Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11]O.[Cl-].[Na+].[BrH:15]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][Br:15]
Reactant: Br
Reactant: COc1cccc(OC)c1CO
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1cccc(OC)c1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After a mixture of 5.7 grams (0.034 mole) of 2,6-dimethoxyphenylmethanol in 40 mL of concentrated hydrobromic acid was stirred at ambient temperature for about one hour, the reaction mixture was taken up in diethyl ether. Solid sodium chloride was added to the mixture to obtain a phase separation. The organic layer was separated and concentrated under reduced pressure, yielding about 4.7 grams of 2,6-dimethoxyphenylmethyl bromide. This compound was used immediately in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[H-].[Na+].Cl[CH2:20][C:21](=O)[CH3:22]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12]2[C:21]([CH3:22])=[CH:20][O:15][C:13]=2[CH2:14]1
Reactant: CC(=O)CCl
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1C1CC(=O)c2c(C)coc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2-methoxyphenyl)cyclohexane-1,3-dione (mp144-145° C.; 1.09 g) in DMF (15 ml) was added 60% sodium hydride (0.22 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added chloroacetone (0.45 ml), and the mixture was stirred at 150° C. overnight (14 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2-methoxyphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.20 g).
Reaction SMILES: C([N+](C[CH2:15][CH2:16][CH3:17])(CCCC)CCCC)CCC.[C:18]([NH:25][C@@H:26]([CH2:30][C:31]1[CH:38]=[C:36]([OH:37])[C:34]([OH:35])=[CH:33][CH:32]=1)[C:27]([OH:29])=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CC(N(C)C)=O.C(OC)(C)(C)C>[OH:37][C:36]1[CH:38]=[C:31]([CH2:30][C@H:26]([NH:25][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:27]([O:29][CH2:17][C@H:16]([O:29][C:27](=[O:28])[CH3:26])[CH3:15])=[O:28])[CH:32]=[CH:33][C:34]=1[OH:35]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Solvent: COC(C)(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)O[C@H](C)COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Yield: 7.3 %

Procedure:
A solution of Boc-L-Dopa tetrabutyl ammonium salt (5.6 g, 104.0 mmol) and crude (1R)-2-bromomethylethyl acetate (46) (2.6 g, 11.6 mmol) in 50-mL dimethylacetamide was stirred overnight at 65° C. The reaction mixture was diluted with methyl tert-butyl ether (500 mL), washed with saturated aqueous NaHCO3 (3×250 mL), brined, dried over Na2SO4, and concentrated to an oil. Chromatography eluting with EtOAc/hexane (2:3) gave 1.5 g (36.7% yield) of the title compound (47). 1H NMR (400 MHz, CDCl3): δ 1.23 (d, J=6.8 Hz, 3H), 1.43 (s, 9H), 2.10 (s, 3H), 2.98 (m, 2H), 4.02 (dd, J=7.2, 6.8 Hz, 1H), 4.30 (dd, J=6.8, 2.8 Hz, 1H), 4.54 (m, 1H), 4.97 (d, 1H, NH), 5.10 (m, 1H). MS (ESI) m/z 398.1 (M+H)+ and 396.1 (M−H)−.
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]#[N:10])=[N:5][C:4]=1[N+:11]([O-:13])=[O:12].C(OCC)(=[O:16])C>OS(O)(=O)=O.O>[Br:1][CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]([NH2:10])=[O:16])=[N:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOC(C)=O
Reactant: Cn1c(C#N)nc([N+](=O)[O-])c1CBr
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(N)=O)nc([N+](=O)[O-])c1CBr
Yield: 84 %

