Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[C:9]([C:11]2[NH:12][C:13](=[O:24])[C:14]3[C:15](=[C:17]([CH2:21][CH2:22][CH3:23])[N:18]([CH3:20])[N:19]=3)[N:16]=2)[CH:10]=1)=[NH:4].[C:30](O)(=[O:32])[CH3:31].Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[C:30]([O:1][N:2]=[C:3]([NH2:4])[C:5]1[CH:10]=[C:9]([C:11]2[NH:12][C:13](=[O:24])[C:14]3[C:15](=[C:17]([CH2:21][CH2:22][CH3:23])[N:18]([CH3:20])[N:19]=3)[N:16]=2)[C:8]([O:25][CH2:26][CH:27]([CH3:28])[CH3:29])=[N:7][CH:6]=1)(=[O:32])[CH3:31]
Reactant: CCCc1c2nc(-c3cc(C(=N)NO)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1c2nc(-c3cc(C(N)=NOC(C)=O)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Yield: 82.1 %

Procedure:
N-Hydroxy-6-isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-pyridinecarboximidamide (Example 39) (65 mg, 0.16 mmol), N,N-dimethylaminopyridine (24 mg, 0.20 mmol), acetic acid (9.7 mg, 0.16 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (37.5 mg, 0.20 mmol) were stirred in dioxan (2 mL) for 14 h. The solvent was removed in vacuo and the product purified by flash column chromatography (eluting with 90% dichloromethane:methanol) to give the product (58 mg) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH3:10])[C:7]3[O:11][C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:6]=3[C:5]=2[CH:17]=O)[CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>>[CH:1]1([C:4]2[C:5]([CH2:17][NH:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[C:6]3[CH2:14][O:13][C:12]([CH3:15])([CH3:16])[O:11][C:7]3=[C:8]([CH3:10])[N:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C2CC2)c(C=O)c2c1OC(C)(C)OC2
Reactant: N#Cc1ccc(N)cc1
Product: Cc1nc(C2CC2)c(CNc2ccc(C#N)cc2)c2c1OC(C)(C)OC2
Yield: 51.4 %

Procedure:
The reductive amination of 6-cyclopropyl-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine-5-carbaldehyde (168) (5.11 g, 20.6 mmol) and 4-aminobenzonitrile (2.9 g, 24.7 mmol), as described in Example 21, gave give 4-[(6-cyclopropyl-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridin-5-ylmethyl)-amino]-benzonitrile (169) (3.7 g, 51% yield).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]=[CH:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]4)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]4)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1ccc2cc(C=CCCN3CCN(c4ccccc4)CC3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: O=c1ccc2cc(CCCCN3CCN(c4ccccc4)CC3)ccc2[nH]1
Reaction time: 6 h

Procedure:
1.5 Grams of 6-[4-(4-phenyl-1-piperazinyl)-1-butenyl]-carbostyril and 0.3 g of 10%-palladium were dispersed in 120 ml of ethanol and catalytically reduced for 6 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure and the residue thus obtained was recrystallized from ethanol and 0.8 g of 6-[4-(4-phenyl-1-piperazinyl)butyl]carbostyril was obtained in colorless needle-like crystals. Melting point: 159°-162° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[N:6][C:5]=1[CH3:21])(=[O:3])[CH3:2].Br[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1.CC(C)([O-])C.[K+]>CN(C)C=O>[C:1]([C:4]1[S:8]/[C:7](=[N:9]\[C:10](=[O:20])[C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])/[N:6]([CH2:23][CH:24]2[CH2:27][CH2:26][CH2:25]2)[C:5]=1[CH3:21])(=[O:3])[CH3:2]
Reactant: BrCC1CCC1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1nc(C)c(C(C)=O)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)=O)c(C)n1CC1CCC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A mixture of the product of Example 238A (0.75 g, 2.3 mmol), (bromomethyl)cyclobutane (0.31 mL, 2.8 mmol), and potassium t-butoxide (0.41 g, 3.5 mmol) in 7 mL N,N-dimethylformamide was warmed to 65° C. and stirred for 16 hours. The mixture was cooled to ambient temperature, quenched with 5 mL of saturated aqueous NH4Cl and diluted with 10 mL of ethyl acetate. The layers were separated and the aqueous phase was extracted twice with 7 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 40% hexanes in ethyl acetate) afforded the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.88-2.15 (m, 6H), 2.51 (s, 3H), 2.75 (s, 3H), 2.83-2.96 (m, 1H), 3.89 (s, 3H), 4.46 (d, J=7.5 Hz, 2H), 7.11 (d, J=9.2 Hz, 1H), 7.45 (dd, J=8.8, 2.7 Hz, 1H), 7.99 (d, J=3.1 Hz, 1H); MS (DCI/NH3) m/z 393 (M+H)+. Anal. Calculated for C19H21ClN2O3S: C, 58.08; H, 5.39; N, 7.13. Found: C, 58.06; H, 5.20; N, 7.06.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH2:43]([C:45]1[S:46][CH:47]=[C:48]([CH2:50][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:49]=1)[CH3:44].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:43]([C:45]1[S:46][CH:47]=[C:48](/[CH:50]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:7]=2)[N:49]=1)[CH3:44]
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)s1
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(CC)n4)cc3OC)c(C)o2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
A mixture of ethyl 5-{4-[(4-[{(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy}methyl]-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (1.80 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.99 g), anhydrous potassium carbonate (0.65 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give ethyl 5-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate as colorless crystals (0.60 g, yield 28%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:20][C:21]([O:23]CC)=O)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][NH:34][C:21](=[O:23])[CH2:20][N:11]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[N:10]1)[CH3:27]
Reactant: CCOC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 45.4 %

