Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH2:38])=[O:37])=[N:34][CH:35]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH3:4].[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([NH2:38])=[O:37])=[N:34][CH:35]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20]1
Reactant: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(N)=O)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccc(C(N)=O)nc4)n4ccnc34)cc2)CC1
Product: N
Temperature: 85 °C
Reaction time: 20 h
Yield: 1.5 %

Procedure:
A degassed mixture of (5-bromoimidazo[1,2-a]pyrazin-8-yl)-(4-(4-methylpiperazin-1-yl)phenyl)amine (59 mg, 0.154 mol), 5-tributylstannanyl-pyridine-2-carboxylic acid amide (0.127, 0.309 mmol), PdCl2(PPh3)2 (0.027 g, 0.038 mmol) in DMF (2 mL), is stirred at 85° C. for 20 hours. The reaction mixture is partitioned between EtOAc and water. The organic layer is washed with water (4×), dried over MgSO4, filtered and concentrated in vacuo. The crude is purified by silica gel column chromatography eluting with DCM followed by 97:3 DCM:NH3 (7M in MeOH) affording the title compound (2.0 mg, 3%). LCMS: Rt 1.75 min (92%) m/z (APCI) 429 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.26 (3H, s), 2.49-2.51 (4H, t), 3.12-3.15 (4H, m), 6.97 (2H, d), 7.62 (1H, s), 7.73 (1H, s), 7.77 (1H, br s), 7.91 (2H, d), 8.08 (1H, s), 8.22 (1H, d), 8.24 (1H, br s), 8.37-8.40 (1H, m), 8.96 (1H, s), 9.61 (1H, s).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[NH2:16][C:17]([CH3:28])([CH3:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(Cl)Cl>[C:12]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([NH:16][C:17]([CH3:28])([CH3:27])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:3]([CH3:15])=[N:4]2)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Reactant: CC(C)(N)CNC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(=O)c1cccc2nc(C)c(NC(C)(C)CNC(=O)OC(C)(C)C)nc12
Yield: 65.5 %

Procedure:
A solution of 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g) (0.65 g, 3.19 mmol), tert-butyl (2-amino-2-methylpropyl)carbamate (1.20 g, 6.37 mmol), and DIEA (2.22 mL, 12.75 mmol) in NMP (6.37 mL) was stirred at 170° C. for 1.5 h when mostly product was observed via lcms. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. brine (4×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 10-40% EtOAc in hexanes to give tert-butyl (2-((8-acetyl-3-methylquinoxalin-2-yl)amino)-2-methylpropyl)carbamate (339a) (0.78 g, 2.09 mmol, 65% yield) as a honey colored solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 1.57 (s, 6H) 2.55 (s, 3H) 2.87 (s, 3H) 3.33 (d, J=6.85 Hz, 2H) 5.25 (t, J=6.55 Hz, 1H) 6.53 (s, 1H) 7.32 (t, J=7.73 Hz, 1H) 7.73 (dd, J=7.34, 1.47 Hz, 1H) 7.88 (dd, J=8.02, 1.37 Hz, 1H). MS (ESI, pos. ion) m/z: 373.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[CH2:19]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCc1cc(C=O)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1cc(C=O)cc(C)c1OCc1ccccc1
Yield: 73.2 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (8.00 g, 48.7 mmol) in acetone (130 mL), K2CO3 (20.2 g, 146.2 mmol) followed by benzylbromide (12.5 g, 73.1 mmol) is added. The suspension is stirred at reflux for 16 h before it is filtered and the solvent of the filtrate is removed in vacuo. The residue is separated by CC on silica gel to give 4-benzyloxy-3-ethyl-5-methyl-benzaldehyde (9.07 g) as a pale yellow oil; LC-MS: tR=1.09 min, [M+1]+=255.08.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C@@H:8]2[C@@:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])([CH3:11])[O:9]2)[CH:7]=1.CO.[Cl-].[NH4+].[N-:24]=[N+:25]=[N-:26].[Na+]>O>[N:24]([C@H:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)[C@@:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[F:19])([OH:9])[CH3:11])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@]1(c2cc(F)ccc2F)O[C@@H]1c1cncc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1
Reaction time: 0.08 h
Yield: 80.8 %

