Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:15]2[CH:14]=[C:13]([CH:16]([CH2:26][CH:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[C:17]([NH:19][C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)=[O:18])[CH:12]=[CH:11][C:10]=2[S:9](=[O:35])(=[O:34])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.Cl.[NH2:37][OH:38]>CO>[OH:38][N:37]=[C:30]1[CH2:31][CH2:32][CH:27]([CH2:26][CH:16]([C:13]2[CH:12]=[CH:11][C:10]3[S:9](=[O:34])(=[O:35])[C:8]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:2]([CH3:1])[C:15]=3[CH:14]=2)[C:17]([NH:19][C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)=[O:18])[CH2:28][CH2:29]1
Reactant: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCC(=O)CC3)C(=O)Nc3ccn(C)n3)cc21
Reactant: NO
Agent: Cl
Solvent: CO
Product: CN1c2ccccc2S(=O)(=O)c2ccc(C(CC3CCC(=NO)CC3)C(=O)Nc3ccn(C)n3)cc21

Procedure:
67 mg of 2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)-3-(4-oxocyclohexyl)propionamide and 14 mg of hydroxylamine hydrochloride are dissolved in 13 ml of methanol and heated at the boil under reflux for three hours. The methanol is then removed under reduced pressure, and the resulting residue is taken up in a mixture of 20 ml of ethyl acetate and 10 ml of water. The organic phase is washed twice with in each case 10 ml of water, dried over MgSO4, concentrated under reduced pressure and then lyophilized. This gives 49 mg of 3-(4-hydroxyiminocyclohexyl)-2-(10-methyl-5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(1-methyl-1H-pyrazol-3-yl)propionamide.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[N:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(N)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(CO)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Amino-pyridine-2-carboxylic acid methyl ester (6-1, Kelly, T. R.; Lang, F. J. Org. Chem. 1996, 61, 4623-4633) 2.37 g (15.6 mmol) was dissolved in 16 mL anhydrous THF and the resulting solution was cooled to 0° C. LAH (15.6 mL of a 1M solution) was added slowly. An additional 8 mL of THF was added during the addition of LAH to keep the mixture from becoming too viscous. After 3 h the reaction was quenched by the sequential addition of 0.59 mL water, 0.59 mL 15% NaOH (aq), and 1.77 mL water. After stirring for 1 h the mixture was filtered through a plug of celite, washing with THF. The filtrate was concentrated to afford 1.6 g of a yellow oil. Purification by flash column chromatography (eluting with a gradient of CH2Cl2 to 90:10 CH2Cl2/MeOH) afforded the titled compound as a white solid. 1H NMR(CDCl3): δ 7.42 (t, 1H, J=7.6 Hz), 6.60 (d, 1H, J=7.7 Hz), 6.41 (d, 1H, J=7.5 Hz), 4.59 (s, 2H), 4.52 (bs, 2H).
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:33][CH:34]=[C:35]([CH3:37])[CH3:36]>C1COCC1>[CH3:36][C:35]([CH3:37])=[CH:34][CH2:33][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:2]1
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC=C(C)C)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (120.0 g, 0.412 mol) in THF (400 ml) cooled at −78° C. was added dropwise 270 mL of sodium bis(trimethylsilyl)amide solution (1M solution in THF from Aldrich, cat #:245585) over 2 h. The mixture was stirred at −78° C. for additional 1 h. Then 1-bromo-3-methylbut-2-ene (Aldrich cat #: 249904) (71 mL, 0.62 mol) was added slowly over 1 h. The mixture was stirred at −78° C. for 30 min, and allowed to warm to r.t. and stirred for an additional 3 h. The reaction mixture was quenched with 1N HCl aq. solution. Most of THF was removed under reduced pressure. The residue was extracted with ethyl acetate. The combined extracts were washed with sat. aq. NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on a silica gel column with 10˜20% ethyl acetate in hexane to yield the desired product (140 g, 94%). LC/MS: m/e=332.2 (M+H)+.
Reaction SMILES: CC1C=CC(S(N[C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[CH2:27]([O:34][C:35]([N:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](=[O:47])[CH2:39][CH2:38]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[K+].Cl>C(O)(C)C>[CH2:27]([O:34][C:35]([N:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:40]([OH:47])[CH2:39][CH2:38]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CC[C@H](O)c2ccccc21
Temperature: 80 °C
Reaction time: 23 h
Yield: 95.4 %

