Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[N:18]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>Cl.O1CCCC1.O>[Br:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:1][N:18]=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(F)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(-c2n[nH]c3ccc(Br)cc23)cc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
To a solution of 2-amino-5-bromo-4′-fluorobenzophenone (13.50 g, 45.9 mmol) in 6 N hydrochloride solution (400 mL) and tetrahydrofuran (500 mL) at −15° C. was slowly dropped a solution of sodium nitrite (4.12 g, 59.7 mmol) in water (20 mL). After stirring for 30 minutes in cold bath, to the reaction mixture was added a solution of tin(II) chloride dihydrate (28.48 g, 126 mmol) in concentrated hydrochloric acid (70 mL) dropwise. A white solid precipitated immediately. After 30 minutes, the white solid was filtered, dissolved in ethyl acetate, and washed with saturated sodium bicarbonate. The filtrate was neutralized with sodium hydroxide and extracted with dichloromethane. The ethyl acetate and dichloromethane layers were combined, dried over magnesium sulfate, and concentrated. Crystallization from ethyl acetate gave the title compound as a white solid (5.266 g). The mother liquor was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide another batch of the title compound (3.429 g, total 8.695 g, 65% yield). 1H NMR (CDCl3) δ 10.54 (br s, 1H), 8.11 (m, 1H), 7.87–7.92 (m, 2H), 7.50 (m, 1H), 7.34 (d, 1H), 7.20–7.26 (m, 2H); ES-MS (m/z) 293 [M+3]+, 291 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3]1.Br[CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:5][CH2:6][N:7]([CH2:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)[CH2:8][CH2:9]2)[CH2:3]1
Reactant: CN1CC2(CCNCC2)c2ccccc21
Reactant: O=C(O)c1ccc(CBr)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC2(CCN(Cc3ccc(C(=O)O)cc3)CC2)c2ccccc21
Yield: 142.5 %

Procedure:
A mixed solution of 1-methylspiro[indolin-3,4′-piperidine] (1.0 g) synthesized according to a method described in [WO 2011/046851 pamphlet, (preparation 15)], 4-(bromomethyl) benzoic acid (1.08 g), and N,N-diisopropylethylamine (2.61 mL) in ethanol (20 mL) was heated and refluxed for 2 hours. To the resultant reaction mixture, N,N-diisopropylethylamine (1.04 mL) was further added, and the resultant reaction mixture was heated and refluxed for 2 hours. The reaction solution was left to reach room temperature, and from the reaction solution, the solvent was distilled off under reduced pressure to obtain a mixture (2.37 g) containing the subject compound. The resultant mixture was used in the next reaction without further purification.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=CC=CC=1[N+:51]([O-:53])=[O:52].C(N(CC)CC)C>[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.CN(C=O)C>[N+:51]([C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)([O-:53])=[O:52]
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3ccccc3[N+](=O)[O-])cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.64 mmol) (from Example 82) was coupled with 1-bromo-2-nitrobenzene (150 mg, 0.74 mmol) (Aldrich) using CuI (13 mg, 0.068 mmol) (Aldrich) and (Ph3P)2PdCl2 (22 mg, 0.031 mmol) (Aldrich) as catalyst in 2 mL DMF and 4 mL triethylamine at 70° C. for 15 hours to give (Z)-1,3-dihydro-5-(2-nitrophenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 115 mg, 51%).
