Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.[CH:18]1([NH:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][CH2:33]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH:18]1([NH:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][N:31]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:32][CH2:33][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([NH2:17])=[O:16])[CH:9]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NC(=O)Nc1cccc(O)c1
Reactant: O=C(CCCCN(CCCl)Cc1ccccc1)NC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)Nc1cccc(OCCN(CCCCC(=O)NC2CCCCCC2)Cc2ccccc2)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (0.92 g, 6.6 mmole) is added to a solution of 3-hydroxyphenylurea (1 g, 6.6 mmole) in dimethylformamide (20 ml) and said mixture is stirred for 10 minutes at 20° C. A solution of N-cycloheptyl-5-[benzyl-(2-chloroethyl)amino]pentanamide (2.21 g, 6 mmole) in dimethylformamide (20 ml) is then added dropwise, the mixture being kept under agitation for 4 hours at 80° C. The solvent is evaporated under reduced pressure, then the residue is taken up in dichloromethane (50 ml) and washed with water. The organic phase is collected and dried then, after evaporation of the solvent, the desired compound is obtained in the form of an oil. It is purified by flash chromatography over silica gel in a mixture of dichloromethane/methanol (95/5) to give 1.75 g (60%) of pure compound. NMR-1H (CDCl3),;1.30-1.90 (m, 16H), 2.12 (t, 2H, J=6 Hz), 2.53 (t, 2H, J=6 Hz), 2.80 (t, 2H, J=6 Hz), 3.63 (s, 2H), 3.95 (m, 1H), 4.07 (t, 2H, J=6 Hz), 4.93 (s, 1H), 5.55 (m, 1H), 6.68 (m, 2H), 7.19 -7.30 (m, 9H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]([O:25][C:26]([C:28]1[N:33]2[C:34](=[O:37])[CH:35]([NH2:36])[C@H:32]2[S:31][CH2:30][C:29]=1[OH:38])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:39]([CH2:41][CH2:42][C:43](Cl)=[S:44])#[N:40].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:33]2[C:34](=[O:37])[CH:35]([NH:36][C:43](=[S:44])[CH2:42][CH2:41][C:39]#[N:40])[C@H:32]2[S:31][CH2:30][C:29]=1[OH:38])=[O:27])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reactant: N#CCCC(=S)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reaction time: 3.5 h

Procedure:
7-Amino-3-cephem-3ol-4-carboxylic acid benzhydryl ester p-toluenesulfonate salt [Helv. Chim. Acta 57, 1919 (1974)], (242 mg.) is dissolved in methylene chloride (5 ml.), cooled in an ice bath, and cyanomethylthioacetyl chloride (68 mg.) in methylene chloride (3 ml.) is added, followed by 125 μl of triethylamine. The mixture is stirred for 3.5 hours at 0°-5° and then is allowed to stand overnight in the refrigerator. After diluting with methylene chloride, the reaction mixture is washed with water, then with pH 4 buffer, and dried (Na2SO4). Solvent is removed in vacuo yielding the desired product as a oil (204 mg.); NMR (CDCl3, δ) 3.33 (m,CH2), 3.45 (s, NCCH2SCH2 --) 5.05 (d, J=4.5 Hz, H6), 5.65 (q. J=4.5, 9Hz, H7), 6.93 (s,CHφ2), 7.33 (s, aromatic H's), 7.80 (d, J=9Hz, NH); νmax (CH2Cl2) 3380, 3310, 2225, 1785, 1735, 1690 cm-1.
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:20][N:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
2-Methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}amino)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (370 mg) obtained in Example 162-2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (297 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCOc1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCOc2ccc(F)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
3-(4-Fluorophenoxy)propanol (7.55 g, 44 mmol) was stirred in 50 mL of pyridine under a nitrogen atmosphere at 5° C. p-Toluenesulfonyl chloride (9.2 g, 50 mmol) was added in one portion and the resulting solution was allowed to stir at 5° C. for 1 hour and then was placed in a refrigerator set at 5° C. overnight. The reaction was then poured into about 300 mL of ice water. This mixture was extracted three times with diethyl ether. The combined extracts were washed 2 times with cold 1N hydrochloric acid and once with cold water. The extracts were then dried over sodium sulfate/potassium carbonate, filtered, and concentrated to give 13.24 g of a solid product. Yield: 93%.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=2)[N:7]=1)(=N)N.BrC[C:33]#[N:34].[OH-].[Na+]>CN(C=O)C.O>[C:33]([CH2:1][S:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:9]=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[N:27]([CH3:28])[CH3:29])=[CH:21][CH:20]=2)[N:7]=1)#[N:34]
Reactant: N#CCBr
Reactant: C[C@H]1COCCN1c1cc(CSC(=N)N)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1cc(CSCC#N)nc(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
3-[4-[4-(Carbamimidoylsulfanylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-1,1-dimethyl-urea (0.38 mmol) was dissolved in DMF (2 mL). This was treated with bromoacetonitrile (0.030 mL) and then the sodium hydroxide (61 mg) in water (1 mL) and stirred at RT for 15 minutes. The reaction mixture was concentrated in vacuo and the residue loaded onto a SCX-2 column, washed with methanol and the desired material removed with 7N ammonia in methanol. The desired material was isolated and used without further chromatography.
Reaction SMILES: [CH3:1]C1C=C2NC(=O)C3C=NC=CC=3N2N=1.[Cl:16][C:17]1[N:31]=[CH:30][C:20]2[C:21](=[O:29])[NH:22][C:23]3[N:24]([N:25]=[C:26]([CH3:28])[CH:27]=3)[C:19]=2[CH:18]=1>>[CH3:28][C:26]1[CH:27]=[C:23]2[N:22]([CH3:1])[C:21](=[O:29])[C:20]3[CH:30]=[N:31][C:17]([Cl:16])=[CH:18][C:19]=3[N:24]2[N:25]=1
Reactant: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1
Reactant: Cc1cc2[nH]c(=O)c3cnccc3n2n1
Product: Cc1cc2n(C)c(=O)c3cnc(Cl)cc3n2n1
Yield: 73 %