Procedure:
Placed 3-bromo-5-((2R,3S)-3-(2,5-difluorophenyl)-3-methyloxiran-2-yl)pyridine (100 mg, 0.307 mmol), methanol (12 mL), water (1.500 mL), ammonium chloride (32.8 mg, 0.613 mmol), and sodium azide (120 mg, 1.840 mmol) in a microware tube and stirred for five minutes then sealed the tube and lowed it to a 110° C. oil bath for 18 hour. The reaction mixture was concentrate to provide a white solid to which was added 25 mL water then extracted it by ether (25 mL×3). Combined all ether layer, dried over magnesium sulfate, concentrated to afford clear wax which was purified via column chromatography (5% to 35% EtOAc/Hex) to provide (1R,2R)-1-azido-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol (96.2 mg, 0.248 mmol, 81% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J=2.1 Hz, 1H), 8.60 (d, J=1.8 Hz, 1H), 8.06 (t, J=1.8 Hz, 1H), 7.40 (ddd, J=9.8, 6.2, 3.2 Hz, 1H), 7.33-7.15 (m, 2H), 6.14 (s, 1H), 5.13 (s, 1H), 1.33 (d, J=0.9 Hz, 3H), Mass spec.: 371.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].C1COCC1.C([Li])CCC.[CH3:36][C:37]1[C:42]([CH:43]=[O:44])=[CH:41][CH:40]=[C:39]([CH3:45])[N:38]=1>CC(C)=O.CCCCCC>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:43]([C:42]3[C:37]([CH3:36])=[N:38][C:39]([CH3:45])=[CH:40][CH:41]=3)[OH:44])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(C=O)c(C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.02 h

Procedure:
To a 100 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.5 g, 5.8 mmol, Intermediate 47: step d) was added THF (55 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. which remained homogeneous and then n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) was added drop wise. The color of the solution became a reddish-brown color. After 1 minute, (2,6-dimethylpyridine-3-carboxaldehyde (1.01 g, 7.5 mmol in 2 mL THF) was introduced and the color of the mixture became a light greenish-yellow color. After 15 minutes, HPLC and TLC (50% acetone-hexane) indicated that the reaction was complete. The mixture was allowed to warm to −20° C. over 40 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The reaction was diluted further with water and extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to provide an orange foam. The crude product was chromatographed on silica gel (10% acetone-hexane increasing to 30% acetone) to afford the title compound as a light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[NH2:5].[CH3:18][CH:19]([C:25]([CH3:27])=O)[C:20](OCC)=[O:21].ClC1C(OC2C=CC(OC)=CC=2)=CC=C2C=1C(O)=C(C)C(C)=N2>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:20]([OH:21])=[C:19]([CH3:18])[C:25]([CH3:27])=[N:5]2)=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COc1ccc(Oc2ccc(N)cc2Cl)cc1
Agent: COc1ccc(Oc2ccc3nc(C)c(C)c(O)c3c2Cl)cc1
Solvent: CCO
Product: COc1ccc(Oc2cc3c(O)c(C)c(C)nc3cc2Cl)cc1
Temperature: 150 °C
Yield: 100 %

Procedure:
A mixture composed of 2.9 g of 3-chloro-4-(4-methoxyphenoxy)-aniline, 2.9 g of ethyl 2-methylacetoacetate, and 0.5 mL of ethanol was added dropwise to 4.2 g of polyphosphoric acid heated to 150° C. This reaction solution was stirred at 140 to 150° C. while removing ethanol by evaporation for 3 hr and was then poured into 195 mL of iced water containing 2 mL of concentrated hydrochloric acid. The crystals were collected by filtration and were washed with n-hexane to give 3.29 g of a mixture of 5-chloro-6-(4-methoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline with 7-chloro-6-(4-methoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline (yield 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17]>>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:14]2[CH2:20][CH2:19][CH2:18][C@H:15]2[CH2:16][OH:17])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: OC[C@@H]1CCCN1
Product: Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1