Reaction SMILES: [CH2:1]([C@@:4]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22](N)=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].N([O-])=[O:34].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[CH2:1]([C@@:4]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22](=[O:34])[NH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=N[O-]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(N)nc3)cc2)C(=O)O1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)[nH]c3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.5 g, 3.47 mmol.) in 3.5 M H2SO4 (25 mL) was added 2 M NaNO2 (15 mL) at 0° C. The reaction mixture was stirred at rt overnight. The reaction was treated with aqueous NaOH solution (8%), and the mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give crude product, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (891 mg, 59%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.15-2.38 (m, 3H), 2.51-2.60 (m, 2H), 2.94 (m, 1H), 4.99-5.11 (m, 2H), 5.65-5.74 (m, 2H), 6.67 (m, 1H), 6.89 (d, 2H), 7.00 (t, 2H), 7.13-7.20 (m, 2H), 7.20-7.27 (d, 2H), 7.33 (m, 1H), 7.46 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([C:11]2[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>N1C=CC=CC=1>[Cl:28][C:29]1[CH:30]=[C:31]([S:36]([NH:1][C:2]2[C:3]([C:9]([C:11]3[C:12]([CH3:18])=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])=[O:10])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=2)(=[O:37])=[O:38])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccnc(C)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
To a solution of (3-Amino-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone (43 mg, 0.16 mmol) and 10 mg of dimethylaminopyridine in 1.0 ml of pyridine was added 3,4-dichlorobenzenesulfonylchloride (70 mg, 0.28 mmol). The mixture was stirred at 80° C. for 3 hours, cooled to room temperature and concentrated. The residue was directly purified by flash column (50% ethyl acetate in hexane) or preparative HPLC (20-80% acetonitrile in water) to afford 18 mg of title compound as an off-white solid. MS: (M+H)/z=470.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46]Cl.[Na+].[Cl-]>C(Cl)Cl>[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(OCOCC[Si](C)(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of thioglycoside 78 (1.40 g, 3.10 mmol) in 15 mL of methylene chloride is added N,N-diisopropylethylamine (0.64 mL, 3.70 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.60 mL, 3.40 mmol). The mixture is stirred at room temperature for 2 h, poured into saturated NaCl (50 mL) and extracted with CH2Cl2 (2×50 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (40% EtOAc/hexane) to give 1.60 g (89%) of 1-deoxy-1-{4-[2(trimethylsilyl)ethoxymethoxy]phenylthio}-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 79 as a colorless oil: Rf 0.4 (33% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.46 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 5.40 (d, J=3.3 Hz, 1H, H-4), 5.22 (s, 2H, SEM), 5.20 (dd, J=9.9, 9.9 Hz, 1H, H-2), 5.02 (dd, J=3.3, 9.9 Hz, 1H, H-3), 4.58 (d, J=9.9 Hz, 1H, H-1), 4.18 (dd, J=6.6, 11.2 Hz, 1H), 4.10 (dd, J=6.6, 11.2 Hz, 1H), 3.89 (dd, J=6.6, 6.6 Hz, 1H, H-5), 3.75 (t, J=8.4 Hz, 2H, SEM), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.04 (s, 3H, OAc), 1.98 (s, 3H, OAc), 0.94 (t, J=8.4 Hz, 2H, CH2 --TMS), 0.01 (s, 9H, SiMe3).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13](I)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:30]2[CH:42]=[CH:41][C:33]([O:34][C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:30]4[CH:42]=[CH:41][C:33]([O:34][C:35]5[N:36]=[CH:37][CH:38]=[CH:39][N:40]=5)=[CH:32][CH:31]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(Oc3ncccn3)cc2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
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: O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 75.7 %

Procedure:
A mixture of 1-(1,4-dioxaspiro[4,5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate N) (1.50 g, 0.00374 mol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-pyrimidine (intermediate BA) (1.23 g, 0.00412 mol), tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.00022 mol) and sodium carbonate (0.993 g, 0.00937 mol) in 40 mL 1,2-dimethoxyethane and 20 mL water was heated at 80° C. for eighteen hours, after which time additional 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.15 g, 0.00037 mol) was added. The mixture was stirred for an additional hour and then allowed to cool to ambient temperature. The precipitate was filtered and washed with 1,2-dimethoxyethane and dried in vacuo, to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (1.26 g, 0.00283 mol): 1H NMR (DMSO-d6, 400 MHz) 8.68 (d, 2H), 8.254 (s, 1H), 7.73 (d, 2H), 7.37 (d, 2H), 7.31 (t, 1H), 6.30-7.20 (bs, 2H), 4.78-4.84 (m, 1H), 3.91 (s, 4H), 2.22-2.30 (m, 2H), 1.73-1.92 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[CH3:17]N(C=O)C.[H-].[Na+].IC>O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
7 g (24.7 mmol) of 3-bromo-2-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene and 40 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. 890 mg (29.6 mmol) of sodium hydride (80% in oil) are added portionwise and the mixture is stirred until the evolution of gas has ceased. 1.7 ml (27 mmol) of iodomethane are then added and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 7.3 g (99%) of the expected product are collected in the form of an oil which crystallizes slowly. Melting point 77-8° C.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[CH:14]([O:17][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)([CH3:16])[CH3:15]
Reactant: CC(C)O
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: CC(C)Oc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
To a solution of sodium (290 mg, 12.5 mmol) in isopropanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 25° C. for 18 h and evaporated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried and evaporated to yield 540 mg (98%) of the title compound.
