Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([C:18]([F:19])([F:20])[F:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)nc1C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCCO
Product: O=C(O)c1cn(-c2cccc(Br)c2)nc1C(F)(F)F
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of ethyl 1-(3-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.5 g, 1.37 mmol) and 2-chlorophenylboronic acid (0.28 g, 1.78 mmol) in n-propanol:water (2.35 ml:0.482 ml) mixture were added palladium acetate (0.005 g), triphenylphosphine (0.016 g) and 2N sodium carbonate (0.497 ml). The mixture was refluxed for 16 hours. A 2N NaOH (1.5 ml) was then added and refluxing continued for an additional 2 hours. The reaction was cooled, acidified with 10% citric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 0.402 g of 1-(3-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=O)C=CC=CC=1.[C:21]([C:23]12[CH2:30][CH2:29][CH2:28][N:27]1[CH2:26][CH2:25][CH2:24]2)#[CH:22]>C1C=CC=CC=1>[CH2:7]([C:8]1[CH:22]=[C:21]([C:23]23[CH2:30][CH2:29][CH2:28][N:27]2[CH2:26][CH2:25][CH2:24]3)[O:11][N:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: C#CC12CCCN1CCC2
Solvent: c1ccccc1
Solvent: O=C=Nc1ccccc1
Product: c1ccc(Cc2cc(C34CCCN3CCC4)on2)cc1
Yield: 52.2 %

Procedure:
2-Phenylnitroethane (895 mg, 5.92 mmol, from step 15b) and phenylisocyanate (1.3 mL, 11.8 mmol) were dissolved in benzene (12 mL) and added to a flask containing 7a-ethynyl-hexahydro-1H-pyrrolizine (400 mg, 2.96 mmol, from step 13a). The solution was stirred at reflux for 5 hours, cooled and stirred for 48 hours at room temperature. The mixture was filtered and extracted with 6N HCl. The aqueous phase was made basic with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford an amber oil (415 mg, 52%). 1H NMR (CDCl3, 300 MHz) δ1.71-1.92 (m, 6H), 2.11-2.23 (m, 2H), 2.58-2.66 (m, 2H), 3.08-3.15 (m, 2H), 3.95 (s, 2H), 5.87 (s, 1H), 7.20-7.34 (m, 5H); MS (CI/NH3) m/z: 269 (M+H)+.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.[Cl:10][CH2:11][CH2:12][CH2:13]Cl>CN(C)C=O>[Cl:10][CH:11]=[CH:12][CH2:13][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCCCCl
Agent: [K]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CC=CCl
Temperature: 60 °C
Yield: 60 %

Procedure:
A mixture of the potassium salt of 5-chloropyrimid-2-one (0.01 mol) and 1.3-dichloropropane (0.02 mol) in dimethylformamide (50 ml) was heated at 60° C. for 8 h. The reaction mixture was then evaporated (1 mm Hg) and the residue dissolved in chloroform (80 ml). This solution was washed with 1 N NaOH (2 ml) and water before drying and evaporation; yield 60%, m.p. 102°-104° C. (benzene/ligroin). (Found: C, 41.83; H, 3.02. Calc. for C7H6ClN2O: C, 41.01; H, 2.95).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)(=[O:8])=[O:7])([CH3:4])[CH3:3].[H][H]>[Pd].C(O)C>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][S:6]([NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)Cc1ccccc1N
Yield: 94.7 %