Procedure:
When in Example 3 the 2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one is replaced by the 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one pf Example 1b, 2,4-dimethyl-8-chloropyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one is obtained, yield: 73%; m.p. 253.8° (DMF).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:22][CH2:23][OH:24]
Reactant: OCCNCCO
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: COC(=O)c1cc([N+](=O)[O-])c(N(CCO)CCO)c([N+](=O)[O-])c1
Yield: 81.1 %

Procedure:
A solution of methyl 4-chloro-3,5-dinitrobenzoate (XIV) (10.0 g, 0.036 mol) and diethanolamine (7.66 g, 0.073 mol) in ρ-dioxane (60 mL) was stirred at 50° C. for 5h. Volatiles were removed under reduced pressure, and the residue was adsorbed directly onto silica gel and chromatographed. Elution with EtOAc/petroleum ether (1:10) gave foreruns, and subsequent elution with EtOAc/petroleum ether (3:2) gave methyl 4-[N,N-bis(2-hydroxyethyl)amino]-3,5-dinitrobenzoate (XV: X=OH, Z=OMe) (9.61 g, 80%), mp (CHCl3 /petroleum ether) 101°-103° C. 1H NMR (CDCl3) δ8.52 (s, 2H, ArH-2,6), 3.97 (s, 3 H, COOCH3), 3.76 (dxt, J=6.5, 4.7 Hz, 4H, CH2OH), 3.26 (t, J=4.7 Hz, 4H, NCH2), 2.76 (t, J=6.5 Hz, 2 H, OH). 13C NMR δ163.14 (COOCH3), 145.50 (C-4), 142.54 (C-3,5), 131.19 (C-2,6), 123.59 (C-1), 59.16 (CH2OH)1, 54.58 (CH2N), 53.14 (OCH3). Anal. (Cl12H15N3O8) C,H,N.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23]>>[OH:25][C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[C:12](=[O:14])[C:13]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[N:7][C:8]=2[N:9]([CH3:16])[C:10]1=[O:15]
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(O)CCCCCl
Product: CCCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
The title compound was prepared by using 7-butyl-3-methylxanthine and 1-chloro-5-hydroxy-5-methylhexane as starting materials.
Reaction SMILES: Cl.[CH2:2]([NH:4][N:5]=[CH:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19][C:18]=3[CH:29]=2)=[O:12])=[CH:9][CH:8]=1)[CH3:3].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[CH2:2]([NH:4][N:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[O:22][CH:21]([CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:19][C:18]=3[CH:29]=2)=[O:12])=[CH:30][CH:31]=1)[CH3:3]
Reactant: CCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)OCC)O3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCNN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.8 g (1.8 mmol) of the ester from Example 71 were suspended in a mixture of 16 ml ethanol, 2 ml 2 N aqueous sodium hydroxide, and some drops of water. It was stirred overnight at room temperature, while the suspension became a solution, which was brought to pH 5 with 2 N acetic acid. The precipitate of the pure title compound was collected by filtration, washed successively with water and acetone, and dried in vacuo. Yield: 0.65 g (95%) of a yellow powder, m.p. 260-262° C.(dec.).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:13]=[C:14]([CH2:15][C:16](O)=[O:17])[C:3]1=2.O1CCCC1.C(N1C=CN=C1)([N:32]1C=CN=C1)=O.N>O.CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]2[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:13]=[C:14]([CH2:15][C:16]([NH2:32])=[O:17])[C:3]1=2
