Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:14])[CH:3]=1.C(N(CC)CCNC(C1C=C(I)C=C2C=1N=CC=C2[F:41])=O)C>>[CH2:19]([N:18]([CH2:21][CH3:22])[CH2:17][CH2:16][NH:15][C:13]([C:4]1[CH:3]=[C:2]([F:41])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=1)=[O:14])[CH3:20]
Reactant: CCN(CC)CCNC(=O)c1cc(I)cc2c(F)ccnc12
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c2cc(I)ccc2n1
Product: CCN(CC)CCNC(=O)c1cc(F)c2cc(I)ccc2n1
Yield: 48 %

Procedure:
This compound was prepared, starting from compound 105 (1.00 g, 2.32 mmol), according to the procedure developed for compound 102. Reaction time at 200° C.: 2 h, reaction time at 140° C.: 5 h; the purification was performed using column chromagraphie (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 106 (458 mg, 1.10 mmol) as a yellow solid. Yield 48%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.42; mp 58-60° C.; IR (KBr) ν 1342, 1486, 1518, 1555, 1681, 2760, 2966, 3385 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.06 (t, 6H, J=7.1 Hz), 2.56 (q, 4H, J=7.1 Hz), 2.69 (t, 2H, J=6.1 Hz), 3.54 (q, 2H, J=6.1 Hz), 7.76 (dd, 1H, 5JH-F=1.2 Hz, J=8.9 Hz), 7.96 (m, 2H), 8.42 (d, 1H, J=1.7 Hz), 8.50 (m, 1H); ESI-MS m/z 415.9 [M+H]+.
Reaction SMILES: F[C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[C:12]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])([CH3:15])([CH3:14])[CH3:13].O>CS(C)=O>[C:6]([C:5]1[CH:8]=[C:9]([CH3:10])[C:2]([NH:20][CH2:19][CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: Cc1cc(C#N)cnc1F
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)cnc1NCCC(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A mixture of 6-fluoro-5-methylnicotinonitrile (Molekula 11370, 10 g, 73.4 mmol), beta-alanine tert-butyl ester hydrochloride (16 g, 88.1 mmol) and TEA (25.6 mL, 183.6 mmol) was prepared in DMSO (100 mL) under nitrogen, and then heated at 150° C. for 4 hours. The reaction mixture was cooled to 100° C. and water (100 mL) was added drop wise. The resulting mixture was stirred at RT for 2 hours, and then the precipitate was filtered off, washed with water and dried under reduced pressure to afford the title compound as a white solid (18 g, 94%). 1H NMR (DMSO-d6, 400 MHz) δ 8.31 (1H, s), 7.56 (1H, s), 6.97 (1H, m), 3.59 (2H, m), 2.50 (2H, m), 2.02 (3H, s), 1.36 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[CH:33][C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: COc1cccc2c1CCNC2
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 23.7 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 6 (23.7% yield). 1H NMR (400 MHz, CDCl3) δ 2.79 and 3.05 (2t, 2H), 3.56 and 4.21 (2t, 2H), 3.84 and 3.89 (2s, 3H), 4.52 and 5.13 (2s, 2H), 6.41-6.43 (m, 0.3H), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 0.7H), 7.10 (m, 0.3H), 7.19-7.30 (m, 2.7H), 7.58-7.65 (m, 1H), 7.93-7.98 (m, 1.3H), 8.02-8.04 (m, 0.7H), 8.15-8.19 (m, 1H), 8.63-8.71 (m, 2H); 19F (376 MHz, CDCl3) δ −110.0; MS (ESI) m/z 414 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21](O)=[O:22].C(OC(=O)[NH:30][CH2:31][CH2:32][NH2:33])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)=[O:12])=[C:5]2[CH2:20][C:21]([NH:30][CH2:31][CH2:32][NH2:33])=[O:22]
Reactant: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCN
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)NCCN)c1