Procedure:
A mixture of 12 g (0.044 mol) of N-(1,1-dimethylethyl)-2-nitrobenzenemethanesulfonamide and 1 g of 10% palladium on carbon in 175 mL ethanol was reduced by shaking in a hydrogen atmosphere at 50 psi for 30 minutes. The catalyst was removed by filtration through a pad of diatomaceous earth with ethanol rinsing. The filtrate was then evaporated under reduced pressure and the residue crystallized from n-butyl chloride and hexanes to afford 10.1 g of the title compound, m.p. 115°-117° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([OH:20])=O)=[N:11][NH:12][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]([OH:41])[CH2:38][NH:39][CH3:40])[CH:32]=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[CH3:40][N:39]([CH2:38][CH:37]([OH:41])[C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)[C:18]([C:10]1[NH:11][N:12]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: CNCC(O)c1cccnc1
Reactant: COC(=O)c1[nH]nc(C(=O)O)c1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1n[nH]c(C(=O)N(C)CC(O)c2cccnc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-benzyloxy-3-carboxy-1H-pyrazole-5-carboxylate (2.0 g, 7.24 mmol) in DMF (30 mL) were added HOBT (1.17 g, 8.69 mmol), 1-(3-pyridyl)-2-methylaminoethanol (1.21 g, 7.96 mmol; prepared by the methods of Tsushima, S., et al., EP 278621 and Cudahy, M. M., et al., WO 2003059911), triethylamine (0.88 g, 8.69 mmol), and EDC (1.67 g, 8.69 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The DMF was removed in vacuo and the residue was purified by prep HPLC (Waters prep LC 4000 System using a Waters Nova Pak column (3 100×40 mm I.D. cartridges, C18, 6 μM pore size) eluting with 95-5% water (0.10% TFA)/acetonitrile (0.10% TFA) at 60 mL/minute). Appropriate fractions were combined and the solvent was removed under reduced pressure to give a yellow solid. The free base of the product was obtained by partitioning between aqueous NaHCO3 and ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to give a gum. ES MS (M+1)=277.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[N:16]=[C:17]([C:20]2[S:21][C:22]3[C:28]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[C:27]([C@H:36]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]([CH3:47])=[CH:25][C:23]=3[N:24]=2)[S:18][CH:19]=1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.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.O>[C:43]([O:42][C@@H:36]([C:27]1[C:26]([CH3:47])=[CH:25][C:23]2[N:24]=[C:20]([C:17]3[S:18][CH:19]=[C:15]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:2]([CH3:1])[N:3]=[CH:4]5)[N:16]=3)[S:21][C:22]=2[C:28]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38])([CH3:44])([CH3:45])[CH3:46]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(Br)cs3)sc2c1-c1ccc(Cl)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3nc(-c4ccc5c(cnn5C)c4)cs3)sc2c1-c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
In a 10 mL reaction vial, 1-methyl-1H-indazol-5-ylboronic acid (31 mg, 0.173 mmol) and (S)-ethyl 2-(2-(4-bromothiazol-2-yl)-7-(4chlorophenyl)-5methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.173 mmol) were mixed with dioxane (5 mL) and water (1 mL). The resulting reaction mixture was bubbled with argon for 5 min. Then potassium carbonate (60 mg, 0.432 mmol) and Pd(PPh3)4 were added sequentially. The reaction mixture was sealed and heated in oil bath at 95° C. for 2 h. The brown mixture was then diluted with EtOAc (20 mL), filtered and the filtrate was concentrated and purified on silica gel column with 0-30% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C33H31ClN4O3S2: 631.2, 633.2, 632.2 (M+H+); found: 631.0, 633.1, 632.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:14]([O-])=O)=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6].[H][H]>C(O)C.[Pd]>[NH2:14][C:3]1[C:2]([CH3:1])=[CH:13][CH:12]=[CH:11][C:4]=1[C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[O:6]
Reactant: [H][H]
Reactant: Cc1cccc(C(=O)NC(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(C(=O)NC(C)C)c1N
Yield: 96.5 %

Procedure:
The 2-nitrobenzamide of Step A (1.70 g, 7.6 mmol) was hydrogenated over 5% Pd/C in 40 mL of ethanol at 50 psi. When the uptake of hydrogen ceased the reaction was filtered through celite and the celite was washed with ether. The filtrate was evaporated under reduced pressure to afford 1.41 g of the title compound as a solid melting at 149-151° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:14]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(OCC)C>[CH2:14]([N:21]1[CH:22]2[CH2:28][CH2:27][CH:26]1[CH2:25][C:24]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)([OH:29])[CH2:23]2)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: OC1(c2ccc(F)cc2)CC2CCC(C1)N2Cc1ccccc1
Temperature: -35 °C

Procedure:
1-Bromo-4-fluoro-benzene (22.7 g) dissolved in diethylether (100 mL) is added to a solution of n-butyllithium (1.7 mol/L in pentane, 86.8 mL) in diethylether (200 mL) cooled to −35° C. The combined solutions are stirred at −35 to −40° C. for 1 h, before 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (22.5 g) dissolved in diethylether (150 mL) is added quickly. The solution is warmed to −10° C. within 1 h and then the reaction is quenched by the addition of aqueous NH4Cl solution. The resulting mixture is extracted with ethyl acetate, the combined extracts are washed with brine, and 4 M hydrochloric acid is added to the organic phase. The organic phase is separated from the aqueous phase and an oily precipitation formed after the addition. The oily and aqueous phase are combined and basified with 4 M aqueous NaOH solution and the resulting mixture is extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and the solvent is evaporated to give the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][NH2:28])=[CH:23][CH:22]=1.CC([O-])=O.[Na+]>CCO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:4]([C:1](=[N:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[CH3:2])[CH:9]=1
Reactant: NOc1ccc(F)cc1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 96.1 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (350 mg, 1.16 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (190 mg, 1.16 mmol) and anhydrous NaOAc (104 mg, 1.27 mmol) in EtOH (16 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum, the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2) and the solvent removed under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:4) to afford N-{4-chloro-2-[1-(4-fluorophenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 129 (458 mg, 96%), as a pale yellow solid. M.p. 71-73° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.23, br s, 1H; 7.69, d, J=9.0 Hz, 1H; 7.59, d, J=2.4 Hz, 1H; 7.40, dd, J=2.4 and 9.0 Hz, 1H; 7.18-7.03, m, 4H; 2.55, s, 3H.
Reaction SMILES: [CH:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2)=[CH2:2].C(=O)([O-])[O-:14].[Na+].[Na+]>ClCCl>[O:14]1[CH2:2][CH:1]1[C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: C=CC12CC3CC(CC(C3)C1)C2
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C1C2CC3CC1CC(C1CO1)(C2)C3
Yield: 123.4 %

