N,N-dimethylformamide was suspended 4.8 g of sodium hydride (52% purity), and 20.0 g of 3-piperidinomethylphenol was added in small portions with stirring under ice-cooling. After the addition, the resulting mixture was subjected to reaction at room temperature for 1 hour. To the reaction mixture thus obtained was added 28.0 g of N-(3-bromopropyl)phthalimide, and the resulting mixture was subjected to reaction for 24 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 300 ml of water and 300 ml of chloroform were added to the resulting residue to dissolve the same. The organic layer was separated and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 35.0 g (yield 88.5%) of oily N-[3-(3-piperidinomethylphenoxy)propyl]phthalimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]([C:12]2[C:13]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:31][C:14]=3[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)=O)[CH:6]=[CH:7][C:8]=1[OH:9].CC(C[AlH]CC(C)C)C.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:13]2[C:12]([CH2:10][C:5]3[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:19][CH:18]=3)[S:15][C:14]=2[CH:31]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O
Agent: CC(C)C[AlH]CC(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0° C. solution of 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-hydroxyphenyl ketone (Part D; 3.85 g, 6.64 mmol) in 100 mL of anhydrous THF was treated with DIBAL-H (17 mL, 1M solution in toluene) dropwise via syringe. After 1 hr at 0° C., the remaining DIBAL-H was quenched with excess MeOH. 100 mL of saturated Na+K+ tartrate and 50 mL of EtOAc were added, and the biphasic mixture was vigorously stirred for 1.5 hr at ambient temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over K2CO3, filtered and concentrated in vacuo. The crude residue was dissolved in 100 mL of 1,2-dichloroethane, and Et3SiH (9.4 mL, 58.7 mmol) was added. Upon cooling to 0° C., TFA (6.5 mL, 83.8 mmol) was added in a dropwise fashion. After 1.5 hr, the reaction mixture was poured into 300 mL of saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (2×150 mL). The combined organic layers were dried over K2CO3, filtered and concentrated in vacuo. Purification by PrepLC (SiO2; gradient of 0.5% to 2% MeOH in CHCl3, saturated with NH4OH) afforded 3.1 g (5.48 mmol; 83%) of a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:26]([Sn](CCCC)(CCCC)CCCC)=[CH2:27]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH:26]=[CH2:27])[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
To a stirred solution of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (1 g, 2.7 mmol) in dioxane (25 mL) under a nitrogen atmosphere was added vinyl tributyltin (1.28 mL, 4.04 mmol) and tetrakis(triphenylphosphine)palladium (156 mg, 0.13 mmol). The reaction was heated at 100° C. for 3 hours and then the solvent was evaporated in vacuo. The resulting black residue was purified by column chromatography (40 g SiO2, Hexanes:Ethyl acetate, 1:0 to 3:1) to give (S)-2-(1-(8-chloro-2-vinylquinolin-3-yl)ethyl)isoindoline-1,3-dione as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.53 (1H, s), 7.76-7.81 (4 H, m), 7.68-7.72 (2H, m), 7.41 (1H, dd, J=7.8, 7.8 Hz), 7.26-7.33 (1H, m), 6.71 (1H, dd, J=16.4, 2.3 Hz), 6.00 (1H, q, J=7.3 Hz), 5.64 (1H, dd, J=10.6, 2.3 Hz), 2.00 (3H, d, J=7.0 Hz). Mass Spectrum (ESI) m/e=362.8 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(=S)=S>[CH3:5][S:6]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1)(=[O:8])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: CS(=O)(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CS(=O)(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mechanically stirred suspension of aluminum chloride (88.0 g, 0.66 moles) and 150 ml of carbon disulfide under N2 is cooled in an ice bath. Methanesulfonanilide as prepared in Preparation 1 (30.0 g, 0.175 mol) and succinic anhydride (17.5 g, 0.175 mol) are combined and added rapidly to the cooled reaction mixture. The ice bath is removed and the mixture is stirred at ambient temperature for 6 hours. The reaction mixture is then heated to 55° C. and allowed to continue for 18 hours. The reaction mixture is separated into two layers the bottom