Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([OH:17])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[N+:1]([C:4]1[C:9]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([CH3:14])[C:5]=1[C:15]([Cl:19])=[O:17])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(=O)Cl

Procedure:
Ten grams of 3,5-dinitro-4-chloro-o-toluic acid is warmed on a water bath with 9.2 grams of phosphorus pentachloride and 30 ml. of benzene. After the solids dissolve, the benzene is distilled and the phosphorus oxychloride is removed under reduced pressure. The desired product as a residual oil solidifies on chilling.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[CH:24]=1
Reactant: OCc1csc(Cl)c1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chloro-3-thienyl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) followed by preparative HPLC to give the title compound (20 mg) as a white solid.
Reaction SMILES: C(O)=O.Cl[C:5]1[CH:6]=[C:7]([N:12]2[CH2:16][CH:15]([CH3:17])[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]>O>[Cl:11][C:10]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:16][CH:15]([CH3:17])[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)=[CH:8][CH:9]=1
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O
Solvent: O=CO
Product: CC1CN(c2ccc(Cl)cc2)N=C1NC=O
Reaction time: 3 h

Procedure:
A 2.2 g. amount of the preceding compound is dissolved in 10.0 ml. of a mixture of formic acid and acetic anhydride (Example 15). The mixture is allowed to remain at room temperature for 3 hours. Water is added and a yellow solid is collected by filtration. The solid is dissolved in dichloromethane. The solution is dried over anhydrous magnesium sulfate and filtered through a hydrous magnesium silicate. The filtrate is concentrated while adding hexane until turbidity occurs. The mixture is cooled and filtered to give 2.1 g. of the product of the Example as a white solid, m.p. 172°-174° C.
Reaction SMILES: [OH:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)=[N:6][CH:7]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:4]=[N:3][C:2]([OH:1])=[CH:7][N:6]=2)[N:9]=1)=[O:18])([CH3:25])[CH3:24]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2cnc(O)cn2)c2c1C[C@H]1C[C@@H]21
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(O)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method RR using (1aR,5aR)-2-(5-hydroxypyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=330.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.36 (td, J=4.5 and 3.3 Hz, 1H), 1.17-1.23 (m, 1H), 1.30 (s, 3H), 1.31 (s, 3H), 2.23-2.28 (m, 1H), 2.54-2.58 (m, 1H), 2.74 (d, J=16.5 Hz, 1H), 2.85 (dd, J=16.3 and 6.3 Hz, 1H), 3.43 (s, 2H), 7.20 (s, 1H), 8.01 (d, J=1.3 Hz, 1H), 8.38 (bs, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([F:16])=[CH:8][CH:7]=1)=[O:5].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:18][CH:3]([CH:2]([CH3:17])[CH3:1])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([F:16])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)CC(=O)c1ccc(F)c2ccccc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(Br)C(=O)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methyl-1-(4′-fluoronaphth-1-yl)butan-1-one (7 g) in anhydrous tetrahydrofuran (80 ml) was added phenyltrimethylammonium tribromide (11.5 g). The resulting mixture was stirred overnight at ambient temperature then partitioned between petroleum ether and water. The organic layer was separated, washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo to yield crude 2-bromo-1-(4′-fluoronaphth-1-yl)-3-methylbutan-1-one. Sodium acetate (2.75 g) and anhydrous dimethylformamide (30 ml) were added and the resulting mixture was stirred at 80° C. for 5 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was back-extracted once with ethyl acetate. The combined organic layers were washed with water, brine, dried with sodium sulphate, filtered and evaporated in vacuo. The title compound (4.8 g) was obtained following silica gel column chromatography of the residue in 30-100% dichloromethane in petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl-].O[NH3+:13]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:13]