Reactant: O=C(O)Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)Cc1nn(-c2ccccn2)c2[nH]c3ccccc3c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a solution of 2-[4-oxo-1-(2-pyridinyl)-4,9-dihydro-1H-pyrazolo[3,4-b]quinolin-3-yl]acetic acid (1.60 g, 5.0 mmol) in a mixed solvent of tetrahydrofuran (100 mL) and N,N-dimethylformamide (20 mL), 1,1′-carbonyldiimidazole (0.89 g, 5.5 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Subsequently, 25% aqueous ammonia solution was added to the mixture and the resulting solution was stirred at room temperature for 1 hour. The solution was poured into water, and the resulting precipitate was collected by filtration. The collected crude crystals were washed with water, and dried to give the title compound (0.94 g, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:7]=1.C[O-].[Na+].[NH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C1(C)C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]([OH:17])=[C:6]([C:8](=[N:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)cc(C(=NCCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
(5-Chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methanone (98.4 g, 0.35 mol), sodium methoxide (19 g, 0.35 mol) and β-alanine (31.2 g, 0.35 mol) are added to 2 liters of toluene and 0.5 liters of methanol. The mixture is heated gradually and the ternary azeotrope (62° C.) is distilled. After a Dean-Stark apparatus has been fitted, the residue is heated at the reflux temperature of toluene for 6 hours. The mixture is then evaporated to dryness in vacuo. The solid residue is triturated with diethyl ether and filtered off. The solid is dissolved in 1.5 liters of water. The aqueous solution is acidified by the addition of citric acid to pH 4. The solid obtained is filtered off and then dissolved in CHCl3. The chloroform solution is dried (MgSO4) and then evaporated in vacuo. The solid obtained is triturated in petroleum ether, filtered off and dried. This gives the desired acid product, melting at 137.5°-138° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)(=O)C.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=2)[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
EX-528C) The 3-[(3-nitrophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (1.93 g, 4.2 mmol) from EX-528B) was dissolved in 60 mL of acetic acid. Zinc dust (2.1 g, 31.5 mmol) was added, and the solution was stirred at room temperature for 18 hours, at which time HPLC analysis indicated that no nitro starting material remained. The reaction mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous saturated sodium bicarbonate. The organic layer was washed with brine, then dried over MgSO4, and concentrated in vacuo to give 1.4 g (78%) of the desired 3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a red oil. The crude product was used without further purification. HRMS calcd. for C18H18F7N2O2: 427.1256 [M+H]+, found: 427.1251. 1H NMR (CDCl3) δ3.4-3.7 (m, 4H), 3.8 (dd, 1H), 4.3 (m, 1H), 4.8 (m, 2H), 5.9 (tt, 1H), 6.1 (s, 1H), 6.2 (m, 2H), 7.0-7.2 (m, 4H), 7.3 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:9][OH:10])[NH2:8])[N:6]=1.[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17](Cl)=O>>[Cl:11][C:12]1[CH:16]=[CH:15][S:14][C:13]=1[C:17]1[O:10][N:9]=[C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)[N:8]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: Cc1nc(C(N)=NO)cs1
Product: Cc1nc(-c2noc(-c3sccc3Cl)n2)cs1

Procedure:
The title compound was prepared from 2-methyl-thiazole-4-amidoxime (24.6 mg, 0.156 mmol) and 3-chloro-thiophene-2-carbonyl chloride (28.7 mg, 0.159 mmol) similar to Example 16, and yielded 18.2 mg (40%) of white solid. 1H NMR (CDCl3): 8.03 (s, 1H), 7.61 (d, J=5.49 Hz, 1H), 7.13 (d, J=5.22 Hz, 1H), 2.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11].[CH3:19][OH:20].C[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:20][CH3:19])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11]
Reactant: Nc1cc(F)c(F)cc1C(=O)c1ccccc1Cl
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1F