Procedure:
A solution of 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole-2-carbonitrile (264) (70 mg, 0.29 mmol) in 90% H2SO4 (1 mL) was heated at 65-70° C. for 1 hour, before being diluted with water and given a standard ethyl acetate workup to give 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole-2-carboxamide (266) (67 mg, 84%), as white solid, m.p. 220-222° C. 1H NMR [(CD3)2SO] δ 8.18 (s, 1H), 7.87 (s, 1H), 5.05 (s, 2H), 4.02 (s, 3H). HR-MS (APC+, 79/81Br) found: m/z 262.9770/264.9752 (M+1), calcd. for C6H879/81BrN4O3+: 262.9774/264.9754.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:12])=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2].[H-].[Na+].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl>C1COCC1>[CH2:1]([C:3]1[C:4]([O:12][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:5][C:6]([CH3:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2]
Reactant: CCc1cc(C=O)c(C)cc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cc(C=O)c(C)cc1OCOCCOC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
A solution of 5-ethyl-4-hydroxy-2-methyl-benzaldehyde (0.9 g, 5.5 mmol) dissolved in THF (10 mL) was added to a cooled 0° C. suspension of NaH (0.29 g, 7.2 mmol, 60% dispersion in mineral oil) in THF (5 ml). After the addition was complete the reaction mixture was warmed up to room temperature and stirred for 30 mins. 2-Methoxyethoxymethyl chloride (0.82 mL, 7.1 mmol) was added and the reaction was stirred for 4 hours. The reaction mixture was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (10% to 20% EtOAc in hexanes) gave the title compound as a clear oil (0.89 g, 65%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.3 Hz, 3 H), 2.63 (m, 5 H), 3.39 (s, 3 H), 3.57 (m, 2 H), 3.84 (m, 2 H), 5.37 (s, 2 H), 6.95 (s, 1 H), 7.62 (s, 1 H), 10.15 (s, 1 H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.CON(C)[C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>C1COCC1>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:35])[CH:17]=[CH:16][N:15]=1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccnc(F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a stirring solution of diisopropylamine (17.69 mL, 0.135 mol) in anhydrous THF (200 mL) at −78° C., under argon, was added n-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mol), followed after 5 min. by a solution of 2-fluoro-4-methylpyridine (10 g, 0.090 mol) in anhydrous THF (20 mL). After stirring for 15 min. at −78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mol) in anhydrous THF (10 mL) was added to the reaction mixture which was then stirred for 5 min., and allowed to warm to 0° C. The reaction was quenched with water (400 mL), and extracted with ethyl acetate (3×200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel (1 kg), eluting with 20% ethyl acetate in hexane to give 21.6 g of the title compound.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[N:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-])=O)=[CH:8][CH:7]=1.[OH-].[NH4+]>[Fe].O>[Cl:5][C:6]1[N:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[CH:8][CH:7]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Cl)nc1N
Yield: 86 %

Procedure:
4.484 g of iron powder is added to a solution containing 78 ml of acetic acid and 3.415 g of 6-chloro-3-nitro-2-pyridinamine. The reaction medium is heated at 60° C.-70° C. for 2 hours 45 minutes, then left to return to ambient temperature. After pouring into 200 ml of water, 200 ml of ammonium hydroxide is added until pH9 is achieved, followed by extraction with ethyl acetate, drying, filtering and concentrating. 3.14 g of crude product is obtained which is chromatographed on silica eluting with an ethyl acetate triethylamine mixture 95/5. 2.43 g of sought product is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]([CH2:25][CH2:26][O:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[S:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=2[CH3:24])(=[O:14])=[O:13])[CH2:10][CH2:9]1>ClCCl>[CH:8]1([N:11]([CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])[S:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=2[CH3:24])(=[O:14])=[O:13])[CH2:9][CH2:10]1
Reactant: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)OC(C)(C)C)C2CC2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N(CCOCC(=O)O)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (13 eq) was added dropwise to a solution of tert-butyl 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)ethoxy)acetate in dichloromethane (10 ml/mmol) at 0° C. and the resulting solution was stirred for 2 h at 25° C. The mixture was concentrated completely and traces of trifluoroacetic acid removed under high vacuum. The crude product was used directly in the next stage with no further processing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:5]=1[NH2:11].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)#[CH:14]>C1COCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:5]=1[NH2:11]
Reactant: C#Cc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccc(I)c1N
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C#Cc2ccc(-c3ccccc3)cc2)c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
To a solution of 2-amino-3-iodo-benzoic acid methyl ester (500 mg, 1.8 mmol), 4-ethynyl-biphenyl (416 mg, 2.3 mmol) in THF (20 mL), CuI (17 mg, 0.09 mmol), bis-(triphenylphosphine)-palladium (II)-chloride (64 mg, 0.09 mmol) and TEA (0.75 mL, 5.4 mmol) were added. This mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was filtered through celite, and the collected filtrate was diluted with ethyl acetate (30 mL), washed with water (2×20 mL) and the combined organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure to obtain brown mass which was purified by column chromatography using 5% ethyl acetate in hexane as an eluent to obtain 450 mg of 2-amino-3-biphenyl-4-ylethynyl-benzoic acid methyl ester as a pale yellow coloured solid (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24].[CH2:27]([N:29]1[C:34](=[O:35])[N:33]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[C:32](=[O:43])[C:31]([C:44](O)=[O:45])=[N:30]1)[CH3:28]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:44]([C:31]2[C:32](=[O:43])[N:33]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:34](=[O:35])[N:29]([CH2:27][CH3:28])[N:30]=2)=[O:45])=[CH:18][C:17]=1[C:23]([F:25])([F:26])[F:24]
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C(F)(F)F)c2cc1OC
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C(F)(F)F)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,7-dimethoxy-quinolin-4-yloxy)-3-trifluoromethyl-phenylamine and 2-ethyl-4-(4-fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid using the procedure for example 1. mp=148-50° C.; LCMS m/z=626 (M+1); 1H NMR (DMSO): 10.95 (s, 1H), 8.52 (d, 1H), 8.32 (s, 1H), 8.04 (m, 1H), 7.35-7.49 (m, 8H), 6.60 (m, 1H), 4.08 (q, 2H, J=7Hz), 3.97 (s, 3H), 3.89 (s, 3H), 1.35 (t, 3H, J=7Hz).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:18]([O:22][C:23](=[O:26])[CH2:24][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=2)[CH:11]=[CH:12]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21