Procedure:
By a procedure substantially similar to that of Example 14, 8 g (0.023 mol) of ethyl 4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetate of Example 3 and 34.3 mL (0.22 mol) of diethylaminopropylamine were reacted to produce 4.45 g of N-[3-(diethylamino)propyl]-4,5-bis(4-fluorophenyl)-1H-pyrazole-1-acetamide. The solid product after trituration in water collapsed to a non-crystalline, white, waxy solid upon drying.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].C[Si](C)(C)Cl.Cl[C:28]1[C:33]([O:34][C:35](=[O:52])[CH:36]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:37](OC2C=CC=CC=2)=[O:38])=[C:32](Cl)[C:31](Cl)=[C:30](Cl)[C:29]=1Cl.C(=O)(O)[O-].[Na+:61]>C(Cl)Cl>[Na+:61].[O:34]([C:35]([CH:36]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:37]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:38])=[O:52])[C:33]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Reactant: O=C(Oc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Temperature: 35 °C
Reaction time: 1 h

Procedure:
56 ml. (0.4 moles) of triethylamine are added to a suspension of 42 g. (0.2 moles) of 6-APA in 600 ml. of methylene chloride. Subsequently 430 g. (0.4 moles, 50 ml.) of trimethyl chlorosilane are added to the obtained solution at 10° C., and the mixture is stirred for 60 minutes. Thereafter the mixture is heated to 35° C., 104 g. (0.2 moles) of phenylmalonic acid phenylester pentachlorophenyl ester are added, and subsequently 28 ml. (0.2 moles) of triethylamine are introduced dropwise into the mixture. The reaction mixture is stirred at room temperature for 3 hours, thereafter it is neutralized to pH=7 with 200 ml. of 8% aqueous sodium bi-carbonate solution.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:7][CH2:6][CH2:5][N:4]([CH2:8][CH2:9][OH:10])[CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[C:22](=[O:37])[N:23]([C:28]4[CH:33]=[CH:32][C:31](O)=[C:30]([O:35][CH3:36])[CH:29]=4)[CH:24]=[CH:25][C:26]=3[N:27]=2)=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH-].[Na+].C1(O)C=CC=CC=1>C1COCC1.C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][C:21]3[C:22](=[O:37])[N:23]([C:28]4[CH:33]=[CH:32][C:31]([O:10][CH2:9][CH2:8][N:4]5[CH2:5][CH2:6][O:7][C:2]([CH3:11])([CH3:1])[CH2:3]5)=[C:30]([O:35][CH3:36])[CH:29]=4)[CH:24]=[CH:25][C:26]=3[N:27]=2)=[CH:15][CH:14]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: CC1(C)CN(CCO)CCO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCN1CCOC(C)(C)C1
Reaction time: 1.5 h
Yield: 6.2 %