Procedure:
By subjecting 3-nitro-benzenesulfonyl chloride and L-prolinol in analogous manner to the procedure described in example B.13, the title compound was obtained. Pale-yellow oil. MS (ISP) 257.3 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:19]=[CH:18][C:17]2[NH:16][C:15](=[O:20])[N:14]3[C:21](=[O:31])[N:22]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[N:23]=[C:13]3[C:12]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]([N:22]2[C:21](=[O:31])[N:14]3[C:15](=[O:20])[NH:16][C:17]4[CH:18]=[CH:19][C:10]([C:8]#[C:7][C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:11][C:12]=4[C:13]3=[N:23]2)=[CH:25][CH:26]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2nc3c4cc(C#Cc5ccccc5)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
To a stirred solution of phenylacetylene (15.0 μg, 0.137 mmol) and 8a (25.3 mg, 0.0682 mmol) in a mixture of 2 mL of DMF and 1 mL of NEt3, was added Pd(OAc)2 (1.53 mg, 6.82 μmol) and triphenylphosphine (3.57 mg, 13.6 μmol) in a seal tube. The tube was sealed under argon and the mixture was stirred at 100° C. for 18 h. The mixture was cooled and concentrated to dryness in vacuo and the crude product was purified by chromatography on a silica gel column. Elution with n-heptane/EtOAc (2:1) as eluent yielded 13a as a white solid (14 mg, 70%). mp: >300° C. (decomp.),
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:11](O)(C)([CH3:13])[CH3:12].N1C2C(=CC=CC=2)C=C1>O.CCCCCCC>[CH:12](=[N:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:11][CH3:13]
Reactant: CC(C)(C)O
Reactant: Nn1ccc2ccccc21
Agent: c1ccc2[nH]ccc2c1
Solvent: CCCCCCC
Solvent: O
Product: CCC=Nn1ccc2ccccc21

Procedure:
To the 1H-indol-1-amine solution prepared in accordance with the procedures set forth in Example 6 in a 150-gal steel reactor, under nitrogen purge, slight exhaust, agitation ca. 150 rpm, at 10–25° C. (preferably 10–18° C.) and with slow jacket cooling, charge approximately 21.6 kg acetic acid to pH 3.9–4.0 (0.1 mL of the reaction mixture in 5 mL water) at a rate of ca. 1 kg/min. Charge incrementally more HOAc if needed to attain the pH level. Rinse pump with ca. 2 L NMP. Charge 10.8 L water (a slight temperature rise of about 3–6° C. is expected), essentially in one portion (ca. 1 min addition time). Charge 14.4 kg (13.9 kg corrected for 97% purity) propionaldehyde at ca. 0.8 kg/min (0.5–1.0 kg/min) while maintaining 10–24° C., preferably 10–20° C. A mild exotherm is expected. Depending on the rate of addition and cooling, expect about a 5° C. temperature rise. Rinse pump with ca. 3 L NMP. Agitate at 10–24° C., preferably 17–20° C., until the reaction is judged complete as evidenced by the HPLC assay, conditions of which are detailed further below (>99% conversion in 2–3 h). Monitor the progress of the reaction by withdrawing samples of the reaction mixture for HPLC assays. When the reaction is judged complete, prepare for a vacuum distillation directly from the reactor to a suitable receiver. Expect a forerun (ca. 45–50 L) of volatiles including tert-butanol and water initially at 50–70° C. and ca. 30–40 mm pressure. As the distillation rate slows, gradually increase the pot temperature to 95–100° C. and reduce the pressure to 5–25 mm and begin collecting NMP. Collect a total of about 320 kg distillates (to give a pot weight of 9.5 parts w/w with respect to the initial indole charge), then release the vacuum with nitrogen and cool to 10–25° C. If necessary, or for convenience of scheduling, the distillation can be interrupted at any time, by releasing the vacuum with nitrogen, cooling to <30° C., storing under nitrogen, and then restarting as required. Work up the reaction by charging 133 L heptane followed by, with chilled water cooling to keep exotherm temperature below 30° C., 234 L water through a reactor charging nozzle (maximum process volume of ca. 450 L is attained). Agitate for >10 min, then separate the phases. Extract the bottom aqueous phase with 54 L heptane. Combine the organic extracts, and wash with aqueous potassium bicarbonate solution (prepared from 0.6 kg potassium bicarbonate dissolved in 58 L (58–95 L) water) followed by a 58 L water wash. Concentrate the organic phase to obtain crude N-propylidene-1H-indol-1-amine as an oil. Purify by short path distillation, first pass to remove volatiles at ca. 120° C. evaporator and ca. 200–800 mbar pressure, and then a second pass at 110° C. evaporator and 0.2–0.4 mbar pressure to collect purified product.
Reaction SMILES: NC(N)=[S:3].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.[OH-].[Na+].Cl[CH2:17][C:18]([O-:20])=O.[Na+].Cl>O.C(Cl)Cl.C1CCCCC1>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][CH2:17][C:18]([OH:20])=[S:3])=[CH:8][CH:7]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C([O-])CCl
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Solvent: ClCCl
Product: OC(=S)CCc1ccc(F)cc1
Yield: 90.6 %

