Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:29].[Na+].OO>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]([NH2:24])=[O:29])[C:17](=[O:28])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(N2CC(c3cccc(OCc4ccccc4)c3)CC2=O)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cccc(N2CC(c3cccc(OCc4ccccc4)c3)CC2=O)c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
To a solution of 3-[4-(3-benzyloxyphenyl)-2-oxo-pyrrolidin-1-yl]benzonitrile (1.3 g, 3.36 mmol) in 25 mL EtOH was added 25% NaOH (0.15 mL) followed by the slow addition of 1.5 mL H2O2 (30%). The reaction mixture was heated to 45° C. and stirred for 5 h. The mixture was then cooled down and concentrated under reduced pressure. The residue was dissolved in 100 mL EtOAc, washed with water and brine, dried over MgSO4 and concentrated again. The residue was purified by column chromatography on silica gel (EtOAc:Hexane=1:3) to give 1.3 g of the desired product. Yield: 99%.
Reaction SMILES: [CH2:1]([C@:8]12[C:21]3[C:16](=[CH:17][C:18](Br)=[CH:19][CH:20]=3)[CH2:15][CH:14]=[C:13]1[CH:12]=[C:11]([O:23][CH2:24][CH3:25])[CH2:10][CH2:9]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH2:1]([C@@:8]12[CH2:9][CH2:10][C:11]([O:23][CH2:24][CH3:25])=[CH:12][C:13]1=[CH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:26]#[N:27])[CH:19]=[CH:20][C:21]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCOC1=CC2=CCc3cc(Br)ccc3[C@]2(Cc2ccccc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC1=CC2=CCc3cc(C#N)ccc3[C@]2(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 96 %

Procedure:
Zinc cyanide (13.4 g, 114 mmol) was added to a solution of 4a(S)-Benzyl-7-bromo-2-ethoxy-3,4,4a,9-tetrahydro-phenanthrene (30 grams, 75.9 mmol) in DMF (200 mL) followed by tetrakis(triphenylphosphine)palladium(0), (10.5 g, 9.11 mmol) in a flask outfitted with a bleach scrubbing system. Additional dimethyl formamide (400 mL) was used to wash the sides of the flask and funnel. The suspension was heated to 80° C. After 7 hours HPLC showed no starting material and the reaction was cooled to room temperature. The suspension was diluted with EtOAc (300 mL) and filtered through a pad of Celite. The filtrate was washed with 2N NH4OH (2 times 500 mL), brine (500 mL) and water (500 mL). Upon addition of water solids began to precipitate out so additional EtOAc (200 mL) was added. The organic layer was concentrated to ½ volume and diluted with ethanol (250 mL) and water (250 mL). The resulting solids were allowed to granulate for 1 hour and then filtered. The mother liquor was concentrated slightly and a second crop was collected. After the combined crops air dried overnight a white solid was collected: 24.9 grams (72.9 mmol), 96% yield; mp 164-165° C., IR (film) ν 2227, 1657, 1631 cm−1; [α]25D+160.06; 1H NMR (acetone-d6) δ 7.62-7.56 (m, 2H), 7.29 (s, 1H), 7.09-7.06 (m, 1H), 7.01-6.95 (m, 2H), 6.51 (d, 2H, J=7.1 Hz), 5.54 (dd, 1H, J=5.4, 2.0 Hz), 5.49 (d, 1, J=1.6 Hz), 3.91 (q, 2, J=7.1 Hz), 3.07 (d, 1, J=12.5 Hz), 2.99 (dd, 1, J=21.6, 5.8 Hz), 2.81-2.72 (m, 1H), 2.73 (d, 1H, J=12.5 Hz), 2.65 (dd, 1H, J=13.7, 6.6 Hz), 2.29 (dd, 1H, J=17.8, 5.4 Hz), 2.15 (d, 1H, J=21.6 Hz), 1.83 (ddd, 1H, J=12.8, 12.8, 6.2 Hz), 1.33 (t, 3H, J=7.1 Hz); 13C NMR (acetone-d6) δ 155.3, 147.4, 138.9, 137.4, 136.0, 131.0, 130.7, 129.5, 127.2, 127.0, 126.2, 119.0, 118.4, 109.5, 98.8, 62.5, 44.2, 42.5, 32.1, 29.9, 25.5, 14.3. Anal. Calcd for C24H23NO: C, 84.42; H, 6.79; N, 4.10. Found: C, 83.82; H, 6.87; N, 4.04. The structure and absolute configuration were confirmed by single crystal X-ray analysis.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 28 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 167B (0.186 g, 0.5 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants and preparative HPLC (C18 column and 55-70% MeCN/H2O with 0.05% AcOH) to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.072 g, 28%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.56 (m, 4H), 7.33-7.47 (m, 5H), 7.24 (d, 1H), 6.51 (s, 1H), 4.71 (m, 2H), 4.55 (m, 2H), 4.33 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.31 (s, 3H); LC-MS (ESI) m/z 635 (M+H)+.