of which solidifies. The upper layer is decanted and the remaining solid layer is decomposed with ice. The resulting suspension is filtered and the solid is washed several times with methylene chloride and dissolved in a mixture of saturated sodium bicarbonate (500 ml) and water (500 ml). This solution is acidified (pH2) with HCl and the resulting precipitate is collected by filtration, redissolved in NaHCO3 and reprecipitated with HCl. The solid, 4-[(methylsulfonyl)amino]-γ-oxobenzenebutanoic acid, is collected by filtration and dried to give the title compound with mp 198°-200° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([NH2:40])=[O:39].C(N(CC)CC)C.[CH2:51](O)[CH2:52][CH2:53][CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH3:60]>C1COCC1>[CH2:51]([O:34][C:35]1[CH:36]=[C:37]([C:38]([NH2:40])=[O:39])[CH:41]=[CH:42][CH:43]=1)[CH2:52][CH2:53][CH2:54]/[CH:55]=[CH:56]\[CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: NC(=O)c1cccc(O)c1
Reactant: CCCC/C=C\CCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC/C=C\CCCCOc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a suspension of polymer-supported triphenyl phosphine (1.4 g, 3 mmol, based on a loading of 2.15 mmol/g [purchased from Argonaut], 1.5 equiv.) swollen in THF (20 ml) at room temperature was added diisopropylazodicarboxylate (0.47 ml, 2.4 mmol, 1.2 equiv.). The mixture was shaken for 5 min before 3-hydroxybenzamide (274 mg, 2 mmol, 1 equiv.), triethylamine (0.28 ml, 2 mmol, 1 equiv.) and cis-5-decenol (313 mg, 2 mmol, 1 equiv.) were added. The resulting suspension was shaken at room temperature for 16 h and then filtered. The resin was washed with additional THF (×3) and then the combined filtrate and washings were concentrated under reduced pressure, to give the crude product as a colourless semi-solid. It was purified by column chromatography on silica eluting with EtOAc/hexane (20%-40% gradient) to give the desired compound as a white solid (390 mg, 71%), mp 98-100° C. HPLC-MS (method 1): m/z 276 [M+H]+, Rt=5.00 min. 1H NMR (CDCl3) δ=7.35 (s, 1H), 7.32-7.28 (m, 2H), 7.08-7.02 (m, 1H), 6.18 (br, 2H), 5.41-5.32 (m, 2H), 3.98 (t, J=6.4 Hz, 2H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.34-1.28 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:32])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:18][C@H:17]([OH:19])[C@H:16]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)[CH2:15]2)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:21][CH2:20][C@H:16]1[C@@H:17]([OH:19])[CH2:18][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:32])[CH2:15]1
Reactant: O=C(NC[C@@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@@H]1O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of phenylmethyl ({(3R,4R)-1-[2-(7-fluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-hydroxy-3-pyrrolidinyl}methyl)carbamate (0.3 g) in dry methanol (15 mL) was treated with 10% Pd/C (0.08 g) and shaken under 15 psi at room temperature for 2 hours. The Pd catalyst was filtered through Celite®. The filtrate was evaporated to dryness to give an oil (0.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH2:27])[CH:22]=[CH:21]2.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:9])[CH:22]=[CH:21]2
Reactant: Nn1ccc2cc(F)ccc21
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1.20 mmol) and K2CO3 (2 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt, and the reaction mixture is stirred at rt overnight. The reaction mixture is extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give a solid. The solid is triturated with EtOAc/heptane to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (122 mg, 35%) as a solid. MS: 348 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.77 (s, 3H), 6.55 (m, H) 7.06 (m, H), 7.32-7.66 (m, 4H), 8.02 (m, H), 8.45 (d, H), 8.79 (s, H), 9.26 (s, H), 12.00 (s, N—H). IC50=17 nM.
Reaction SMILES: F[C:2]1[N:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5].[OH-].[NH4+:32]>>[NH2:32][C:2]1[N:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: [NH4+]
Reactant: Cc1cnc(F)c(C(=O)c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Agent: [OH-]
Product: Cc1cnc(N)c(C(=O)c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: 110 °C
Yield: 18 %