Procedure:
A solution of 2.01 g (0.0075 mole) of (2-amino-4,5-difluorophenyl)-(2-chlorophenyl)-methanone (Xmm), 24 mL of methanol and 2.08 mL of 25% sodium methoxide solution was heated to reflux under an inert atmosphere for 80 minutes. The mixture was then cooled, taken up in ethyl acetate and washed twice with brine. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2.04 g of aminobenzopheneone (2-amino-5-fluoro-4-methoxyphenyl)-(2-chlorophenyl)-methanone (Xa) as a crystalline yellow solid. MH+/Z=280.
Reaction SMILES: [NH2:1][C@H:2](/[C:29](/[CH3:37])=[CH:30]/[C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3][C@@H:4]1[O:28][C@:5]1([CH3:27])[CH2:6][CH2:7][C:8](=[O:26])[C@H:9]([CH3:25])[C@H:10]([OH:24])[C@@H:11]([CH3:23])[C:12](=[O:22])[C:13]([CH3:21])([CH3:20])[C@@H:14]([OH:19])[CH2:15][C:16]([OH:18])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.CN(C)C=O.O>[O:28]1[C@@H:4]2[C@@:5]1([CH3:27])[CH:6]=[CH:7][C:8](=[O:26])[C@H:9]([CH3:25])[C@H:10]([OH:24])[C@@H:11]([CH3:23])[C:12](=[O:22])[C:13]([CH3:21])([CH3:20])[C@@H:14]([OH:19])[CH2:15][C:16](=[O:18])[NH:1][C@H:2]([C:29]([CH3:37])=[CH:30][C:31]1[N:32]=[C:33]([CH3:36])[S:34][CH:35]=1)[CH2:3]2
Reactant: C/C(=C\c1csc(C)n1)[C@@H](N)C[C@@H]1O[C@]1(C)CCC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CC(=Cc1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)C=CC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of (3S,6R,7S,8R,12R,13S,15S,16E)-15-amino-3,7-dihydroxy-5,9-dioxo-12,13-epoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-16-heptadecenoic acid (540 mg) in acetonitrile/dimethylformamide (20:1 v/v, 150 mL) is cooled to 0° C. and treated sequentially with 1-hydroxybenzotriazole (0.135 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.5 g). The mixture is warmed to ambient temperature and kept for 12 hours, then diluted with water and extracted with ethyl acetate. The extract is washed sequentially with water, sat. NaHCO3, and brine, then dried over Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][NH:14][CH2:15][C:16]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]3[C:17]=2[CH2:18][CH:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]3)=[CH:11][CH:10]=1)C1C=CC=CC=1.COC1C=C2C(CC(C3C=CC(OC)=CC=3)C2)=C(CN)C=1.Cl.[N:59]1([CH2:66]COC2C=CC(C(O)=O)=CC=2)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>>[N:59]1([CH2:66][CH2:1][O:8][C:9]2[CH:36]=[CH:35][C:12]([CH2:13][NH:14][CH2:15][C:16]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]4[C:17]=3[CH2:18][CH:19]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[CH2:20]4)=[CH:11][CH:10]=2)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc(C2Cc3cc(OC)cc(CNCc4ccc(OCc5ccccc5)cc4)c3C2)cc1
Agent: COc1ccc(C2Cc3cc(OC)cc(CN)c3C2)cc1
Agent: Cl
Product: COc1ccc(C2Cc3cc(OC)cc(CNCc4ccc(OCCN5CCCCCC5)cc4)c3C2)cc1

Procedure:
Synthesized from (4-benzyloxybenzyl)[6-methoxy-2-(4-methoxyphenyl)indan-4-yl]methylamine according to an analogous synthetic method to Example 22, [6-methoxy-2-(4-methoxyphenyl)indan-4-yl]methylamine (553 mg) and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride (795 mg) were used according to an analogous synthetic method to Example 152 to provide [4-(2-azepan-1-ylethoxy)benzyl][6-methoxy-2-(4-methoxyphenyl)indan-4-yl]methyl amine (172 mg). This compound was used according to an analogous synthetic method to Example 111 to provide the title compound (64 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](OCCCCCCCC)=[CH:9][CH:10]=3)[C:5]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]=2[CH:3]=1.[CH2:40]([C:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].[C:58](=[O:61])([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[CH2:32]([C:5]1([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:4]2[CH:3]=[C:2]([C:52]3[CH:53]=[CH:54][C:49]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:50][CH:51]=3)[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([O:61][CH2:58][CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH3:11])=[CH:9][CH:10]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCc1ccc(B(O)O)cc1
Reactant: CCCCCCCCOc1ccc2c(c1)C(CCCCCCCC)(CCCCCCCC)c1cc(Br)ccc1-2
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCc1ccc(-c2ccc3c(c2)C(CCCCCCCC)(CCCCCCCC)c2cc(OCCCCCCCC)ccc2-3)cc1

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.5 g, 4.64×10−4 mol), 2-bromo-9,9-dioctyl-7-octyloxyfluorene (5.04 g, 0.00844 mol), 4-nonylphenylboronic acid (2.30 g, 0.00929 mol), 20% aqueous sodium carbonate solution (40 cm3) and N,N-dimethylformamide (150 cm3) was heated under reflux overnight. The reaction mixture was filtered and extracted into diethyl ether (2×100 cm3). The combined organic layers were washed with water (2×100 cm3), dried (MgSO4), filtered and the solvent removed under partially reduced pressure. The residue was purified by column chromatography [silica gel, dichloromethane: hexane: 30:70] (yield 3.65 g, 60.0%).