Procedure:
Dissolve 2-(2,2-dimethyl-morpholin-4-yl)-ethanol (88 mg, 0.55 mmol) in 4.5 mL THF (4.5 mL). Add 2-(4-chloro-phenyl)-5-(4-hydroxy-3-methoxy-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (211 mg, 0.55 mmol). This forms a slurry to which is added 217 mg (0.83 mmol) of triphenylphosphine (217 mg, 0.83 mmol) followed by 161 μL (0.83 mmol) of diisopropyl azodicarboxylate (DIAD). The reaction then becomes a solution. Heat the reaction to 80° C. for 16 h. Pour into 1N NaOH (200 mL) and extract with CH2Cl2 (2×150 mL). Purify via silica gel chromatography, using a gradient of 0% to 10% (2N NH3 in MeOH)/CHCl3 as eluent, to obtain a mixture of product and starting phenol. Dissolve the mixture in CH2Cl2 (300 mL) and extract with 5N NaOH (5×100 mL) until all the phenol is removed from the organic layer. Wash the organic layer with brine (100 mL) and concentrate. Dissolve the residue in CH2Cl2 (30 mL) and treat with 4M HCl in dioxane (100 μL). Diethyl ether is added until the solution becomes cloudy. Let sit at room temperature for 1.5 h then filter the resulting precipitate to give 18 mg (6%) of the desired product. MS (ES+) 526.0 (M+1)+, 1H NMR (400 MHz, (CD3OD): δ 8.11 (d, J=8.5 Hz, 2H), 7.66 (d, J=7.3 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.09 (d, J=7.3 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 4.51-4.43 (m, 2H), 4.07-4.00 (m, 2H), 3.93-3.90 (m, 1H), 3.89 (s, 3H), 3.70-3.56 (m, 4H), 3.26-3.19 (m, 1H), 3.07 (d, J=12.2 Hz, 1H), 1.44 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH:12](B(OCCCC)OCCCC)=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)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>[F:11][C:3]1[C:2]([CH:12]=[CH2:13])=[N:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1ccnc(Cl)c1F
Reactant: C=CB(OCCCC)OCCCC
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: CC(=O)N(C)C
Solvent: O
Product: C=Cc1nccc(C(=O)O)c1F
Temperature: 135 °C

Procedure:
A solution of 2-chloro-3-fluoroisonicotinic acid (1.50 g, 8.55 mmol, Matrix), dibutyl vinylboronate (2.82 mL, 12.8 mmol, Aldrich), and potassium carbonate (1.42 g, 10.25 mmol) in N,N-dimethylacetamide (9 mL) and water (3 mL) was degassed by bubbling a stream of nitrogen through the solution for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.59 g, 0.51 mmol) was added and the mixture was similarly degassed for a further 10 minutes. The reaction vessel was sealed and heated in the microwave for 25 minutes at 135° C. The reaction mixture was filtered and purified using preparative HPLC (UV-detection) eluting with a gradient of H2O/MeCN containing 0.1% TFA. This reaction was run again on the same scale and the product of both runs were pooled. Solvent was removed from the eluent containing desired product in vacuo (1.3 g, 46%). 1H NMR (300 MHz, CD3OD): δ 8.45 (d, 1H), 7.69 (dd, 1H), 7.07 (ddd, 1H), 6.44 (dd, 1H), 5.65 (dd, 1H); 19F NMR (282 MHz, CD3OD): δ−129.64 (d, 1F); LCMS (M+H)+: 167.9.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH:35]=[C:36](OS(C(F)(F)F)(=O)=O)[CH2:37]2)=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([O:30][C:31]([N:33]1[CH:38]2[CH2:39][CH2:40][CH:34]1[CH:35]=[C:36]([C:14]1[CH:13]=[CH:12][C:11]([N:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]3)=[CH:16][CH:15]=1)[CH2:37]2)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2C=C(OS(=O)(=O)C(F)(F)F)CC1CC2
Reactant: CC1(C)OB(c2ccc(N3CCN(S(C)(=O)=O)CC3)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: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C2C=C(c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)CC1CC2
Yield: 37.8 %