Procedure:
A microwave vial was charged with tert-butyl 4-(6-(2-fluoro-5-methylnicotinoyl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (280 mg, 0.68 mmol) and a saturated aqueous solution of ammonium hydroxide (1.5 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 30 minutes. The mixture was cooled down to room temperature and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as an orange solid (49 mg, 18% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:41]=[CH:40][C:17]([O:18][CH2:19][C:20]4[CH:39]=[CH:38][CH:37]=[CH:36][C:21]=4[O:22][CH:23]([C:31]([O:33]CC)=[O:32])[CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]4[CH:39]=[CH:38][CH:37]=[CH:36][C:21]=4[O:22][CH:23]([C:31]([OH:33])=[O:32])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:40][CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(Oc1ccccc1COc1ccc(C=Cc2ccc3ccc(Cl)cc3n2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(Oc1ccccc1COc1ccc(C=Cc2ccc3ccc(Cl)cc3n2)cc1)C(=O)O

Procedure:
The crude product is purified by column chromatography to give ethyl 4-(2-(4-(2-(7-chloroquinolin-2-yl)ethenyl)phenoxymethyl)phenoxy)-4-carbethoxybutyrate. The ester is treated with 1N NaOH solution (30 mL) in dioxane overnight. The reaction mixture is then acidified, and purified by flash chromatography which gives 4-(2-(4-(2-(7-chloroquinolin-2-yl)ethenyl)phenoxymethyl)phenoxy)-4-carboxybutyric acid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:11]Br.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:11][C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1
Reactant: BrBr
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
To a solution of ethyl 1H-pyrrole-2-carboxylate (1.17 g) in carbon tetrachloride (40 ml), a solution of bromine (1.48 g) in carbon tetrachloride (80 ml) was added dropwise at −15° C., and the mixture was stirred for one hour. The mixture was warmed to a room temperature, and a 2-N sodium hydroxide aqueous solution (80 ml) was added thereto. The resulting mixture was subjected to extraction with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:6) to give ethyl 4-bromo-1H-pyrrole-2-carboxylate (700 mg, 38%).
Reaction SMILES: [CH3:1][C:2]([N+:15]([O-])=O)([CH3:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1>[Ni].C(O)C>[CH3:14][C:2]([NH2:15])([CH3:1])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: CC(C)(Cc1ccc2ccccc2c1)[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CC(C)(N)Cc1ccc2ccccc2c1
Reaction time: 12 h

Procedure:
Raney nickel W2 (200 mg) was suspended in ethanol (10 ml), to the suspension was added 2-(2-methyl-2-nitropropyl)naphthalene (134 mg) obtained in Step 5, and hydrogenation was performed at a pressure of 3.5 atom for 12 hr.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[C-:25]#[N:26].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19][C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: COCOc1ccc(OCc2ccccc2)c(CBr)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCOc1ccc(OCc2ccccc2)c(CC#N)c1
Reaction time: 13 h
Yield: 91.2 %

Procedure:
To a mixture of 1-benzyloxy-2-bromomethyl-4-methoxymethoxybenzene (0.30 g) and dimethyl sulfoxide (3 mL) was added an aqueous solution (0.3 mL) of sodium cyanide (0.05 g) at room temperature and the mixture was stirred for 13 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-(2-benzyloxy-5-methoxymethoxyphenyl)acetonitrile as a colorless oil (0.23 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:9][CH:10]=1)[CH:7]=O.[CH3:12][O:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][S:19]([CH2:22][C:23](O)=[O:24])(=[O:21])=[O:20])=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][S:19]([C:22]2[C:23](=[O:24])[O:11][C:5]3[C:6]([CH:7]=2)=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:20])=[O:21])=[CH:26][CH:27]=1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc(CS(=O)(=O)c2cc3ccc(OC)cc3oc2=O)cc1
Yield: 43 %

Procedure:
A solution of 4-methoxysalicylaldehyde (1 mmol) and 2-(4-methoxybenzylsulfonyl)acetic acid (1 mmol) in acetic acid (10 mL) was subjected to the General Procedure 2, Method A to generate a 43% yield of the title compound; m.p. 179-180° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][C:17](OC)=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[CH:12][C:11]=2[CH2:15][CH2:16][CH2:17][OH:18])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCc1cnoc1-c1ccc([N+](=O)[O-])cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2oncc2CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of methyl 3-[5-(4-nitrophenyl)-4-isoxazolyl]propionate (1.60 g) in tetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 20 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-nitrophenyl)-4-isoxazolyl]propan-1-ol (1.36 g, yield 95%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 132–133° C.