Reaction SMILES: ClS(N=C=O)(=O)=O.C(O)=O.[Si]([O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]2[C@H:25]3[C@H:34]([CH2:35][CH2:36][C@:20]12[CH3:21])[C:33]1[CH:32]=[C:31]([CH:37]=[O:38])[C:30]([OH:39])=[CH:29][C:28]=1[CH2:27][CH2:26]3)(C(C)(C)C)(C)C.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[OH:39][C:30]1[C:31]([CH:37]=[O:38])=[CH:32][C:33]2[C@@H:34]3[C@H:25]([C@H:22]4[C@@:20]([CH2:36][CH2:35]3)([CH3:21])[C@@H:19]([OH:18])[CH2:24][CH2:23]4)[CH2:26][CH2:27][C:28]=2[CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Agent: O=C=NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4cc(C=O)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of chlorosulfonyl isocyanate (0.13 mL, 1.5 mmol) in CH2Cl2 (1.0 mL) was added formic acid (0.31 mL of a CH2Cl2 solution, 5.0M, 1.6 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h. To a solution of 17β-tert-butyldimethylsilyloxy-3-hydroxyestra-1,3,5(10)-triene-2-carbox aldehyde (9, 0.129 g, 0.31 mmol) in DMF (3.0 mL) was added sodium hydride (0.044 g of a mineral oil dispersion, 60%, 1.1 mmol) at 0° C. The reaction mixture was stirred for 1 h, the pre-prepared reagent was added, and stirring continued for 4 h at room temperature. The reaction mixture was quenched with saturated aqueous NH4Cl at 0° C. and extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (MgSO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:acetone (2:1→1:1, v/v) to afford 0.017 g of 2a (18% yield) and 0.030 g of 10 (27% yield), m.p. 170°-172° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:8][C:7]([SH:9])=[N:6][N:5]=1)[CH3:2].[H-].[Na+].Cl[C:13]1[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][N:18]=1>CN(C=O)C.C1C=CC=CC=1>[CH2:1]([S:3][C:4]1[S:8][C:7]([S:9][C:13]2[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][N:18]=2)=[N:6][N:5]=1)[CH3:2]
Reactant: N#Cc1nccnc1Cl
Reactant: CCSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CCSc1nnc(Sc2nccnc2C#N)s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Example 1 by using 5-(ethylthio)-1,3,4-thiadiazole-2-thiol (592 mg, 3.33 mmol), NaH (60% dispersion in mineral oil, 146 mg, 3.66 mmol), and 3-chloropyrazine-2-carbonitrile (422 mg, 3.02 mmol) in DMF and benzene (8 ml, 1/1) by stirring at 90° C. under nitrogen atmosphere overnight.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1I.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CCCC)CCCC)CCC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:23]([C:22]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCC#CCCCCCCCC
Reactant: Ic1ccsc1-c1sccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCCCCc1c(CCCCCCCC)c2ccsc2c2sccc12
Temperature: 130 °C
Yield: 84.8 %

Procedure:
To a two-necked RB flask under nitrogen was added 1.39 g (3.3 mmol) of 3,3′-diiodo-2,2′-bithiophene, 222 mg (0.33 mmol) of Pd(OAc)2, 2.5 g (10 mmol) of 9-octadecyne, tributyl amine 1.85 g (10 mmol), and 10 mL of anhydrous DMF. The mixture was heated at 130° C. for 4 hours. After cooling down to room temperature, 50 mL of ether ethyl was. The organic phase was washed with water several times, dried by MgSO4, concentrated under reduced pressure. The residue was further purified by flash chromatography on silica gel (hexane as eluent) to afford the pure product as a colorless liquid (1.16 g, yield: 85%). 1H NMR (300 MHz, CDCl3) δ 7.46 (d, 2H, J=5.43 Hz), 7.37 (d, 2H, J=5.42 Hz), 3.01 (t, 4H, J=7.89 Hz), 1.68 (m, 4H), 1.51 (m, 4H), 1.30 (m, 16H), 0.89 (t, 6H, J=6.7 Hz). 13C NMR (400 MHz, CDCl3) δ 137.47, 131.58, 131.32, 123.55, 123.38, 31.87, 31.52, 30.43, 30.16, 29.48, 29.27, 22.63, 14.04. MS: m/z=414.7 [M]+ (Calcd.: 414.7).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[CH:11]2[CH2:12][CH2:13][N:14]([C:17]([NH:19][C:20]3[S:21][C:22]4[CH2:23][NH:24][CH2:25][CH2:26][C:27]=4[N:28]=3)=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)N3CCC(N4CCc5ccc(F)cc54)CC3)sc2C1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1nc2c(s1)CNCC2)N1CCC(N2CCc3ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 2-(4-(6-fluoroindolin-1-yl)piperidine-1-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (501 mg, 1.0 mmol) in CH2Cl2 (2 mL) was added TFA (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 45 min and then Et2O (40 mL) was added. The resulting mixture was stirred vigorously for 20 min and the solid was filtered. The solid was washed with Et2O (2 mL×3) and dried to yield 4-(6-fluoroindolin-1-yl)-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperidine-1-carboxamide as a TFA salt.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH2:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:31][C:29]1[CH:30]=[C:25]([CH:20]([C:21]([F:24])([F:23])[F:22])/[CH:18]=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: C=Cc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: CC(C)(C)OC(=O)N1CCc2cc(/C=C/C(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc21