Procedure:
The title compound was prepared according to the procedure described in Example 43 from [5-chloro-2-(4-methylpyridine)-1H-indol-3-yl]acetic acid (Example 36) and N-(2-aminoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[Cl:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[CH:21]=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH2:1][CH3:3])([OH:12])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (204 mg), 2-chloro-4-fluorobenzonitrile (314 mg) and lithium carbonate (205 mg), the title compound was obtained as pale-yellow oil (yield: 262 mg, yield: 87%).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[CH:10]=[CH:9][C:8]([F:30])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)ccc1F
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To 270 mg of N,N-dimethylformamide were added 55 mg of 1-(6-amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 80 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 15 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 62 mg of the title compound as a colorless powder.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](O)=[O:40])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[S:46]([NH:50][CH2:51][CH2:52][NH2:53])(=[O:49])(=[O:48])[NH2:47].[Cl-].[NH4+]>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39](=[O:40])[NH:53][CH2:52][CH2:51][NH:50][S:46](=[O:49])(=[O:48])[NH2:47])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCCNS(N)(=O)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/C(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(/C=C/C(=O)NCCNS(N)(=O)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 26 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-2-carboxyvinyl]-2-methylphenyl}methyl)-5-isopropyl-1H-pyrazole and N-sulfamoylethylenediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and ammonium chloride, respectively.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[Si:17]([O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1cccc(CO)c1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (1.40 g) in THF (70 mL) was slowly added 1,3-phenylenedimethanol (4.84 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. tert-Butylchlorodiphenylsilane (9.63 g) was added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.97 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1.[CH3:17]S(C)=O>>[I:3][C:4]1[CH:5]=[C:6]([C@@H:10]2[CH2:17][C@H:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)/C=C/c1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)[C@@H]1C[C@H]1c1cccc(I)c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Me3SOI (379 mg, 1.72 mmol) was suspended in 3 mL of DMSO. NaH (60% suspension in mineral oil, 70 mg, 1.72 mmol) was added. Stirred at room temperature before the 3-iodoethyl cinnamate (400 mg, 1.32 mmol) from Example 1A was added. The resulting mixture was heated at 65° C. for 20 minutes before it was stirred at room temperature for 2 hours. The resulting mixture was then worked up by partitioning between diethyl ether and water. The organic layer was washed with water and brine, dried over MgSO4, filtered, evaporated to provide the titled compound (127 mg, 31.8 mmol) as a light brown oil.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][CH:11]=[N:12][O:13][CH3:14])=[O:9])=[C:6]([CH3:17])[CH:5]=1.ClN1C(=O)CCC1=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:37]([C:39]([F:42])([F:41])[F:40])=[CH2:38])[CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1.C(=O)([O-])O.[K+]>COCCOC.O>[Cl:26][C:27]1[CH:28]=[C:29]([C:37]2([C:39]([F:40])([F:41])[F:42])[O:1][N:2]=[C:3]([C:4]3[CH:16]=[CH:15][C:7]([C:8]([NH:10][CH:11]=[N:12][O:13][CH3:14])=[O:9])=[C:6]([CH3:17])[CH:5]=3)[CH2:38]2)[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1
Reactant: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: CON=CNC(=O)c1ccc(C=NO)cc1C
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CON=CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 11.7 %

Procedure:
In a solution of 81 mg of 4-hydroxyiminomethyl-N-(methoxyiminomethyl)-2-methyl benzoic acid amide in 10 ml of 1,2-dimethoxyethane, 60 mg of N-chlorosuccinimide was added, and stirred at 70° C. for 45 minutes. Then, the reaction mixture was left and cooled to room temperature, and then 60 mg of 3-chloro-5-trifluoromethyl-1-(1-trifluoromethylethenyl)benzene, 40 mg of potassium hydrogen carbonate and 3 drops of water were added, and continued to stir at room temperature further for 15 hours. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (15 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that were eluated with ethyl acetate-hexane (gradient of 1:5 to 1:3) to obtain 13 mg of the aimed product as colorless resinous substance.
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: ClCCOc1cccc2c1OCC2
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4c3OCC4)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-7-yloxy)ethylchloride (0.38 g, 1.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.93 g, 4.8 mmol), triethylamnine (0.48 g, 4.8 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.52 g (77%) of product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](F)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C(#N)C.O>[F:1][C:2]([F:20])([F:19])[C:3]([OH:18])([CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Reactant: C1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1)C(F)(F)F
Temperature: 22 °C
Yield: 82.9 %