Procedure:
To a mixture of 16.2 g of 1-vinyladamantane, 120 ml of dichloromethane, and 5.3 g of sodium carbonate, 36.9 g of 70-m-chloroperbenzoic acid was added over 30 minutes on a water bath. The resultant mixture was stirred at room temperature for further 2 hours, was washed with a 5% sodium sulfite aqueous solution and saturated aqueous sodium bicarbonate, and the obtained organic layer was then concentrated. The residue was purified by column chromatography on a silica gel (SiO2400 g, developing solution: hexane/ethyl acetate=15/1) to give 11.0 g of 1-(1,2-epoxyethyl)adamantane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:55])[CH2:7][N:8]([CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:45])[C:28]3[CH:27]=[C:26]([F:29])[C:25]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][C:18]([F:44])=[C:19]([O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:20]=3)=[CH:11][C:10]=1[OH:46])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61]>CN(C=O)C>[C:51]([O:50][C:48](=[O:49])[CH2:47][N:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:45])[C:28]3[CH:27]=[C:26]([F:29])[C:25]([O:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:24][C:23]=3[O:22][C:21]3[C:16]2=[CH:17][C:18]([F:44])=[C:19]([O:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH3:43])[CH:20]=3)=[CH:11][C:10]=1[O:46][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(O)c1)c1cc(F)c(OCOCCOC)cc1O2
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCC(=O)OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
A solution of 15 (497 mg, 0.64 mmol) in DMF (10 mL) was treated with sodium hydride (18.5 mg, 0.77 mmol) at 0° C. under an Ar atmosphere. After stirring at 0° C. for 30 min, benzyl 2-bromoacetate (0.15 mL, 0.96 mmol) was added. The mixture was stirred at 0° C. for another 30 min and then warmed to room temperature overnight. The solvent was evaporated to dryness and extracted with EtOAc/H2O. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 40% EtOAc in Hexane (with 0.1% Et3N) to yield 453 mg (76%) of 16 as a light yellow oil. Rf=0.28 (in 40% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 7.32 (m, 5H), 6.96 (d, 2H, J=7.2 Hz), 6.86 (d, 1H, J=8.4 Hz), 6.72 (dd, 1H, J=7.8 and 1.5 Hz), 6.59 (m, 3H), 5.28 (s, 4H), 5.15 (s, 2H), 4.89 (s, 1H), 4.64 (s, 2H), 4.01 (s, 4H), 3.86 (m, 4H), 3.58 (m, 4H), 3.39 (s, 6H), 1.39 (s, 18H); 13C NMR (75 MHz, CDCl3) 6170.3, 168.8, 150.7, 149.9, 147.5, 146.6, 146.5, 144.4, 144.3, 139.1, 138.9, 135.3, 128.6, 128.4, 128.3, 122.9, 120.0, 117.0, 116.9, 116.2, 116.1, 115.8, 105.9, 94.7, 81.2, 71.5, 68.1, 66.7, 66.6, 59.0, 54.5, 42.6, 28.0; 19F NMR (282 MHz, CDCl3) δ −140.2 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (M−17) 909.4, Found 910.1.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]([CH2:38][CH2:39][C:40]([OH:42])=O)[CH:31]=[C:30]2[C:43]1[NH:51][C:46]2=[N:47][CH:48]=[CH:49][CH:50]=[C:45]2[CH:44]=1.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]([CH2:38][CH2:39][C:40]([N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1)=[O:42])[CH:31]=[C:30]2[C:43]1[NH:51][C:46]2=[N:47][CH:48]=[CH:49][CH:50]=[C:45]2[CH:44]=1
Reactant: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCC(=O)O)c2cc1OC
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CCC(=O)N3CCOCC3)c2cc1OC
Reaction time: 1 h

