Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH:22]=[O:23]>O.O1CCCC1>[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH:22]([OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccccn1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
A hexane solution (1.53M, 3.92 ml, 0.6 mmol) of n-butyl lithium was added dropwise to a tetrahydrofuran (10 ml) solution of 2-bromopyridine (572 μl, 6 mmol) under an argon atmosphere at −78° C., followed by stirring for 30 minutes. To the resulting brown solution was added dropwise 2,5-difluorobenzaldehyde (655 μl, 6 mmol) and the temperature of the reaction mixture was gradually raised to room temperature. To the reaction mixture was added water. The resulting mixture was then extracted with ethyl acetate. After the solvent was dried, the residue obtained by concentration under reduced pressure was purified by purification by silica gel chromatography to give the title compound (120 mg, 9%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].C(N(CC)CC)C.[C:17](Cl)(Cl)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:17]=[O:18])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(N)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N=C=O)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To the stirred mixture of 4-chloro-3-methylaniline (F1, 1.01 g, 7.13 mmol) and triethylamine (866 mg, 8.56 mmol) in methylene chloride (20 mL) at −20° C. under nitrogen was added phosgene solution (0.15 weight/weight in toluene, 6.15 g, 9.13 mmol) dropwise over 5 min. After addition, the reaction mixture was warmed up to room temperature over 2 h, and then stirred at room temperature for another 2 h. After this time, the reaction mixture was cooled to 0° C., and slowly quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (100 mL). The organic extract was washed with 2 M hydrochloric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was triturated with methylene chloride (40 mL) and filtered. The filtrate was concentrated under reduced pressure to provide compound F2 as a light brown liquid (1.08 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.27 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.88-6.84 (m, 1H), 2.34 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[C:6]=1[Cl:14])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[C:1]([C:5]1[C:6]([Cl:14])=[C:7]([C:10]([F:13])([F:12])[F:11])[N:8]([CH2:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[O:24])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)c1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)c1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C(F)(F)F)c1Cl

Procedure:
Protocol T was followed using 5-tert-Butyl-4-chloro-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.94-7.22 (m, 2H), 6.84-6.92 (m, 2H), 5.3 (s, 2H), 3.68-3.8 (m, 2H), 3.6-3.68 (m, 2H), 3.04-3.2 (m, 4H), 1.4 (s, 9H). 13C NMR (400 MHz, CDCl3): 164.8, 119, 118.4, 118.2, 116.2, 116, 54, 51, 50.8, 45.4, 42.2, 30, 29, 27.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28]>>[CH2:27]([O:26][C:25](=[O:29])[NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)[CH3:28]
Reactant: CCOC(=O)Cl
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: CCOC(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 42 and ethyl carbonochloridate were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.45 (d, J=7.8 Hz, 1H), 8.14-8.16 (bs, 1H), 7.73-7.97 (m, 3H), 7.30-7.50 (m, 4H), 5.38-5.49 (bs, 1H), 4.69 (d, J=5.4 Hz, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.80-3.82 (m, 2H), 1.27 (t, J=6.2 Hz, 3H); MS (ESI−) M/Z 413 (M−H)−.
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.Cl.[CH2:37]([O:44][C:45]1[CH:53]=[CH:52][C:48]([C@H:49]([NH2:51])[CH3:50])=[CH:47][CH:46]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[C:14]([NH:13][C@@H:12]([C:11]([NH:51][C@@H:49]([C:48]1[CH:52]=[CH:53][C:45]([O:44][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:46][CH:47]=1)[CH3:50])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: C[C@@H](N)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(OCc2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine-o-nitrophenyl ester (3.11 g; 6.37 mmol), (R)-4-benzyloxy-α-methylbenzylamine hydrochloride (1.68 g; 6.37 mmol), TEA (1.94 g; 19.10 mmol) and CH2Cl2 (200 mL), 18 hours reaction time. The resultant yellow solution was concentrated to afford the crude sub-title compound which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:24]1([NH:27][C:28](=[O:45])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)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>[CH:24]1([NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:2]3[CH:23]=[CH:22][C:5]4[C:6]([N:9]5[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]5)=[N:7][O:8][C:4]=4[CH:3]=3)[CH:30]=2)=[O:45])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3cc(Br)ccc23)CC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)noc2c1
Yield: 60.2 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(6-bromo-1,2-benzisoxazol-3-yl)-1-piperazinecarboxylate (Intermediate 25) (0.04 g), N-Cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.035 g), 2N aqueous sodium carbonate (2 ml) and tetrakis(triphenylphosphine)palladium(0) (1 mg) in isopropanol (6 ml) was stirred at reflux under nitrogen for 16 h. The residue was absorbed onto silica Merck 7734) and applied to a Varian Bond-Elut SPE cartridge (silica, 5 g). Elution with dichloromethane:methanol (98:2) gave the title compound as a cream solid (0.03 g).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([OH:24])=O)[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.Cl.[NH2:40][C@H:41]([C:46]([CH2:48][F:49])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44]>C1COCC1.CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:40][C@H:41]([C:46]([CH2:48][F:49])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C[C@H](N)C(=O)CF
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)CF
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a solution of Boc-LeuCH2F (1.53 g, 6.19 mmol) in ether (30 mL) was added a saturated solution of HCl in ether (20 mL). The mixture was stirred vigorously; a precipitate formed within 15 minutes. After 1 hour, the mixture was filtered, the solids were washed with ether (2×30 mL) and were then pumped dry overniqht: a second crop was obtained from the filtrate, giving 0.60 g (54%) of LeuCH2F hydrochloride. Boc-Phe-Gly-LeuOH (synthesized in several steps via mixed anhydride coupling of the appropriate amino acid benzyl esters and subsequent hydrogenolyses, 0.762 g, 1.69 mmol) was dissolved in THF (10 mL), and was cooled to -20° C. NMM (0.186 mL, 1.69 mmol) was added, followed by IBCF (0.219 mL, 1.69 mmol). After 5 minutes, HCl.LeuCH2F (0.31 g, 1.69 mmol) was dissolved in DMF (2 mL), to which solution was added NMM (0.186 mL, 1.69 mmol). This mixture was swirled for approximately 15 seconds and was added to the mixed anhydride solution. After 45 minutes, the reaction was quenched with 1M HCl (20 mL), extracted with ethyl acetate (2×30 mL), the combined organics were washed with saturated aqueous NaHCO3 (30 mL), brine (20 mL), dried over MgSO4, filtered, and evaporated. The thick oil was then dissolved in 1:1 ether/CH2Cl2 (20 mL), and hexane (50 mL) was added. After one day, the evaporated to dryness, yielding 0.14 g of Boc-Phe-Gly-Leu-LeuCH2F.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1.OS(O)(=O)=O.[CH3:16]O>O>[CH3:16][O:9][C:8]([C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[S:7][CH:6]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)c1csc(CO)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1csc(CO)c1
Yield: 56 %