Temperature: 150 °C
Yield: 11.7 %

Procedure:
To a stirred solution of tert-butyl-5-vinylindoline-1-carboxylate (1.28 g, 5.23 mmol) in 1,2-dichlorobenzene (10.0 mL), was added 5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene (3.4 g, 10 mmol), CuCl (103 mg, 1.05 mmol) and 2,2-bipyridyl (0.326 g, 2.092 mmol) and the resultant reaction mixture was degassed with argon for 30 min and heated to 150° C. for 1 h. The reaction mixture was cooled to RT and filtered and the filtrate was concentrated under reduced pressure. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 2% ethyl acetate/petroleum ether) to afford the title compound as a pale yellow gummy solid (0.3 g, 61%): 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=6.0 Hz, 2H), 7.22 (s, 2H), 7.16 (d, J=8.4 Hz, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.21 (dd, J=16.0, 7.6 Hz, 1H), 4.07 (m, 3H), 3.10 (t, J=8.4 Hz, 2H), 1.55 (s, 9H); ESIMS m/z 433.79 ([M−H]−); IR (thin film) 1168, 858 cm−1.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[F:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:25]3[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[N:19]([CH2:18][CH2:17][F:16])[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2].[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:21]3[C:20](=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])[N:19]([CH2:18][CH2:17][F:16])[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1CCCC(Br)C1=O
Reactant: FCCNc1cccc(F)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CCCc2c1c1c(F)cccc1n2CCF
Product: CCN(CC)C(=O)C1CCCc2c1c1ccc(F)cc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 3 %
Yield: 6 %

Procedure:
A mixture of 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35; prepared according to Example 7(c)) (161 mg, 0.6 mmol) and (2-fluoro-ethyl)-(3-fluoro-phenyl)-amine (43) (184 mg, 1.2 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (1 mL) and dry zinc chloride (245 mg, 1.8 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and washed with 2 N HCl (5 mL), water (2×5 mL) and aqueous potassium carbonate solution (2×5 mL) then dried and concentrated in vacuo. The crude material was purified by semi preparative HPLC eluting with water (A) and methanol (B) (Gemini 5 u, C18, 110A, 150×21 mm, 50-95% B over 20 min, 21 mL/min) to afford 20 mg (6%) of 7-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide as a white solid and 10 mg (3%) of 5-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent 10) as a white solid. The structure of 7-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.14 (3H, t, J=7 Hz, N(CH2CH3)2), 1.33 (3H, t, J=7 Hz, N(CH2CH3)2), 1.80-2.15 (4H, m, 2- and 3-CH2), 2.70-2.80 (2H, m, 1-CH2), 3.50-3.80 (4H, m, N(CH2CH3)2), 4.20-4.35 (1H, m, 4-CH), 4.40 (2H, dm, J=21 Hz, NCH2CH2F), 4.60 (2H, dm, J=41 Hz, NCH2CH2F), 6.70-6.80 (1H, m, NCCHCFCHCH), and 7.00-7.10 (2H, m, NCCHCFCHCH).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[O:4]=[C:3]([CH:5]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)C=Cc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 0.020 moles of titanium tetrachloride in 15 ml of carbon tetrachloride was added over a period of 10 minutes to a cold (5°) solution of 0.015 moles of ethyl acetoacetate and 0.015 moles of benzaldehyde in 60 ml of tetrahydrofuran. After the mixture was stirred for 1.5 hours, a solution of 0.060 mole of triethylamine in 15 ml of tetrahydrofuran was added dropwise. The reaction mixture was then stirred for 20 hours, after which the title compound was isolated by the extraction and chromatography methods described in Example 1. The material prepared by this procedure was identical to that prepared by the method of Example 1, as indicated by the reverse phase chromatographic method described in Example 2.