Procedure:
In analogy to the procedure described in example 1 b], 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole was reacted with bromo-acetic acid tert-butyl ester in the presence of cesium carbonate to obtain [6-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: S1C=CC=C1[CH2:6][C:7](O)=[O:8].[N:10]([C@@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH3:25])[CH2:14]1)=[N+]=[N-]>>[C:7]([NH:10][C@@H:13]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH3:25])[CH2:14]1)(=[O:8])[CH3:6]
Reactant: C[C@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reactant: O=C(O)Cc1cccs1
Product: CC(=O)N[C@H]1C[C@H](C)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
Under a nitrogen atmosphere, 0.27 mL (280 mg, 3.7 mmol) of thiolacetic acid was added to 210 mg (0.93 mmol) of (2S,4S)-4-azido-1-t-butoxycarbonyl-2-methylpyrrolidine. The reaction mixture was stirred at room temperature for approximately four hours and concentrated with a rotary evaporator. The resulting oil was subjected to flash column chromatography using 1:1 ethyl acetate/hexane followed by ethyl acetate as eluant to obtain 190 mg of (2S,4S)-4-acetamido-1-t-butoxycarbonyl-2-methylpyrrolidine (84% yield) as a yellow oil which solidified on standing. Recrystallization of a small sample from hexanes provided a white solid, mp 108-110 degrees C. The material thus obtained was found to be identical to the material obtained by a two-step procedure that provides for the hydrogenation of (2S,4S)-4-azido-1-t-butoxycarbonyl-2-methylpyrrolidine with hydrogen and Pd/C followed by a separate acetylation step utilizing acetic anhydride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.O.[OH-].[Li+:22]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O-:12])=[O:11])=[CH:7][CH:8]=1.[Li+:22]
Reactant: COC(=O)C(c1ccc(OC)cc1)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C(=O)[O-])N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Methyl 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (400 mg, 1.52 mmol) was dissolved in THF/water (12 ml/4 ml). Lithium hydroxide hydrate (127 mg, 3.04 mmol) was added and the solution was stirred at room temperature for 8 hours. Then a second portion of lithium hydroxide hydrate (63.7 mg, 1.52 mmol) was added and the mixture was stirred at 40° C. for 16 hours, then at 50° C. for 7 hours. The solvents were evaporated, the residue was taken up with Et2O and the insoluble were filtered off. The clear solution was evaporated to obtain lithium 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (384 mg, 99% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[F:14][C:15]([F:35])([F:34])[C:16]1[C:25]([C:26](Cl)=[O:27])=[C:24]([OH:29])[C:23]2[C:18](=[CH:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][CH:22]=2)[N:17]=1>C(OCC)(=O)C>[F:34][C:15]([F:14])([F:35])[C:16]1[C:25]([C:26]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:27])=[C:24]([OH:29])[C:23]2[C:18](=[CH:19][C:20]([C:30]([F:33])([F:31])[F:32])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Nc1nccs1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)c1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc2c1O
Yield: 37.6 %

