Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)=O.[C:16]([NH:19][C:20]([NH2:22])=[NH:21])(=[O:18])[CH3:17]>C(#N)C>[F:15][C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[NH:22][CH:2]=2)[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)NC(=N)N
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Yield: 25.5 %

Procedure:
To a stirred solution of 2-bromo-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (4.5 g, 15.73 mmol) in acetonitrile (45 ml) was added acetyl guanidine (2.38 g, 23.60 mmol). The reaction mixture was stirred and refluxed for overnight. The solvent was evaporation under reduced pressure and diluted with water and extracted with ethyl acetate (75 ml×3) and organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 2% methanol in chloroform to obtain 1.15 g of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6): δ 2.07 (s, 3H), 7.58 (s, 1H), 7.69-7.78 (m, 3H), 11.31 (br s, 1H), 11.91 (br s, 1H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:10][O:11][CH2:12][CH2:13][NH:14][C:15](=[O:18])[CH2:16]Cl.C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:16][C:15](=[O:18])[NH:14][CH2:13][CH2:12][O:11][CH3:10])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: COCCNC(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCCNC(=O)COC(=O)/C=C/C(=O)OC
Yield: 7.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-(2-methoxyethyl)chloroacetamide (0.69 g, 4.60 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.07 g (8% yield) of the title compound (5) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.94-6.92 (m, 2H), 6.46 (br s, 1H), 4.68 (s, 2H), 3.83 (s, 3H), 3.52-3.46 (m, 4H), 3.36 (s, 3H). MS (ESI): m/z 245.98 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:31][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=3)[CH:14]([OH:15])[CH3:31])[CH2:10]2)=[CH:29][CH:28]=1
Reactant: C[Mg]Cl
Reactant: O=CC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 805 mg (1.81 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}(3,5-difluorophenyl)acetaldehyde in 20 mL of THF was added slowly a solution of 1.33 mL (4.0 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h and 3 g of sodium sulfate decahydrate was added to quench the reaction, followed by stirring for 1 h at rt. The quenched reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-1-(3,5-difluorophenyl)propan-2-ol as a white solid. Mass Spectrum m/e=460 (M+1 35Cl, 35Cl) and 462 (M+1 35Cl, 37Cl).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])[CH2:3]1.[OH-].[Na+].Cl>>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:8]=2)[CH2:5][CH:4]([C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])[CH2:3]1
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)N3CCCCC3)c2)C1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(NC(=O)C1CC(=O)N(c2cccc(NC(=O)N3CCCCC3)c2)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-({5-oxo-1-(3-(piperidylcarbonylamino)phenyl)pyrrolidin-3-yl}carbonylamino)-3-(3-pyridyl)propanoate (169 mg, 0.333 mmol, 1.0 eq) was added a solution of NaOH (0.84 mL, 2.0 M, 1.67 mmol, 5.0 eq). After the reaction mixture was stirred at room temperature overnight, it was neutralized with a solution of aqueous HCl (0.84 mL, 2.0 M, 1.67 mmol). Following removal of solvent under reduced pressure, product was dissolved in 10% MeOH-CH2Cl2, and filtered. Concentration under reduced pressure afforded the title compound as an orange solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.47 (m, 4), 1.56 (m, 2), 2.56-2.77 (m, 2), 2.82 (m, 2), 3.29 (m, 5), 3.73-3.83 (m, 1), 3.91-4.01 (m, 1), 5.25 (m, 1), 7.19 (m, 1), 7.28 (m, 1), 7.55 (m, 1), 7.70 (d, 1 J =12.5), 7.96 (d, 1, J =7.9), 8.50 (d, 1, J=8.7), 8.55 (m, 1), 8.65 (s, 1), 8.82 (d, 1, J=7.8), 12.4 (br s, 1). MS (ES+): 480 (M+H)+; (ES−) 478 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][CH2:6][NH:7][CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[CH2:11][O:10]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:32][CH2:33][C:34](Cl)=[O:35]>O>[CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][CH2:6][N:7]([CH2:8][CH:9]1[O:14][CH:13]([CH3:15])[CH:12]([CH3:16])[CH2:11][O:10]1)[C:34](=[O:35])[CH2:33][Br:32])[CH3:2]
Reactant: CCOC(CCNCC1OCC(C)C(C)O1)OCC
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CCN(CC1OCC(C)C(C)O1)C(=O)CBr)OCC