Procedure:
0.036 g of O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate is added to a solution of 0.035 g of 3-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]propionic acid in 3 ml of dimethylformamide, under an inert argon atmosphere at a temperature in the region of 20° C. The reaction medium is agitated at this temperature for 1 hour. 0.01 ml of morpholine and then 0.017 ml of diisopropylethylamine are added. After agitation at the same temperature for 3 hours, 10 ml of water and 10 ml of ethyl acetate are added. After separation by settling out, the organic phase is dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified by flash-pack chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents). The fractions containing the product are concentrated under reduced pressure. 0.025 g of 3-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]-1-morpholin-4-ylpropan-1-one is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[CH2:5]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1=[S:14])[CH:6]=[CH2:7].N1CCOCC1>C(OCC)(=O)C>[CH2:5]([N:8]1[C:12](=[O:13])[C:11](=[C:2]([CH3:4])[CH3:1])[NH:10][C:9]1=[S:14])[CH:6]=[CH2:7]
Reactant: CC(C)=O
Reactant: C=CCN1C(=O)CNC1=S
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Product: C=CCN1C(=O)C(=C(C)C)NC1=S

Procedure:
A flask equipped with a reflux condenser and nitrogen atmosphere was charged with acetone (20 mL), 3-allylthiohydantoin (2.0 g, 0.013 mol), and morpholine (1.1 g, 0.013 mol). The mixture was heated at reflux for 80 min and, after cooling, was diluted with 40 mL of ethyl acetate. The resulting solution was washed with 2×20 mL 1.2 M HCl, 20 mL of water, and 20 mL of saturated aqueous NaCl. The solution was then filtered through 1 PS paper and concentrated to dryness at aspirator pressure and then high vacuum. The off-white crystalline residue weighed 2.3 g (92%). No other components were detectable by HPLC at 215 nm. NMR (CDCl3) δ 9.9 (bs, 1H), 5.1-6.1 (m, 3H), 4.6 (d, 2H), 2.3 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[CH:12][CH:11]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CC(C)CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)CCOCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
Sodium hydride (purity: 55%, 700 mg) and 1-bromo-3-methylbutane (2.56 mL) were added to a solution of 4-bromobenzylalcohol (2.0 g) in N,N-dimethylformamide (40 mL) under ice-cooling, and the mixture was stirred at room temperature for five hours. A saturated ammonium chloride solution was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→50:1→30:1) to give the title compound (2.31 g, 85%).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH2:7]C.[CH2:9]([N:16]1[CH2:21][CH2:20][C:19]([N:24]([CH3:26])[CH3:25])([C:22]#N)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH4+].[Cl-]>CCOCC.C1COCC1.CO.C(Cl)(Cl)Cl>[CH2:9]([N:16]1[CH2:17][CH2:18][C:19]([CH2:22][CH2:5][CH2:6][CH3:7])([N:24]([CH3:25])[CH3:26])[CH2:20][CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCBr
Reactant: CN(C)C1(C#N)CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCCCC1(N(C)C)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To a mixture of 17.7 g (6 equiv.) of magnesium and 50 ml of dry ether there were added first a small amount of iodine and then, over a period of 1 hour, 100 g (6 equiv.) of bromobutane dissolved in 100 ml of dry ether. This reaction mixture was stirred for 1 hour at room temperature. The Grignard reagent prepared above was added over a period of 20 minutes to a solution of 30 g (1 equiv.) of 1-benzyl-4-(dimethylamino)piperidine-4-carbonitrile dissolved in 210 ml of dry THF, and the resulting reaction mixture was then stirred for 12 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (10% MeOH/CHCl3). When the reaction was complete, the reaction solution was cooled to 0° C.; saturated NH4Cl solution was added, the mixture was filtered over Celite and extracted with ethyl acetate (3×200 ml), and the combined organic phases were dried over Na2SO4. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (aluminium oxide neutral; hexane). 18.2 g (53%) of product were obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: C1COCCN1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCOCC2)cc1
Yield: 47.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(morpholinomethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), morpholine (0.081 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.038 g (47%) of the title compound as a white solid.
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1Cl)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10].[N:26]1([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(N(C)C)=O>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1[N:29]1[CH2:30][CH2:31][N:26]([C:32]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:33])[CH2:27][CH2:28]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(Cl)c2cccnc2[nH]c1=O
Reactant: O=C(c1cccs1)N1CCNCC1
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2[nH]c1=O
Temperature: 110 °C
Yield: 39.6 %

Procedure:
DABCO (0.57 g, 5.14 mmol) was added to a solution of 4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (15) (0.65 g, 2.57 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (0.60 g, 3.08 mmol) in dimethylacetamide at room temperature. The solution was heated overnight at 110° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried to yield 420 mg (39%) of 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (16) as white solids. MP: 239° C.; 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.0 Hz, 3H), 3.13 (m, 4H), 3.87 (m, 4H), 4.30 (q, J=7.0 Hz, 2H), 7.15 (dd, J=3.5, 4.8 Hz, 1H), 7.40 (dd, J=4.8, 8.0 Hz, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.24 (dd, J=1.5, 7.5 Hz, 1H), 8.56 (dd, J=1.5, 7.5 Hz, 1H) 12.25 (s, 1H); EIMS: 413 (M+1).