Procedure:
A solution of 15.2 g (0.2 mol) of thiourea in 100 ml of water is introduced into a 1 liter 3-necked flask equipped with a magnetic stirrer, a condenser and dropping funnel, and 28.9 g (0.2 mol) of p-fluorobenzylchloride are introduced, at 50°-60° C., in a single operation. The mixture is heated to refux and boiling is maintained for about 15 minutes; the solution becomes limpid. Thereafter the mixture is cooled and a solution of 32 g (0.8 mol) of NaOH in water is added dropwise at about 60° C. The whole is heated under reflux for about 30 minutes and cooled and a solution of about 0.28 mol of sodium chloroacetate (obtained by neutralising 26.46 g of chloroacetic acid in 200 ml of water with 23.52 g of sodium bicarbonate) is added dropwise at 60°-70° C. Thereafter the whole is heated under reflux for 30 minutes, and then cooled. The mixture is acidified with 3 N HCl, the oil obtained is taken up in methylene chloride, the solution is washed with a dilute solution of sodium bicarbonate, filtered over charcoal and acidified once more with 3 N HCl and p-fluorobenzylthioacetic acid thus precipitates and is filtered off. After recrystallisation from cyclohexane, 33.4 g (yield: 83%) of the said acid are collected. Instantaneous melting point: 68°-69° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.F[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>CN1C(=O)CCC1.O>[N+:23]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:14]=1[NH:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:7]=1)[C:18]([OH:20])=[O:19])([O-:25])=[O:24]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(-c2nccs2)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc(Nc2cccc(-c3nccs3)c2)c([N+](=O)[O-])c1
Yield: 83.4 %

Procedure:
To a solution of 3-thiazol-2-yl-phenylamine (14.0 g, 79 mmol) in anhydrous NMP (50 ml) was added 4-fluoro-3-nitrobenzoic acid (15.0 g, 127 mmol). The resultant mixture was stirred at 90° C. over night. The cooled reaction cake was suspended in water and the solid was filtered off, washed with water and dried in the air to afford the desired product (22.5 g, 83%).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7](C)[C:8](C1C=CC=CC=1)=CC=[N+](C)C.[CH3:21][N:22]([CH3:35])[CH:23]=[CH:24][C:25](=O)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].F[B-](F)(F)F.C([O+](CC)CC)C.CNC>ClCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH3:6][N:7]([CH3:8])[C:25]([C:26](=[O:27])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:24][CH:23]=[N+:22]([CH3:35])[CH3:21]
Reactant: CN(C)C(=CC=[N+](C)C)c1ccccc1
Reactant: CN(C)C=CC(=O)C(=O)c1ccccc1
Agent: CC[O+](CC)CC
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CN(C)C(=CC=[N+](C)C)C(=O)c1ccccc1

Procedure:
The procedure is as in Example 24 for the preparation of N-(3-dimethylamino-3-phenylpropenylidene)-N-methylmethanaminium tetrafluoroborate, starting with 4-dimethylamino-1-phenyl-3-butene-1,2-dione (9.3 g), triethyloxonium tetrafluoroborate (10.3 g) and dimethylamine (3.2 cc) in dichloromethane (140 cc). After precipitation in ethyl acetate (30 cc), N-(3-dimethylamino-3-benzoylpropenylidene)-N-methylmethanaminium tetrafluoroborate (5 g), m.p. 140° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]([C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:20]3[C:25]([C:26]=2[C:27]=1[CH2:28][O:29][CH3:30])=[CH:24][C:23]([OH:31])=[CH:22][CH:21]=3)=[O:14])[CH3:11]>N1C(C)=CC(C)=CC=1C.[Cu-]=O>[CH2:10]([O:12][C:13]([C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:20]3[C:25]([C:26]=2[C:27]=1[CH2:28][O:29][CH3:30])=[CH:24][C:23]([O:31][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:22][CH:21]=3)=[O:14])[CH3:11]
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(O)cc3c2c1COC
Agent: O=[Cu-]
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)c1ncc2[nH]c3ccc(Oc4ccc(OC)cc4)cc3c2c1COC
Reaction time: 35 h
Yield: 41.9 %