Reaction SMILES: [CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](Cl)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1>N1C=CC=CC=1>[CH2:1]([N:6]([C:10]1[CH:19]=[CH:18][C:17]2[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=2[CH:11]=1)[C:7](=[O:8])[NH:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][N:26]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C(=O)Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(N)nc1
Solvent: c1ccncc1
Product: CCCCCN(C(=O)Nc1ccc(C(=O)OC)cn1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 72 h
Yield: 11.2 %

Procedure:
A solution of pentyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-carbamoyl chloride (53) (0.24 g, 0.73 mmole) in 3 mL pyridine was treated with 0.22 g of methyl 6-aminonicotinate (Bionet) and stirred at 40° C. for three days. Volatile materials were removed in vacuo and the residue was subjected to flash chromatography (SiO2, 10%-50% ethyl acetate/hexanes) to yield 37 mg of methyl 6-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-nicotinate (55).
Reaction SMILES: [C:1]1([PH:7](=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:12]CN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.C1COCC1>[C:1]1([PH:7](=[O:8])[O:9][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=[PH](O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: CO[PH](=O)c1ccccc1
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a solution of phenylphosphinic acid (5.00 g, 35.2 mmol), anhydrous methanol (7.0 mL, 170 mmol) and 4-dimethylaminopyridine (425 mg, 3.48 mmol) in 50 mL of THF (distilled from ketyl) was added EDAC (8.05 g, 42 mmol) at room temperature. The reaction was stirred for 24 hours then partitioned between HCl solution (75 mL of 1M aq) and ethyl acetate (75 mL). The organic layer was separated, washed with HCl solution (75 mL of 1M aq), sodium bicarbonate solution (75 mL of 5% aq) then dried (sodium sulfate) and concentrated in vacuo to afford the crude title compound as a colorless liquid (1.24 g, 7.95 mmol, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([OH:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)Cl>C(Cl)(Cl)Cl>[C:14]([S:21][CH2:11][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OC(=S)c1ccccc1
Reactant: C=C(Cc1ccc(Cl)cc1)C(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(SCC(Cc1ccc(Cl)cc1)C(=O)O)c1ccccc1

Procedure:
A solution of 2-(p-chlorobenzyl)acrylic acid (3.93 gm., 22 mmoles) and thiobenzoic acid (2.6 ml., 20 mmoles) in 40 ml. of methylene chloride was heated at reflux for 16 hours. The reaction mixture was evaporated to dryness and product crystallized from hexane (4.5 g.). Additional product was obtained by evaporation of the hexane mother liquor and chromatography of the residue (7.1 g.) on 200 g. of silica gel (230-400 mesh) with chloroform as eluant; 1.8 g., m.p. 111°-114° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](O)=[O:18])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])=[O:24])[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([C:17](=[O:18])[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])[CH:26]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=C(O)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CCOC(=O)c1cccc(NC(=O)C2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)c1
Yield: 94.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxy-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.92 mmol) and m-ethoxycarbonylaniline (200 mg, 1.2 mmol) to give 410 mg of the title compound (94%): mp 262°~265° C.; 1H NMR (270 MHz, DMSO-d6) δ12.2 (br, 1H), 10.60 (s, 1H), 8.23 (bs, 1H), 7.81 (d, 1H, J=8.0 Hz), 7.67 (d, 1H, J=8.0 Hz), 7.47 (t, 2H, J=8.0 Hz), 7.22 (bs, 1H), 7.19 (bs, 1H), 5.29~5.34 (m, 1H), 4.30 (q, 2H, J=7.1 Hz), 2.85 (dm, 1H, J=16.8 Hz), 2.50~2.82 (m, 2H), 2.03~2.20 (m, 1H), 1.30 (t, 3H, J=7.1 Hz).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.