Procedure:
1-Methanesulfonyl-4-[4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)phenyl]-piperazine (1.8 g, 4.9 mmol) and 3-trifluoromethanesulfonyloxy-8-azabicyclo[3.2.1]-oct-2-ene-8-carboxylic acid tert-butyl ester (3.8 g, 5.9 mmol) are placed in 35 ml of DME and 6.14 ml of a 2N aqueous solution of K2CO3. After degassing with nitrogen, tetrakis(triphenylphosphine)palladium (1.136 g, 0.98 mmol) is added. The reaction medium is refluxed for 6 h. After hydrolysis and addition of ethyl acetate, the reaction medium is filtered on Celite®. The aqueous phase is then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaHCO3 and than with water. After drying over MgSO4 and concentration to dryness, the crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of ethyl acetate in dichloromethane ranging from 0% to 20%. 0.83 g of 3-[4-(4-methanesulfonylpiperazin-1-yl)phenyl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:9]=1[C:10]#[N:11]>CN(C=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: C1CNCCN1
Reactant: N#Cc1cc(F)ccc1F
Solvent: CN(C)C=O
Product: N#Cc1cc(F)ccc1N1CCNCC1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
A mixture of piperazine (Aldrich; 1.28 g), 2,5-difluorobenzonitrile (Lancaster; 0.422 g), and DMF (4mL) is stirred at 80° C. for 1.5 h, after which the mixture is cooled and partitioned between dichloromethane, water, and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate, concentrated, and the residue is crystallized from dichloromethane/ethyl ether/hexane to give 0.282 g of 5-fluoro-2-(piperazin-1-yl)benzonitrile; mp 83-83.5° C.; 1H NMR (CDCl3) δ 3.10, 7.00, 7.21, 7.21, 7.27.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[N:7]1([CH:12]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15]Cl)[CH:11]=[CH:10][N:9]=[CH:8]1>O1CCCC1>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([C:12]2([N:7]3[CH:11]=[CH:10][N:9]=[CH:8]3)[CH2:1][CH2:15][CH2:14][CH2:13]2)=[CH:18][CH:19]=1)#[N:22]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1ccc(C(CCCCl)n2ccnc2)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(n3ccnc3)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of potassium tert-butoxide (1.10 g) in tetrahydrofuran (50 mL) is added dropwise to a solution of 4-[1-(1-imidazolyl)-4-chlorobutyl]benzonitrile (2.50 g) in tetrahydrofuran at 0° (ice-bath). The reaction is allowed to proceed at 0° for 30 minutes and is then allowed to warm to room temperature during 3 hours. The reaction is then quenched with water (100 mL) and the mixture is subsequently extracted with ethyl acetate (100 mL). The organic extract is extracted with 3N hydrochloric acid (3×30 mL) and the combined acid extracts are made basic with 6N sodium hydroxide. The crude product is extracted into ethyl acetate (3×30 mL) and the combined extracts are dried (MgSO4) and evaporated to afford 1-(4-cyanophenyl)-1-(1-imidazolyl)cyclopentane as an oil. The compound is dissolved in acetone and treated with ethereal HCl to afford the hydrochloride salt, m.p. 217°-219°.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]#[CH:26])#C.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:28]=1.C#C>C1C=CC=CC=1.CO.ClC1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([C:20]1[CH:19]=[CH:24][C:23]([C:27]#[CH:28])=[CH:22][CH:21]=1)#[CH:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C#Cc1ccccc1C#C
Agent: C#C
Agent: C(C#Cc1ccccc1)#Cc1ccccc1
Solvent: Clc1ccccc1
Solvent: CO
Solvent: c1ccccc1
Product: C#Cc1ccc(C#C)cc1
Reaction time: 1 h