Procedure:
0.2 g of 4-methoxybromobenzene, 0.3 g of 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, and 0.15 g of copper(I) oxide are heated in 5 ml of collidine to boiling for 35 hours. After cooling, the mixture is filtered and evaporated under vacuum. The residue is taken up in ethyl acetate, extracted repeatedly with ice-cold 25% ammonia solution and then washed with saturated sodium chloride solution, dried over calcium sulfate, and evaporated. Chromatography on silica gel with methylene chloride-ethanol (10:1) yields 0.17 g of 6-(4-methoxyphenoxy)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, mp 154.0° C.
Reaction SMILES: F[C:2]([O:4][CH2:5][CH2:6]F)=[O:3].[F-:8].[Na+].[CH2:10]([OH:12])[CH3:11]>>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:12][CH2:10][CH2:11][F:8]
Reactant: [F-]
Reactant: CCO
Reactant: O=C(F)OCCF
Agent: [Na+]
Product: CCOC(=O)OCCF
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL PFA-flask fluoroethyl fluoroformate (27.0 g, 245 mmol) was added to dry NaF (15 g; 357 mmol). After cooling the mixture to −78° C. ethanol (12 mL, 310 mmol) was added over a period of 15 min. The mixture was stirred at −78° C. for 30 min. After warming up to room temperature the reaction was stirred for further 16 h. After addition of 5 g molecular sieve (0.4 nm) and stirring for 4 h at room temperature, all solids were removed by filtration and the resulting crude product was purified by distillation under reduced pressure (100 mbar).
Reaction SMILES: CC1(F)CC[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:24])(=O)=O)=CC=1.[O:34]1C[CH2:37][CH2:36][CH2:35]1>>[C:4]1([CH2:3][O:12][C:35]([CH:36]([CH3:37])[F:24])=[O:34])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1(F)CCc2ccccc2C1=O
Reactant: C1CCOC1
Product: CC(F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 47 %

Procedure:
This Example is directed to the fluorination of ethyl phenylacetate (C6H5CH2CO2C2H5) to form C6H5CH2CO2CHFCH3. The precursor was stirred with 2 millimoles lithium diisopropylamine (preparation described in Example 12) in tetrahydrofuran at -78° C. for 1 hour. 1.2 equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 3 milliliters tetrahydrofuran were added to the mixture which was stirred for 80 minutes. Stirring was continued as the mixture was allowed to warm up to room temperature, quenched with ammonium chloride, extracted with dichloromethane, dried, and evaporated. Purification was carried out on a silica gel column. C6H5CH2OCOCHFCH3 was obtained in 47% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: C1COCCN1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 was dissolved in N,N-dimethylformamide (2 ml). Morpholine (17 mg, 0.20 mmol), EDC (43 mg, 0.23 mmol) and HOBT (36 mg, 0.26 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (22 mg, Yield 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.ClC1C=CC2C(N3CCNCC3)C3=NC=CC=C3CCC=2C=1.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:47]=1.N1C=CC(CC(O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:53](=[O:54])[CH2:52][C:48]4[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12
Reactant: O=C(O)Cc1cccnc1
Reactant: Clc1ccc2c(c1)CCc1c(Cl)ccnc1C2N1CCNCC1
Agent: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Agent: O=C(O)Cc1ccncc1
Product: O=C(Cc1cccnc1)N1CCN(C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Yield: 88.8 %

Procedure:
By substituting in Example 75, 4,8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (0.3 g, 0.86 mmoles) (Preparative Example 41) for 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 3-pyridylacetic acid (0.1181 g, 0.86 mmoles) for 4-pyridylacetic acid and using the method described in Example 75, one obtains the title compound (0.357 g, 88%, MH+467).