Procedure:
A mixture of 5-hydroxymethyl-thiophene-3-carboxylic acid (14.5 g, 91.7 mmol), concentrated H2SO4 (5.2 mL, 93.5 mmol) and methanol (250 mL) is heated to reflux for 3.5 h. After cooling, the mixture is poured into water and extracted with dichloromethane (3×). The combined extracts are washed successively with saturated aq NaCl, aq NaHCO3 and water followed by drying over Na2SO4, filtration and concentration in vacuo. The residue is purified by distillation to give 5-hydroxymethyl-thiophene-3-carboxylic acid methyl ester (8.8 g, 56%) as a clear oil: bp 155-157° C./6-7 mbar; 1H NMR (CDCl3, 300 MHz) δ 7.98 (s, 1 H), 7.35 (s, 1 H), 4.78 (s, 2 H), 3.80 (s, 3 H), 2.63 (s, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2C(C3C=CC(CN(C)C)=CC=3)C(=O)[C:18]3[C:17]([C:32]([O:34]C)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].[CH3:36][N:37]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH:55](C3C=CC(CN(C)C)=CC=3)C(=O)C3C(C(OCC)=O)=CC=CC=3N2)=[CH:42][CH:41]=1)[CH3:38].O.[NH2:73][NH2:74]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:55](=[N:73][NH:74][C:32](=[O:34])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:46]2[C:43]2[CH:42]=[CH:41][C:40]([CH2:39][N:37]([CH3:36])[CH3:38])=[CH:45][CH:44]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(CN(C)C)cc2)cc1
Temperature: 40 °C
Reaction time: 6 h
Yield: 22 %

Procedure:
A mixture of methyl 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline -5-carboxylate and ethyl 2,3-bis(4-((dimethylamino)methyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (165 mg, 0.34 mmol) in hydrazine monohydrate (12 mL) and methanol (5 mL) was stirred at 40° C. for 6 hrs. The mixture was filtered to give crude product. The crude product was purified by prep-HPLC to give 8,9-bis(4-((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (33.7 mg, yield: 22%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ: 2.04 (s, 6H), 2.05 (s, 6H), 3.19-3.20 (m, 2H), 3.24-3.26 (m, 2H), 4.09-4.11 (d, J=8.8 Hz, 1H), 4.52-4.54 (d, J=8.8 Hz, 1H), 6.88-6.90 (m, 2H), 6.99-7.07 (m, 7H), 7.42-7.46 (m, 2H). LC-MS (ESI) m/z: 454 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[N:8]([CH3:12])[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: Cn1c(=O)sc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(=O)sc2cc(N)ccc21