[C:26]1([C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([CH:42]=[O:43])=[CH:37][CH:38]=3)[N:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CC(C)=O>[Cl:19][C:20]1[C:25]([CH:42]([C:36]2[CH:35]=[C:34]3[C:39]([CH:40]=[CH:41][C:32]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[N:33]3)=[CH:38][CH:37]=2)[OH:43])=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Reactant: Clc1cnccn1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (0.820 mL, 0.686 g, 4.86 mmol) in dry THF (15 mL), cooled by CO2(s)/acetone, is added nBuLi (2.5M in hexanes; 1.95 mL, 4.88 mmol). The cooling bath is replaced with an ice/water bath for 15 min, and then the solution is re-cooled to −78° C. After 5 min, a solution of 2-chloropyrazine (0.370 mL, 0.475 g, 4.14 mmol) in THF (0.5 mL) is added. 25 min later, a solution of 2-phenylquinoline-7-carbaldehyde (890 mg, 3.82 mmol) in dry THF (7 mL) is added slowly over 5 min from a syringe which is then rinsed with THF (1 mL), and the mixture is stirred at −78° C. for 2 h and then warmed up to 0° C. for 0.5 h. The reaction is quenched by adding citric acid (0.25M aqueous solution). The mixture is extracted with EtOAc (4×30 mL), and the combined EtOAc extracts are washed with water, sodium bicarb solution, and brine and dried over MgSO4. The crude material is chromatographed on silica gel [Jones Flashmaster, 50 g/150 mL cartridge, eluting with CH2Cl2 (4×50 mL, then 1-16)→2% EtOAc in CH2Cl2 (17-30)→5% (31-59)→7% (60-85)→10% (86-110)] to obtain the title compound as an off-white foam. 1H NMR (CDCl3, 400 MHz) δ 4.80 (d, J=7.6 Hz, 1H), 6.25 (d, J=7.6 Hz, 1H), 7.43-7.56 (m, 3H), 7.58 (dd, J=1.8, 8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 8.06 (brs, 1H), 8.10-8.15 (m, 2H), 8.20 (d, J=8.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H). MS (ES+): m/z 348.0/350.0 (100/37) [MH+]. HPLC: tR=3.3 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1F)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[CH3:34][O:35]C1C=C(C=C(OC)C=1OC)C=O>>[CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6](=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:35][CH3:34])[CH:21]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)c(OC)c1

Procedure:
The same procedure was carried out as in Examples (1a) to (1d), except that 3,4,5-trimethoxybenzaldehyde was used instead of 2-fluoro-4,5-dimethoxybenzaldehyde in Example (1a), to give the title compound.
Reaction SMILES: Br.Br[CH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[NH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([SH:20])[N:14]=1.C(N(CC)CC)C>CCO>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[CH2:3][S:20][C:15]1[N:14]=[C:13]([NH2:12])[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: Cc1cc(N)nc(S)n1
Reactant: Clc1cncc(Cl)c1CBr
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)nc(SCc2c(Cl)cncc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A mixture of 4-(bromomethyl)-3,5-dichloropyridine hydrobromide (2.9 g, 10.5 mmol), 4-amino-6-methylpyrimidine-2-thiol (1.0 g, 7.1 mmol), and triethylamine (3 mL, 21.5 mmol) in absolute EtOH (80 mL) was stirred at room temperature overnight. The mixture was evaporated, co-evaporated with EtOAc (20 mL), and dried in vacuo. The solid residue was treated with water (150 mL). The solid product was recovered by filtration, washed with water (2×25 mL), diethyl ether (2×25 mL), and hexanes (2×25 mL), and dried in vacuo, affording the title compound (1.9 g, 92% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 3H), 4.78 (s, 2H), 6.29 (s, 1H), 8.45 (s (br), 2H), 8.69 (s, 2H); M+ 302.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3=[N:14][C:15]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:17]=[C:12]3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[C:22](OCC)(OCC)(OCC)[CH3:23].N12CCCN=C1CCCCC2>C(O)CCC>[CH3:22][C:23]1[O:19][C:18]([C:15]2[N:14]=[C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][O:11][C:12]3=[CH:17][CH:16]=2)=[N:20][N:21]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CSc1ccc(-c2coc3ccc(C(=O)NN)nc23)cc1
Solvent: CCCCO
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1ccc(-c2coc3ccc(-c4nnc(C)o4)nc23)cc1
Yield: 68.2 %

Procedure:
A solution of 3-[4-(methylthio)phenyl]furo[3,2-b]pyridine-5-carbohydrazide (0.20 g, 0.68 mmol) and triethyl orthoacetate (0.27 mL, 1.49 mmol) in n-butanol (5 mL) was heated under reflux for 1.5 hr. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.10 mL, 0.68 mmol) was added to the reaction mixture, and the mixture was further heated under reflux overnight. After cooling, the precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (0.15 g, yield 67%) as colorless crystals.