Procedure:
N-(3,3-Diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and bromoacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(3,3-diethoxypropyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-bromoacetamide as the residue.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[CH:7][C:8]([C:16]([OH:18])=O)=[N:9][C:10]=2[O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[NH2:19][C@@H:20]([CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:21]([NH2:23])=[O:22]>>[C:21]([C@@H:20]([NH:19][C:16]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[N:9]=1)=[O:18])[CH2:24][CH:25]1[CH2:27][CH2:26]1)(=[O:22])[NH2:23]
Reactant: O=C(O)c1ccc(NC2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropylamino-6-cyclopropylmethoxy-pyridine-2-carboxylic acid and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=359.2 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH:13]2[CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]>C1C=CC=CC=1>[C:1]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([O:9][CH3:8])=[CH:18][CH:17]=2)[CH:13]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])[C:14]1=[O:19])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)C(=O)N2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(CCNC(C)=O)C(=O)N2C(C)=O

Procedure:
Acetic anhydride (0.5 ml) is added with stirring to N-[2-(5-methoxy-2-oxo-2,3-dihydroindol-3-yl)ethyl]acetamide (120 mg) dissolved in benzene (5 ml). The mixture is heated for 1 h in refluxing benzene. The solvent is evaporated off and the crude product is separated on a silica plate. N-[2-(1-acetyl-2-oxo-5-methoxyindol-3-yl)ethyl]acetamide (6) is thus obtained.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[Cl:22][C:23]([Cl:28])([Cl:27])[CH:24](O)[OH:25]>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][CH:24]([OH:25])[C:23]([Cl:28])([Cl:27])[Cl:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(O)C(Cl)(Cl)Cl

Procedure:
Add 2.9 g. of dl-13-ethyl-17β-hydroxygon-4-en-3-one to a solution of 1.9 g. of chloral hydrate in 10 ml. of benzene at 5°C. Keep the mixture overnight at this temperature. Filter off the product and recrystallize it successively from ethyl acetate and petroleum ether-benzene to obtain the title substance, m.p. 175°-176°; ultraviolet peak at 240 mμ (ε17,500); infrared peaks at 3.10, 6.05, 6.20 μ.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([O-:10])[O:7][CH2:8][CH3:9])[CH3:4].[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Br.C(OP([O-])OCC)C.[Na+]>O1CCCC1>[CH2:3]([O:5][P:6]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][Br:11])(=[O:10])[O:7][CH2:8][CH3:9])[CH3:4]
Reactant: BrCc1ccccc1CBr
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccccc1CBr)OCC
Yield: 16.1 %

Procedure:
A suspension of sodium hydride (60% in oil, 1.4 g, 35 mmol) in anhydrous tetrahydrofuran (75 ml) is stirred under a nitrogen atmosphere and a solution of diethylphosphite (4.82 g, 34.9 mmol) in tetrahydrofuran (20 ml) is added dropwise. The reaction mixture is stirred an additional 20 minutes. A solution of 1,2-bis(bromomethyl)benzene (10.56 g, 40 mmol) in anhydrous tetrahydrofuran (150 ml) is treated dropwise with the solution of sodium diethylphosphite generated above. The reaction mixture is stirred 6.5 hours at room temperature, and then quenched with water and diluted with diethyl ether. The diethyl ether layer is separated, washed with water (2×100 ml), and dried over magnesium sulfate. After filtration and evaporation, the residue is chromatographed over silica gel (ethyl acetate as eluant) to give a clear oil (1.8 g).
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[CH2:39]([N:46]1[C:55]2[C:50](=[C:51]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)[C:52]([C@H:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:58][OH:59])=[C:53]([CH3:56])[CH:54]=2)[CH:49]=[CH:48][C:47]1=[O:72])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)CO)(C)(C)C>>[CH2:39]([N:46]1[C:55]2[C:50](=[C:51]([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][CH:66]=3)[C:52]([C@H:57]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[C:58]([OH:6])=[O:59])=[C:53]([CH3:56])[CH:54]=2)[CH:49]=[CH:48][C:47]1=[O:72])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cc2c(ccc(=O)n2Cc2ccccc2)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Product: Cc1cc2c(ccc(=O)n2Cc2ccccc2)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-(1-Benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic acid (65B) (5.4 mg) was prepared in a similar manner as compound ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-1-benzyl-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one instead of ((S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 7.6-7.5 (m, 3 H), 7.4-7.2 (m, 8 H), 6.59 (d, J=9.6 Hz, 1 H), 5.64 (s, 2 H), 5.02 (s, 1 H), 2.47 (s, 3 H), 0.94 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C29H29ClNO4: 490.2. Found: 490.2; LCMS-ESI+ (m/z): [M+H]+ calcd for C29H27ClNO4: 488.2. Found: 488.0.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[O:4]CC1>C(O)C.S(=O)(=O)(O)O.C(OCC)(=O)C>[N:13]1([C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[O:4])=[O:12])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(C1CCCCC12OCCO2)N1CCOCC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CCCCC1C(=O)N1CCOCC1
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of (1,4-dioxa-spiro[4.5]dec-6-yl)-morpholin-4-yl-methanone (59 mg, 0.23 mmol) in 60% aqueous ethanol (1.1 mL) were added 2 drops of conc. sulfuric acid (20 uL) and the mixture was heated to 80° C. for 2 h. The mixture was cooled to 20° C., diluted with ethyl acetate (20 mL) and washed with saturated aqueous sodium carbonate solution (10 mL), and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (17 mg, 35%) as a white solid. MS ISP (m/e): 211.9 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([CH2:15][CH2:16][O:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[N:4]=1)[CH3:2]
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: CCc1n[nH]c(=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nn(CCOc2ccc(C=O)cc2)c(=O)c2ccccc12
Yield: 53.7 %