Procedure:
A mixture of 6-nitro-3-methyl-2-benzothiazolinone (J. Heterocyclic Chem. 1992, 29, 1069–1076, 4.85 g, 23.1 mmol) and 10% palladium-on-carbon (491 mg, 0.461 mmol) in a mixture of MeOH (45 mL) and tetrahydrofuran (45 mL) is shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 17 h. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure and triturated with ethyl acetate/hexanes. Filtration then provides the title compound, mp 188–190° C.; MS (ESI+) for C8H8N2OS m/z 181 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C@H:12]([CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>C(Cl)Cl>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C@:13]([OH:20])([C@H:12]([N:11]([C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([C:38]([F:37])([F:48])[F:49])=[CH:40][CH:41]=1)[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:29])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](NCCOCc1ccccc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](N(CCOCc1ccccc1)C(=O)c1ccc(C(F)(F)F)cc1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 140 %

Procedure:
To a solution of (2R*,3R*)-3-[(2-benzyloxyethyl)amino]-2-[2,4-difluorophenyl]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (4.40 g, 11.4 mmol) (obtained as described in reference example 2) in CH2Cl2 (40 mL) was added triethylamine (1.74 mL, 12.5 mmol). The resulting mixture was cooled in an ice bath and a solution of 4-(trifluoromethyl)benzoyl chloride (2.61 g, 12.5 mmol) in CH2Cl2 (5 mL) was carefully added and the mixture was stirred for 1 h at 0° C. and then for 18 h at room temperature. The resulting solution was diluted with CH2Cl2 and washed with 5% aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and the solvent was removed, to afford a thick oil (9.17 g) that was purified by chromatography on silica gel (EtOAc: hexane 1:1). The title compound of the example was obtained as a white foam.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:11])C=CC=C[CH:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.B(Cl)(Cl)Cl.[OH2:24]>>[NH2:17][C:16]1[CH:18]=[CH:19][C:13]([Br:12])=[CH:14][C:15]=1[C:6](=[O:24])[CH2:5][CH3:11]
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1ccccc1
Reactant: O
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(=O)c1cc(Br)ccc1N
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
A three-necked round bottom flask under N2 was charged with AlCl3 (775 mg, 5.81 mmol), then add 5.00 mL of toluene. The slurry was cooled to −10° C. and 4-bromoaniline (1.0 g, 5.81 mmol) was added in one portion. To this was added BCl3 (6.4 mL of 1.0 M solution in xylene) to the mixture at −10° C. slowly, and the mixture was purged with N2 until no more smoke appeared. Propioitrile (1.88 mL, 25.6 mmol) was added and the temperature was allowed to raise to no great than 45° C. The reaction was heated at 63° C. for 10 minutes and maintained at 63° C. for 5 minutes to give a homogeneous solution. Another 4.0 mL of toluene was added into another three-necked flask, and heated to reflux under N2. The solution from previous flask was added to the toluene at reflux over 10 minutes. The mixture was heated to reflux for an additional 4 hours, while continuing to purge the reaction with N2. Toluene would be lost during this process, added more toluene to the mixture if necessary. The reaction was cooled to room temperature and 10 mL of water was added under efficient stirring for ˜30 minutes. The mixture was heated to 55° C. and stirred for 15 minutes before allowing separation into two layers. The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a crude solid. The residue was purified though column chromatography (0-50% EtOAc/Heptane gradient) to afford 1-(2-amino-5-bromophenyl)-propan-1-one as a yellow solid (144.0 mg, 10.9%).
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS([C:13]1[S:14][C:15]([C:30]2[CH:34]=[CH:33][NH:32][N:31]=2)=[C:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[C:18](=[O:29])[C:17]=12)(=O)=O>C1COCC1>[CH:1]1([S:6][C:13]2[S:14][C:15]([C:30]3[CH:34]=[CH:33][NH:32][N:31]=3)=[C:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:29])[C:17]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3cc[nH]n3)sc(S(C)(=O)=O)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCc2c(-c3cc[nH]n3)sc(SC3CCCC3)c21
Temperature: 25 °C