Reactant: [NH3+]O
Reactant: O=Cc1cccc(O)c1Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cccc(O)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-hydroxybenzaldehyde [(2 g, 12.8 mmol) WO 2005007633, p 34] and hydroxyl ammonium chloride (1.33 g, 19.6 mmol) in acetic acid (20 mL) was heated under reflux for 2 hours. The reaction mixture was then cooled to room temperature and partitioned between diethyl ether and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a white solid. The solid was then dissolved in ethyl acetate washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid in quantitative yield. 1H NMR (400 MHz, CD3OD) δ: 7.18 (d, 1H), 7.26 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.[C:17]([NH:24][CH2:25][CH2:26][NH2:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:27][CH2:26][CH2:25][NH:24][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(NCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-chloro-3-nitro-phenyl)-acrylic acid methyl ester (Ia, 0.243 g, 1.00 mmol), N-Boc-ethylenediamine (0.316 mL, 2.0 mmol) and triethylamine (0.50 mL, 3.59 mmoL) in dioxane (7 mL) was heated at 80° C. for about 80 h. The solution was evaporated and the residue was added MeOH. The resulting solid was filtered and washed with MeOH. 3-[4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-phenyl]-acrylic acid methyl ester (IIIa1) was obtained as bright yellow solid (0.193 g, 52.6%). HPLC purity at 254 nm: 96.0˜98.1%; tR=3.27 min. LCMS (ESI) m/z: 366 ([M+H]+), 310 (M+H-56), 266 (M+H-Boc). 1H NMR (CDCl3) δ 8.41 (1H, br t like, NHAr), 8.31 (1H, d, J=1.8 Hz), 7.63 (1H, dd, J=9.0, 1.7 Hz), 7.57 (1H, d, J=16.0 Hz), 6.98 (1H, d, J=8.9 Hz), 6.30 (1H, d, J=15.9 Hz), 3.80 (3H, s), 3.52 (2H, m), 3.45 (2H, m), 1.45 (9H, s); 13C NMR (CDCl3) δ 166.9, 155.7, 145.8, 142.3, 134.1, 131.5, 127.1, 121.8, 115.4, 113.9, 79.5, 51.2, 42.7, 39.1, 27.9.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[F:13][CH2:14][CH2:15][O:16][NH2:17]>CS(C)=O>[F:13][CH2:14][CH2:15][O:16][N:17]=[C:4]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: O=C1Nc2ncccc2C1=O
Reactant: NOCCF
Agent: Cl
Solvent: CS(C)=O
Product: O=C1Nc2ncccc2C1=NOCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of compound 134a (300 mg, 1.03 mmol) in DMSO (25 mL) was heated at 95° C. at 15 torr for 6.5 hours, The solution containing the corresponding 7-aza isatin was cooled to room temperature, followed by the addition O-(2-Fluoro-ethyl)-hydroxylamine hydrochloride (131 mg, 1.13 mmol). After stirring for 1 hour at room temperature the mixture was quenched with water and extracted with ethyl acetate (6×25 mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (gradient, 2% MeOH in methylene chloride to 3%) to give 1H-Pyrrolo[2,3-b]pyridine-2,3-dione 3-[O-(2-fluoro-ethyl)-oxime] (200 mg, 93%) as an orange solid that was further purified by trituration from diethyl ether-methylene chloride (1:1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH2:28][CH2:29][C:30](O)=[O:31])[CH:3]=1.[NH2:33][C:34]1[C:39]([NH2:40])=[CH:38][C:37]([I:41])=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[NH2:33][C:34]1[C:39]([NH:40][C:30](=[O:31])[CH2:29][CH2:28][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:5]=2)=[CH:38][C:37]([I:41])=[CH:36][N:35]=1
Reactant: Cc1cc(CCC(=O)O)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: Nc1cc(I)cnc1N
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCC(=O)Nc2cc(I)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 54.9 %