Procedure:
##STR32## The title compound (450 mg, 54%) was prepared from 4-ethyl-1(2H)-phthalazinone (450 mg, 2.6 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 375-441), 4-[2-bromoethoxy]benzaldehyde (600 mg, 2.6 mmol) and K2CO3 (720 mg, 5.2 mmol) by a similar procedure to that described in preparation 2. mp: 110° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:25])([F:24])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O.[OH-].[K+]>C1COCC1>[F:7][C:8]([F:24])([F:25])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:23]=[CH:22][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (2.0 M THF solution, 3.0 mL, 6.00 mmol) in dry THF (10 mL), commercially available 4-[4-(trifluoromethyl)-phenyl]-benzoic acid (0.4 g, 1.5 mmol) in dry THF (10 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.23 mL), 3.0 M KOH solution (0.23 mL) and H2O (0.77 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered, concentrated to dryness and the resulting crude product purified by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:EtOAc (from 100:0 to 70:30) to afford the title compound (0.3 g, 79%), as white solid. 1H NMR (DMSO-d6): δ 4.56 (d, J=5.7 Hz, 2H), 5.25 (t, J=5.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.1 Hz, 2H), 7.89 (d, J=8.1 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Brc1ccncc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 4-bromopyridine according to the general procedure C. Obtained as a yellow solid (379 mg).
Reaction SMILES: I[C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[CH:14][C:4]=2[CH:3]=1)[CH:12]=[CH:11][CH:10]=[CH:9]3.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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:4]1([CH:3]=[CH:2][C:2]2[S:6][C:5]3[CH:7]=[C:8]4[C:13](=[CH:14][C:4]=3[CH:3]=2)[CH:12]=[CH:11][CH:10]=[CH:9]4)[CH:14]=[CH:13][CH:8]=[CH:7][CH:5]=1
Reactant: Ic1cc2cc3ccccc3cc2s1
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: [Cs+]
Solvent: CN(C)C=O
Product: C(=Cc1cc2cc3ccccc3cc2s1)c1ccccc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 4,4,5,5-Tetramethyl-2-[(1E)-2-(phenylethenyl]-1,3,2-dioxaborolane (15, 1.62 g, 7.04 mmol), 2-iodonaphtho[2,3-b]thiophene (5, 1.04 g, 3.35 mmol), Cs2CO3 (6.53 g, 20.04 mmol), and Pd(PPh3)4 (154.5 mg, 0.134 mmol, 4% mol) in dry DMF (70 mL) was heated at 80° C. for overnight for 2 days. The reaction mixture was then allowed to cool to room temperature, the formed precipitate was filtered and washed with methanol, water, and hexanes to yield a green crude solid. The crude solid was purified by vacuum sublimation in high vacuum (Tsub=250° C.) to give PVNT as an off-white solid (480 mg, 50% yield). 1H NMR (500 MHz, C2D2Cl4) δ 8.24 (s, 1H), 8.15 (s, 1H), 7.96 (m, 1H), 7.89 (m, 1H), 7.45 (m, 5H), 7.34 (s, 1H), 7.32 (d, J=16.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 6.98 (d, J=16 Hz, 1H). Anal. calcd. for (C20H14S): C, 83.88; H, 4.93. Found: C, 84.37; H, 4.74. m.p. 305-307° C.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([CH3:40])=[C:24]([NH:28][CH2:29][C:30]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:31]=4[C:32]([OH:34])=O)[CH:25]=[CH:26][CH:27]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O.C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:39][C:36]1[CH:35]=[C:31]2[C:30]([CH2:29][N:28]([C:24]3[C:23]([CH3:40])=[C:22]([C:7]4[C:8]5[C:16]6[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=6)[NH:10][C:9]=5[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=4)[CH:27]=[CH:26][CH:25]=3)[C:32]2=[O:34])=[CH:38][CH:37]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(Cl)cc4C(=O)O)c3C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC(C)NC(C)C
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N4Cc5ccc(Cl)cc5C4=O)c3C)c12
Temperature: 45 °C
Yield: 68.2 %