Procedure:
A solution of 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide (0.2 g), piperidine (0.1 g), and 4-dimethylaminopyridine (5 mg) in dry acetonitrile (4 ml) was heated at reflux for 3 hours. After cooling to 22° C., the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with 1N HCl, brine, dried (Na2SO4), and the solvent evaporated under reduced pressure. Recrystallization from methyl-t-butyl ether/hexane gave the title compound as a colourless crystalline solid, (0.2 g); mp 164°-166° C.; MS: m/z=381(M+1); NMR (250 MHz, CDCl3): 1.42 (m, 2), 1.64 (m, 4), 1.77 (s,3), 2.97 (t,4), 3.79 (s,1), 7.73 (s), 8.67 (s,1). Analysis for C15H19F3N2 04S: Calculated: C, 47.36; H, 5.03; N, 7.37. Found: C, 47.38; H, 5.16; N, 7.30.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[F:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[C:3]([C:9]([N:15]2[CH2:16][CH:13]([F:12])[CH2:14]2)=[O:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: FC1CNC1
Reactant: O=C(O)c1ncc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ncc(F)cc1F)N1CC(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
To a solution of 3,5-difluoropicolinic acid (16.40 g, 103.1 mmol), 3-fluoroazetidine (8.59 g, 114 mmol) and triethylamine (27.70 ml, 199.0 mmol) in 100 mL of DMF was added HATU (45.40 g, 119.0 mmol). The mixture was stirred at room temperature for 3 hr, quenched with water, extracted with 3×EtOAc, The combined organic layer was washed with 2×H2O, dried with Na2SO4, and concentrated to provide an oil that was purified by Biotage eluting with 25-40% EtOAc in hexanes to give a yellow solid (11.49 g, 46.3% yield). 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J=2.53 Hz, 1 H) 7.31-7.46 (m, 1 H) 5.27-5.52 (m, 1 H) 4.62-4.79 (m, 1 H) 4.42-4.59 (m, 2 H) 4.22-4.38 (m, 1 H); MS for C9H7F3N2O m/z 217.00 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[Cl:26]Cl>C(O)(=O)C>[Cl:26][C:9]1[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: ClCl
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(Cl)cc2Cl)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylate (3.0 g, 7.6 mmol) in acetic acid (30 ml) at room temperature was bubbled chlorine gas for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours and the resulting solution was quenched with water (100 ml). The organic solution was extracted with diethyl ether (100 ml×2). With saturated sodium bicarbonate solution, remained acetic acid was removed and organic phase was evaporated with reduced pressure. The crude residue was purified with silica gel column (hexane/ethyl acetate=5/1) to produce title compound (3.1 g, 95% yield) as white solid.
Reaction SMILES: C1COCC1.[CH2:6]([Mg]Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(Br)CCCCCCCCC.Br[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([O:40][CH3:41])[CH:34]=[CH:33]2>O.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:6]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([O:40][CH3:41])[CH:34]=[CH:33]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCC[Mg]Br
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCBr
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCc1ccc2cc(OC)ccc2c1