Procedure:
1.30 g of 3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]-propionic acid acid and 724 mg of 2,3-diamino-5-iodo-pyridine are dissolved in 37 ml of pyridine and sequentially treated with 1.06 g of O-[(ethoxycarbonyl)canomethylene-amino]—N,N,N′,N′-tetramethyl-uronium tetrafluoro-borate and 579 μl of diisopropylethyl amine. The reaction mixture is warmed to 50° C. for 24 h. Thereafter the solvents are evaporated in vacuo. The remaining residue is coevaporated twice with toluene yielding 3.55 g of crude product. Purification by chromatography on LiChroprep® NH2 (25-40 μm, Merck, Darmstadt) (75 g, eluent: toluene/ethyl acetate 1:1) affords 1.08 g of the title compound as an amorphous solid. ESI-MS: 640.0 (MH+). TLC: Rf=0.16 (toluene/ethyl acetate 1:1, LiChroprep® NH2 HPTLC).
Reaction SMILES: C[N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1O>C1COCC1.ClCCl>[CH:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:27]=1[O:9][CH:6]1[CH2:7][CH2:8][NH:2][CH2:3][C:4]2[CH:13]=[C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=[CH:10][C:5]1=2
Reactant: Oc1ccc2ccccc2c1
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1cnnc(-c2ccc3c(c2)CNCCC3Oc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a solution of (−)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol (80 mg, 0.31) from Step H above in THF (5 mL) was added napthalen-2-ol (67 mg, 0.47 mmol), tributylphosophine (95 mg, 0.47 mmol) and 1,1′-(azodicarboyl)dipiperidine (118 mg, 0.47 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (98:2 to 95:5 ethyl acetate/methanol), followed by HPLC to give the (+)-5-(naphthalen-2-yloxy)-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (60 mg, 48%) as a gum-like solid.
Reaction SMILES: [CH2:1]([C:3]1([OH:13])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)[CH3:2].C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>CC(CC(C)C)=O>[C:21]([O:13][C:3]1([CH2:1][CH3:2])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CCC1(O)C2CC3CC(C2)CC1C3
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(CC)C2CC3CC(C2)CC1C3
Temperature: 40 °C
Yield: 80 %

Procedure:
180 g of 2-Ethyl-2-adamantanol, 303 g of triethylamine and 500 g of methylisobutyl ketone were mixed by stirring at 40° C. While stirring, 136 g of acrylic acid chloride was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for three more hours. Then, extraction and distillation were conducted to obtain 2-ethyl-2-adamantyl acrylate at the yield of 80%.
Reaction SMILES: [CH:1]([C:3]1[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCCOc1cccc(OC)c1C=O
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CCCCOc1cccc(O)c1C=O