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4].N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CCOCC>[CH2:28]([O:27][C:25]([S:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[C:3]([OH:5])=[O:4])=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2cc(C(S)C(=O)O)ccc2c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)SC(C(=O)O)c1ccc2cc(OC)ccc2c1
Reaction time: 2 h

Procedure:
A solution of α-mercapto-6-methoxy-2-naphthylacetic acid (0.02 moles) in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 mol (0.022 moles) of ethyl chloroformate. The mixture is then stirred for 2 hours, diluted with ether and filtered. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered. The solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[CH:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:38]1[CH:37]=[CH:36][N:28]2[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])=[CH:40][CH:39]=3)=[O:24])[CH2:26][C:27]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1F
Reaction time: 0.05 h
Yield: 88.4 %

Procedure:
To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257-260° C.
Reaction SMILES: C1COCC1.[Na].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].Cl[C:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([C:24]([Cl:27])([F:26])[F:25])[N:17]=[C:16]([C:28]([F:31])([F:30])[F:29])[C:15]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O>[Cl:27][C:24]([F:25])([F:26])[C:18]1[N:17]=[C:16]([C:28]([F:31])([F:29])[F:30])[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:14]([O:10][CH2:9][C:8]([F:12])([F:11])[F:7])[C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To 100 ml of dry THF was added 0.29 g (0.013 mol) of sodium metal. To this mixture 1.28 g (0.013 mol) of 2,2,2-trifluoroethanol was added dropwise. The solution was stirred under N2 until all of the sodium metal had been consumed. Then 5.0 g (0.0126 mol) of product of Example 28 was added to the sodium salt solution and the reaction mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was poured into 100 ml of H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concentrated in vacuo to yield 5.48 g of a gold crystalline solid. This solid was recrystallized in hexane to yield 4.2 g (72.4%) of product as a tan solid; mp 62°-63° C.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].N12CCCCC1C=NCCC2.Cl.[Cl:18][CH2:19][C:20]([NH2:22])=[NH:21].O>C(#N)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:22]=[C:20]([CH2:19][Cl:18])[N:21]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)CCl
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccnc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
Solutions of 2-chloroacrylonitrile (15.7 g.) in acetonitrile (20 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (27 g.) in acetonitrile (20 ml.) were added simultaneously over 30 minutes to a stirred, ice-cooled solution of 2-chloroacetamidine hydrochloride (19.2 g.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (22.5 g.) in acetonitrile (200 ml.), keeping the temperature below 30° and the mixture stirred a further 4 hours at room temperature after the addition was complete. The resulting mixture was stirred with a mixture of water (100 ml.) and ethyl acetate (200 ml.) and then filtered through a pad of diatomaceous earth and the ethyl acetate phase separated. The aqueous phase was further extracted with ethyl acetate (2×100 ml.) and the combined ethyl acetate extracts dried and evaporated to dryness to give 4-amino-2-chloromethylpyrimidine (14.5 g.) which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([CH3:11])=[O:10].[OH-].[Na+].O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:8][C:9](=[O:10])[CH:11]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccs1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccs1)C=Cc1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
2-Thiophenecarboxaldehyde (33, 0.50 ml, 5.3 mmol) and acetone (19, 0.20 ml, 2.7 mmol) were combined in ethanol (10 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.30 g, 7.5 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol/water to give 0.55 g (82%) of a yellow solid: mp 115-117° C. [expected mp 115-117° C.]; 1H NMR: δ 6.80 (d, 2H, J=15.5 Hz), 7.06 (dt, 2H, J=3.6, 1.4 Hz), 7.31 (d, 2H, J=3.4 Hz), 7.39 (d, 2H, J=5.0 Hz), 7.82 (d, 2H, J=15.5 Hz); 13C NMR: δ 124.4, 128.2, 128.7, 131.7, 135.5, 140.2, 187.5.