Procedure:
A THF solution of n-decyl magnesium bromide (prepared as a THF (2 ml) solution of n-decyl bromide (2.2 ml, 11 mmol) and Mg (292 mg, 12 mmol)) was added to 6-bromo-2-methoxynaphthalene (2.37 g, 10 mmol) easily available from a reagent manufacturer and a THF (10 ml) solution of Ni(dppp)Cl2 (271 mg, 0.5 mmol), and the mixture was heated under reflux for 19 hours. After cooling, the mixed solution was diluted with water (10 ml), and non-reacted Mg was filtered out. The filtered solution was extracted with ether (5 ml×3). The extracted organic phases were collected (10 ml×3), and dried with MgSO4, and condensed with an evaporator. The condensed organic phase was recrystallized with hexane to obtain 6-n-decyl-2-methoxynaphthalene (compound (3)-64) as a light yellow solid.
Reaction SMILES: NOS(O)(=O)=O.[C:7]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl-].[NH4+:17].O>C(O)=O>[C:7]1(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:17]1
Reactant: O=C1CCCCCCC1
Reactant: [NH4+]
Agent: NOS(=O)(=O)O
Agent: [Cl-]
Solvent: O
Solvent: O=CO
Product: O=C1CCCCCCCN1
Temperature: 105 °C
Yield: 65 %

Procedure:
A 5 L three-neck round bottom flask was fitted with a heating mantle, an overhead mechanical stirrer, an addition funnel, and a thermometer. The reaction was performed under an argon atmosphere. Hydroxylamine-O-sulfonic acid (196.7 g, 1.74 moles, 1.10 equiv.) and formic acid (1 L) were charged into the round bottom flask and stirred to form a white slurry. A solution of cyclooctanone (200.0 g 1.58 moles, 1.0 equiv.) in formic acid (600 mL) was added dropwise to the white slurry via the addition funnel. After the addition, the addition funnel was replaced by a reflux condenser, and the reaction was heated to reflux (internal temperature about 105° C.) for 1 hour to give a brown solution. After the solution was cooled to room temperature, it was poured into a mixture of saturated aqueous ammonium chloride (1.5 L) and water (1.5 L). The aqueous mixture was extracted with chloroform (3×1200 mL). The combined chloroform layers were transferred into a beaker, and saturated sodium bicarbonate (2 L) was added slowly. The chloroform layer was then separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford a brown oil. The oil was placed in a 500 mL round bottom flask with a magnetic stirrer. The round bottom flask was placed in a silicon oil bath and was fitted with a short path vacuum distillation head equipped with a thermometer. A Cow-type receiver was connected to three 250 mL flasks. 2-Azacyclononanone (145 g, 65%, mp 64–69° C.) was obtained by vacuum distillation (fraction with head temperature range from 80 to 120° C. at pressures between 3.0 and 3.4 mmHg).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:19])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C)c(C(C)=O)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)=O)c(C)cc3OC)CC2)c1
Yield: 91 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 170 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[N:7]=1.[CH2:19]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:18][C:3]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([C:27]([NH:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:28])=[C:30]([F:38])[CH:31]=2)=[N:7][C:6]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:5][N:4]=1
Reactant: Nc1ncc(C2CCC3(CC2)OCCO3)nc1Br
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Nc1ncc(C2CCC3(CC2)OCCO3)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Yield: 46.6 %

Procedure:
To 3-bromo-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-amine (630 mg, 2.005 mmol) was added (4-(benzylcarbamoyl)-3-fluorophenyl)boronic acid (767 mg, 2.81 mmol), PdCl2(dppf)CH2Cl2 adduct (164 mg, 0.201 mmol), DME (9 mL) and then last sodium carbonate 2M (3.01 mL, 6.02 mmol). The reaction was microwaved at 115° C. for 12 min. To the reaction was added 400 mL of ethyl acetate washed with water (2×), dried with sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel chromatography using 40 gram column eluting with 20-100% ethyl acetate and heptane. The desired fractions were concentrated to constant mass to give 432 mg of the desired product as free base used as is, (47% yield). LCMS (m/z): 463.2 (MH+), 0.82 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94-8.81 (m, 1H), 7.89 (s, 1H), 7.80-7.69 (m, 1H), 7.67-7.52 (m, 2H), 7.33 (d, J=4.3 Hz, 4H), 7.27-7.18 (m, 1H), 6.09 (s, 2H), 4.49 (d, J=5.9 Hz, 2H), 3.85 (s, 4H), 2.70-2.61 (m, 1H), 1.84-1.67 (m, 6H), 1.65-1.48 (m, 2H).