Procedure:
A mixture of 2-((3-(1-carbamoyl-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylamino)methyl)-5-chlorobenzoic acid, TFA (38 mg, 0.056 mmol), N,N-diisopropylamine (0.015 mL, 0.085 mmol), BOP (32.5 mg, 0.073 mmol), and N-methylmorpholine (0.024 mL, 0.220 mmol) in DMF (4 mL) was heated at 45° C. for 1 hr. The mixture was diluted with ethyl acetate (60 mL), washed sequentially with water (3×25 mL) and brine (25 mL), and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by prep. Reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with CH2Cl2 (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (21.7 mg, 0.039 mmol, 68.2% yield) as a yellow solid. LCMS (M+H)+=541.33. 1H NMR (500 MHz, DMSO-d6) δ: 11.66 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H), 7.82 (s, 1H), 7.77-7.73 (m, 3H), 7.67 (m, 1H), 7.54 (m, 1H), 7.45 (m, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.14 (d, J=8.9 Hz, 1H), 6.71 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.04 (d, J=17.5 Hz, 1H), 4.95 (d, J=17.5 Hz, 1H), 4.16 (m, 2H), 3.72 (m, 2H), 3.34 (s, 3H), 1.87 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[OH-:20].C([N+](C)(C)C)C1C=CC=CC=1.O=O>O.CO>[C:1]1(=[O:20])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: [OH-]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: O=C1C=CC=C2C1=Cc1ccccc12
Yield: 94 %

Procedure:
Into a 150 ml three-necked flask, 6.5 g of the thus obtained fluorene compound and 100 ml of pyridine were introduced. The mixture was cooled with ice and then 0.5 ml of a 40% methanol solution of benzyltrimethylammonium hydroxide was added thereto. The resulting mixture was stirred for one hour in an oxygen stream. After completion of the reaction, the contents were poured into 100 ml of water, resulting in a yellow precipitate. This precipitate was filtered off, washed with diluted hydrochloric acid and then with water, and dissolved in methylene chloride. This solution was dried with Na2SO4 and then purified with a silica gel short column (methylene chloride/hexane=1/1). Subsequently, the solvent was removed by evaporation under reduced pressure, and then the residue was recrystallized from a mixture of ethyl acetate and ethanol. Thus, 6.5 g (yield 94%) of a fluorenone compound having the following structural formula was obtained as orangish yellow needle crystals. The melting point of this compound was 172°-173.5° C. ##STR6##
Reaction SMILES: [C:1]([OH:14])(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(Cl)(=O)C([Cl:18])=O>ClCCl>[C:1]([Cl:18])(=[O:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCC/C=C/C=C/C(=O)O
Solvent: ClCCl
Product: CCCCCCC/C=C/C=C/C(=O)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2E,4E)-dodeca-2,4-dienoic acid (2.5 g) was dissolved in dichloromethane (25 ml). Oxalyl chloride (2.23 ml) was added and the reaction mixture was stirred at room temperature for 3 h. Solvent and excess oxalyl chloride were removed, and the residue was stripped several times with DCM. The crude acid chloride was used as such in next step.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:13]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:21](=[O:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:15][CH2:14]1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Li+].[BH4-]>>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([N:13]1[C:19](=[O:20])[CH2:18][CH2:17][N:16]([C:21](=[O:31])/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH2:15][CH2:14]1)[CH2:3][OH:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)N1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)CC(CO)N1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Yield: 84 %

Procedure:
In analogy to the procedure described in example 6B, 2-{4-[(E)-3-(3-chloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-succinic acid 4-tert-butyl ester 1-methyl ester (intermediate 8C) and 2 eq. of LiBH4 gave, after only 1 night of stirring and purification on a SiO2-column (dichloromethane/MeOH 98:2-95:5), the titled compound in 84% yield as white foam. MS: 436.9 (MH+, 1Cl).