Procedure:
A copolymer prepolymer of diphenylbutadiyne and p-diethynylbenzene was prepared in refluxing benzene solvent. The polymerization vessel was charged with 63 parts of diphenylbutadiyne, 2 parts of diethynylbenzene, 600 parts of benzene, and 2 parts of chlorobenzene. After heating to reflux, 2 parts of a catalyst mixture prepared by mixing 2 parts of nickelacetylacetonate and 4 parts of triphenylphosphine in 20 parts of benzene were added. After 1 hour, an additional 10 parts of diethynylbenzene was added. After 2 hours, 10 parts of diethynylbenzene and 2 parts of catalystsolution were added. After 3 hours, 20 parts of diethynylbenzene and 4 parts of catalyst solution were added. After a total reaction period of 7 hours, gas-liquid chromatographic analysis of the reaction mixture showed that 10% of each of the monomeric components remained. The solution was added to 5 times its volume of methanol, and 77 parts of the copolymer wasprecipitated. It had an acetylene content of 8.4 % and an aromatic to olefin hydrogen ratio of 8:1.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14]C)[CH:8]=2)[N:3]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:14])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cc2cc(O)ccc2nc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a −78° C. mixture of 2-chloro-6-methoxyquinoline-3-carbaldehyde (4.64 g, 20.9 mmol) in dichloromethane (130 mL) was added boron tribromide (4.0 mL, 42 mmol). The mixture was allowed to warm to room temperature and stir for 4 hours. The reaction was neutralized by the careful addition of saturated aqueous sodium bicarbonate. The mixture was then extracted with 2-methyl tetrahydrofuran (3×). The combined organics were filtered, and the filtrate was washed with saturated aqueous sodium bicarbonate (3×) and once with brine. The organics were dried over sodium sulfate, filtered, and concentrated to a yellow solid. The solid was partially dissolved in 2-methyl tetrahydrofuran and filtered. The filtrate was concentrated to a solid and again partially dissolved in 2-methyl tetrahydrofuran, filtered, and concentrated. Purification by flash column chromatography (10-100% ethyl acetate/heptanes) gave the title compound (2.65 g, 61%) as a pale yellow solid. +ESI (M+H) 208.1; 1H NMR (400 MHz, CDCl3, δ): 10.54 (s, 1 H), 8.59 (s, 1 H), 7.98 (d, J=9.17 Hz, 1 H), 7.47 (dd, J=9.17, 2.73 Hz, 1 H), 7.25 (d, J=2.93 Hz, 1 H), 5.57 (br. s., 1 H).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([C:18]([OH:20])=[O:19])=[CH:6][CH:7]=2.[OH:21]O>S(=O)(=O)(O)O>[O:21]=[C:2]1[O:1][C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([C:18]([OH:20])=[O:19])=[CH:4][C:3]1=2
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1cc(C(=O)O)ccc1-2
Reactant: OO
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc2c(c1)oc(=O)c1cc(C(=O)O)ccc12
Temperature: 0 °C

Procedure:
A suspension of 12.0 g (0.045 mole) of 9-oxo-fluorene-2,7-dicarboxylic acid in 100 ml of concentrated sulfuric acid is slowly reacted with 12.0 ml of a 30% hydrogen peroxide solution. The reaction is strongly exothermic and is controlled by cooling the stirred reaction mixture in a water bath. The cooled reaction mixture is poured onto 500 ml of an ice water mixture, filtered and washed with water. The residue is resuspended in water, stirred, filtered and washed with a total of about 350 ml of deionized water, to yield 11.2 g of 6-oxo-6H-dibenzo[b,d]pyran-3,8-dicarboxylic acid having a m.p. greater than 300°C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[C:12]([N+:25]([O-:27])=[O:26])=[CH:13][C:14]([OH:24])=[C:15]([C:17]([CH3:23])([CH3:22])[C:18](OC)=[O:19])[CH:16]=1)([CH3:10])([CH3:9])[CH3:8].Cl>C1COCC1.CO>[C:7]([C:11]1[C:12]([N+:25]([O-:27])=[O:26])=[CH:13][C:14]([OH:24])=[C:15]([C:17]([CH3:23])([CH3:22])[CH2:18][OH:19])[CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: COC(=O)C(C)(C)c1cc(C(C)(C)C)c([N+](=O)[O-])cc1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1cc(C(C)(C)CO)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1M solution of lithium aluminum hydride in THF (11.80 mL, 11.80 mmol) was added to a solution of methyl 2-(5-tert-butyl-2-hydroxy-4-nitrophenyl)-2-methylpropanoate (5.36 g, 18.15 mmol) in THF (50 mL). The mixture was stirred at ambient temperature for 3 h, and then diluted with methanol. The mixture was acidified with 1N HCl (pH 1-2) and the aqueous phase was extracted with MTBE. The organic phase was dried in vacuo to afford 4-tert-butyl-2-(1-hydroxy-2-methylpropan-2-yl)-5-nitrophenol which was used without further purification in the next step. 1H-NMR (400 MHZ, DMSO-d6) δ 10.12 (s, 1H); 7.37 (s, 1H); 6.80 (s, 1H); 4.77 (s, 1H); 3.69-3.65 (m, 2H); 1.30 (s, 9H); 1.29 (s, 6H)