Procedure:
To a stirred solution of ethyl 5-(2-formyl-3-methoxyphenoxy)pentanoate (Example 4) (4.38 g, 0.0156 M) in dry tetrahydrofuran (45 ml) was added dropwise a solution of magnesium iodide (6.533 g, 0.0235 M) in dry ether (95 ml). The mixture was then stirred under reflux (5 hr). The cooled mixture was poured into 10% hydrochloric acid (65 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with water, dried (sodium sulphate) and evaporated. The oily residue was chromatographed on silica gel eluting with chloroform to give ethyl 5-(2-formyl-3-hydroxyphenoxy)pentanoate, m.p. 32°-33° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17](I)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=3)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1nccc2c1c(I)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(cis-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (100 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (70.6 mg), tetrakis(triphenylphosphine)palladium(0) (23.8 mg) and potassium carbonate (56.8 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (22.7 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=O)[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[OH:32][CH:33]1[CH2:38][CH2:37][N:36]([C:28](=[O:30])[CH2:27][CH:24]2[S:23][C:22]([C:19]3[NH:20][C:21]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[N:12]([CH3:31])[S:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])(=[O:11])=[O:10])=[N:26][CH2:25]2)[CH2:35][CH2:34]1
Reactant: OC1CCNCC1
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)N4CCC(O)CC4)S3)[nH]c12
Temperature: 25 °C
Yield: 74 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (150 mg), 4-hydroxypiperidine (43 mg), 1H-1,2,3-benzotriazol-1-ol (67 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0-90:10), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (131 mg, yield 74%) as colorless prism crystals. MS: 543 (MH+). melting point 166-167° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:28]([CH3:30])[CH3:29].CN(C=O)C>O>[CH:28]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)([CH3:30])[CH3:29]
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(OC(C)C)ccc3c2=O)cc1
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A mixture of Formononetin (1, 1.34 g, 5 mmol) (G. Y. Gao, et. al. Bioorg. Med. Chem. 2003, 11, 4069), K2CO3 (0.69 g, 5 mol), 2-bromopropane (1.23 g, 10 mmol) and DMF (10 mL) was refluxed with stirring for 3 hrs (TLC monitoring). The mixture was then cooled and evaporated in vacuo to give a residue which was treated with H2O (50 mL). The precipitate thus obtained was collected, purified by column chromatography (MeOH/CH2Cl2=1:100), and crystallization from EtOH to give 2 (1.46 g, 94% yield). M.p.: 245-246° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]1([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=[C:19]([CH:20]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:18]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: CC1(C)CC(=O)C=C(N)C1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(-c2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-phenylbenzaldehyde in an analogous manner to that described in Example 1 to give 9-(3-biphenylyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a pale yellow crystalline solid of melting point 227-229° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])(=[O:4])[CH:2]=[CH2:3].C1(C=CC(O)=CC=1)O.[CH2:20]1[S:24](=[O:26])(=[O:25])[O:23][CH2:22][CH2:21]1>C(#N)C>[C:1]([NH:5][CH2:6][CH2:7][CH2:8][N+:9]([CH3:11])([CH3:10])[CH2:22][CH2:21][CH2:20][S:24]([O-:23])(=[O:26])=[O:25])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)NCCCN(C)C
Reactant: O=S1(=O)CCCO1
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: C=CC(=O)NCCC[N+](C)(C)CCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
The solution of 6.2 g 3-acrylamidopropyldimethylamine (M=156.23 g/mol-39.7 mmol) and of 88 mg hydroquinone (M=110.11 mol/l-0.02 eq.) in 17 ml anhydrous acetonitrile is magnetically stirred at ambient temperature in an argon stream. The solution of 3.5 ml distilled propanesultone (M=122.14 g/mol-d=1.392-1 eq.) in 5 ml anhydrous acetonitrile is added drop by drop. A white precipitate appears. The suspension is stirred in an argon stream for 24 hours at ambient temperature. The precipitate is then filtered, washed with anhydrous acetonitrile, then with anhydrous acetone, and dried. 10.3 g 3-[(3-acrylamidopropyl)dimethylammonio]propanesulfonate (M=278.36 g/mol) are thus obtained. Yield: 93%. The purity of the product is controlled by elemental analysis: C: 47.27%; H: 7.88%; N: 10.41%; S: 11.55%, the percentages calculated from the empirical formula (C11H22N2O4S) being as follows: C, 47.46%, H: 7.97%, N: 10.06%; S, 11.52%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26](O)=[O:27].C(N=C=NC(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25][C:26]([O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)=[O:27]
Reactant: OCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)Cc1cc(F)ccc1Br
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cc(F)ccc1Br)OCc1ccc(OCc2ccccc2)cc1

Procedure:
A suspension of 3 g (2.73 mmol) of Wang resin (p-benzyloxybenzyl alcohol resin, 100-200 mesh) in 49 ml of dichloromethane is stirred (orbital stirring) at room temperature for 15 minutes. 2.8 g (12.0 mmol) of (2-bromo-5-fluorophenyl)acetic acid dissolved in 20 ml of dichloromethane are then added, followed by addition of 0.067 g (0.55 mmol) of 4-dimethylaminopyridine and 1.88 ml (12.0 mol) of N,N′-diisopropylcarbodiimide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:16]=[C:17](Cl)[C:18]2[S:23][CH2:22][CH2:21][C:19]=2[N:20]=1>C(O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:17]2[C:18]3[S:23][CH2:22][CH2:21][C:19]=3[N:20]=[C:15]([Cl:14])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3c2SCC3)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.3 %

Procedure:
454 mg piperazine-1-carboxylic acid tert-butyl ester in 5 mL ethanol was added to 0.5 g 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine in 5 mL dichlormethane. The reaction was stirred 2 h at RT, 3 h at 60° C. and over night at RT. The solvents were removed and water was added to the residue. The precipitate was filtered and dried to give 0.83 g of the desired product.