Procedure:
A solution of 5.37 g of 2-amino-thiazole, 16.27 g of triethylamine and 214 ml of ethyl acetate were added with stirring over 25 minutes at 7° C. to a solution of 18.62 g of the product of Step F in 320 ml of ethyl acetate, and after the temperature returned to room temperature, the mixture was refluxed for one hour and cooled. The mixture was vacuum filtered and the filtrate was washed with water, dried and evaporated to dryness under reduced pressure at 40° C. The 19.22 gm of residue which was the triethylamine salt of the acid was taken up in 180 ml of 2 N sodium hydroxide solution and the mixture was refluxed for 3-4 minutes and was cooled. The mixture was vacuum filtered and the pH of the filtrate was adjusted to 1 by addition of 20% hydrochloric acid. The mixture was vacuum filtered and the recovered product was crystallized from acetic acid to obtain 8.22 g of 2,7-bis-(trifluoromethyl)-4-hydroxy-N-(2-thiazolyl)-3-quinolinecarboxamide melting at 270° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH2:26]([NH2:30])[CH:27]([NH2:29])[CH3:28]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:26][CH:27]([NH2:29])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(N)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)N)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and propane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 7.91 (dd, J=7.83, 1.01 Hz, 1 H), 7.83 (d, J=7.33 Hz, 1 H), 7.69 (s, 1 H), 7.58 (d, J=1.26 Hz, 1 H), 7.44 (d, J=8.59 Hz, 1 H), 7.38-7.31 (m, 1 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13 (brs, 2 H), 3.56 (t, J=4.67 Hz, 2 H), 3.52-3.41 (m, 4 H), 3.37 (s, 1 H), 2.41 (s, 3 H), 1.38 (d, J=6.06 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]#[CH:30].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:30][C:29]#[CH:28])=[CH:4][C:3]=1[C:10]1[C:11](=[O:21])[N:12]([CH3:20])[C:13]([C:16]([F:18])([F:17])[F:19])=[CH:14][N:15]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
First, 150 mg of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357) was dissolved in 0.90 ml of N,N-dimethylformamide, to which 92 mg of potassium carbonate and 58 mg of propargyl bromide were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 160 mg (yield, 96%) of 3-[2,4-dichloro-5-(propargyloxy)phenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-370; m.p., 123.7° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-:18])[CH:15]=[C:16](F)[C:11]2=[N:10]1.[CH3:20][O-:21].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-:18])[CH:15]=[C:16]([O:21][CH3:20])[C:11]2=[N:10]1
Reactant: C[O-]
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Agent: [K+]
Solvent: CO
Product: COc1c[n+]([O-])cc2cn(-c3c(Cl)cccc3Cl)nc12
Yield: 85.1 %

Procedure:
A suspension of 2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine-5-oxide (1.5 g, 5 mmol) and potassium methoxide (525 mg, 7.5 mmol) in methanol (10 mL) was sealed in a microwave vial, purged with nitrogen and irradiated at 150° C. for 30 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with ether to afford the title compound as a beige solid (1.32 g, 85% yield). LCMS (Method D): RT=2.31 min, m/z: 310 [M+H+].
Reaction SMILES: Br.[CH2:2]([N:19]([CH2:21][CH:22]([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])C>>[CH2:2]([NH:19][CH2:21][CH:22]([OH:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:10][CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCC(O)CN(C)CCCCCCN(C)CC(O)CCCCCC
Agent: Br
Product: CCCCCCC(O)CNCCCCCCNCC(O)CCCCCC

Procedure:
In a manner similar to that of Example 22, methylation of N,N'-(1,6-hexylene)-bis[2-hydroxyoctylamine] (35 g.) and treatment of the resulting product (b.p. 177°-182° C./1 mm.) with hydrogen bromide gave N,N'-(1,6-hexylene)-bis[N-methyl-2- hydroxyoctylamine] (I: R= CH3 (CH2)5, R' = CH3, X= (CH2)6, Z= H) dihydrobromide (19.1 g., m.p. 167.0°-158.8° C.).