Procedure:
To a solution of cyclopentanethiol (54 μL, 0.50 mmol) in THF (0.5 mL) at 0° C. was added NaH (20.0 mg, 0.50 mmol). The reaction mixture was warmed to rt and tert-butyl 3-(methylsulfonyl)-4-oxo-1-(1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridine-5(4H)-carboxylate (100 mg, 0.25 mmol) was added, After 30 min, the reaction was quenched with aqueous NH4Cl and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient elution, 0-100% EtOAc /hexanes) afforded the title compound. 1H NMR (400 MHz, ppm, CD3OD) δ 7.73 (d, J=2.3 Hz, 1 H); 6.50 (d, J=2.4 Hz, 1 H); 3.77 (m, 1 H); 3.44 (t, J=6.2 Hz, 2 H); 3.04 (t, J=6.3 Hz, 2 H); 2.32-2.22 (m, 2 H); 1.85-1.77 (m, 2 H); 1.76-1.65 (m, 4 H). HRMS (ES+) m/z 320.0879 [(M+H)+; calcd for C15 H17N3OS2: 320.0886].
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Br:12])=[CH:5][N:6]=[CH:7]2.CCO.N([O-])=O.[Na+].[F:20][B-](F)(F)F.[H+]>O.CCOCC>[Br:12][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[F:20])[CH:7]=[N:6][CH:5]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1cccc2cncc(Br)c12
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Fc1cccc2cncc(Br)c12
Temperature: 0 °C
Yield: 42 %

Procedure:
5-Amino-4-bromo-isoquinoline (see Gordon et al., J. Heterocycl. Chem., 4, 1967, 410-411) (1.86 g, 8.34 mmol) was stirred in 48% fluoroboric acid (15 mL)/EtOH (15 mL) until completely dissolved. The solution was cooled to 0° C., and sodium nitrite (660 mg, 9.59 mmol) in H2O (1 mL) was added dropwise. The solution was diluted with Et2O (30 mL), and the tan diazonium fluoroborate salt was collected by filtration and dried under vacuum. The solid was placed in a flask and carefully heated over a flame to expel nitrogen. The dark brown residue was diluted with 10% NaOH and extracted with chloroform. Organics were washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (40% to 50% ethyl acetate/hexanes) gave 798 mg (42%) of 4-bromo-5-fluoro-isoquinoline as a white solid. 1H NMR (300 MHz, CDCl3) δ9.36 (d, 1H, J=2.4 Hz), 8.74 (s, 1H), 8.07-8.11 (m, 1H), 7.70-7.80 (m, 2H). Anal. (C9H5BrFN) C, H, N.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=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>[N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:17])[CH:23]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(N=[N+]=[N-])c1ccc2ccccc2c1Br
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(N=[N+]=[N-])c1ccc2ccccc2c1-c1cccc(F)c1
Temperature: 100 °C
Yield: 41.4 %

Procedure:
To a mixture of 2-(1-azidoethyl)-1-bromonaphthalene (0.080 g, 0.29 mmol) and (3-fluorophenyl)boronic acid (48.6 mg, 0.348 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate in water (0.34 mL, 19 mmol) and tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.0145 mmol). The reaction mixture was heated at 100° C. overnight. After cool to room temperature, the mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and then concentrated. The residue was purified on silica gel, eluting with 0 to 20% EtOAc in hexane, to give the desired product (35 mg, 41.5%). LCMS calculated for C18H14FN3Na(M+Na)+: m/z=314.1; found: 314.3.
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].[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=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: C#Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1[N+](=O)[O-]
Yield: 97.7 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (5.64 g, 15 mmol) and phenylacetylene (2.47 mL, 22.5 mmol) according to the general procedure F. Obtained as a yellow solid (4.96 g).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>ClCCl>[C:17]1([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:6]2[CH2:7][CH2:8][C:9]3[S:1][CH:2]=[CH:3][C:4]=3[CH2:5]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1cc2c(s1)CCNC2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCc3sccc3C2)cc1
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 100 g (0.718 mole) of 4,5,6,7-tetrahydro thieno [3,2-c]pyridine in 200 ml of dichloromethane, are added 80 ml (0.789 mole) of triethylamine, then 200.2 g (0.718 mole) of triphenylmethylchloride is added, drop by drop, at ambient temperature. The reaction medium is left overnight at ambient temperature. The reaction medium is poured into 2000 ml of water. The organic phase is decanted, dried over sodium sulfate and evaporated to dryness. The residue is purified by filtration on a silica bed (elution with dichloromethane). The product is white crystals, M.P.=95° C. (pasty); yield: 96%; NMR 1H (in ppm) (CDC13): 7.57-6.90 (m, 15H); 6.80 (c, J =6.5 Hz, 1H); 6.43 (d, J=6.5 Hz, 1H); 3.35 (s, 14), 3.00-2.33 (m, 4H).