Procedure:
A mixture of 30.6 mg of [RuI2(p-cymene)]2, 73.3 mg of (S,S)-TsDPEN and 25 mL of isopropyl alcohol was heated in a nitrogen stream at 80° C. for 1 hour. The reaction solution was cooled to 25° C., and then to the reaction solution were added 281 mg of 1-benzyloxycarbonyl-4-oxo-1,2,3,4-tetrahydroquinoline, 28.1 mg of potassium hydroxide and 10 mL of isopropyl alcohol in series. The mixture was stirred at 25° C. for 23 hours. To the reaction solution was added 10 mL of 0.1N hydrochloric acid and the mixture was stirred, and then concentrated under reduced pressure, and to the residue was added 10 mL of ethyl acetate. The organic layer was separated, dried over magnesium sulfate, and then filtered. The filtrate was concentrated, and the resulting residue was purified by column chromatography on silica gel (solvent; hexan/ethyl acetate=4/1) to give 270 mg of (4S)-1-benzyloxycarbonyl-4-hydroxy-1,2,3,4-tetrahydroquinoline (optical purity: 99% ee, yield: 95%).
Reaction SMILES: Br.[C:2]([C:5]1[CH:6]=[CH:7][C:8](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:14]/[C@@H:15]2[N:19](CC3C=CC(OC)=CC=3OC)[C:18](=[O:31])[CH2:17][CH2:16]2)=[N:9][C:10]=1[O:11]C)(=[O:4])[CH3:3].O>O1CCOCC1>[C:2]([C:5]1[C:10](=[O:11])[NH:9][C:8](/[C:13](/[C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:14]/[C@H:15]2[CH2:16][CH2:17][C:18](=[O:31])[NH:19]2)=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)=O)c(OC)n2)c(OC)c1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
48% hydrobromic acid (3.0 mL) was added to a solution of (5R)-5-[(E)-2-(5-acetyl-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (300 mg) in 1,4-dioxane (3.0 mL), and the mixture was stirred at 65° C. for 0.5 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Anisole (2 mL) was added to a solution of the residue (278 mg) in trifluoroacetic acid (1 mL), and the mixture was stirred at 80° C. for 4.5 hours. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give the title compound as a yellow powder (103 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13].Cl>C1COCC1>[C:1]1([CH2:7][CH2:8][S:9]([NH2:13])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)CCc1ccccc1
Reactant: N
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-phenylethanesulfonyl chloride (40.94 g) in THF (250 ml) was cooled to −20° C. before it was treated with sat. aq. ammonia (50 ml). The brown suspension was stirred at rt for 16 h. The mixture was neutralised with aq. HCl and the organic solvent was evaporated. The remaining suspension was diluted with water and extracted four times with EA. The organic layers were combined and evaporated to give 2-phenyl-ethanesulfonic acid amide (33.06 g) as orange solid. 1H-NMR(300 MHz, CDCl3): 3.15–3.21(m, 2H), 3.38–3.45(m, 2H), 4.59(s br, 2H), 7.21–7.37(m, 5H).
Reaction SMILES: [C:1]1([CH:7]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)[CH2:8][S:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=C([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)CBr>CO>[F:32][C:33]([F:46])([F:47])[C:34]1[CH:35]=[C:11]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:10][S:9][CH2:8][CH:7]([N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH2:14]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)SCC(c1ccccc1)N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCN(C(CSCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 114.1 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer 2.76 g (6.6 mmoles) of thioacetate 83 and 250 ml of degassed methyl alcohol are introduced. The mixture is cooled to 0° C. and 356 mg (6.6 mmoles) of sodium methylate are added. The mixture is stirred under argon for one hour at 0° C., and 1.9 g (7.26 mmoles) of 3,5-bis-trifluoromethyl-benzyl bromide are added. The mixture is stirred for 48 hours, volatile substances are removed under reduced pressure, and 100 ml of water are added. The aqueous phase is extracted three times with methylene chloride, the combined organic phases are washed with brine and dried over magnesium sulfate. Volatile substances are removed under reduced pressure, affording 4.54 g of crude 1-[2-(3,5-bis-trifluoromethyl-benzylsulfanyl)-1-phenyl-ethyl]-4-(toluene-4-sulfonyl)-piperazine (compound 84) as a colorless oil. This oil was purified by chromatography on silica gel (eluent: methylene chloride-hexane 65/35 (v/v)), affording 3.26 g of compound 84 as a colorless oil. Yield: 82%.
Reaction SMILES: [C:1]1([C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[C:1]1([C@H:7]([CH:10]([CH3:12])[CH3:11])[CH2:8][Br:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](CO)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[C@H](CBr)c1ccccc1
Reaction time: 16 h
Yield: 51.2 %

Procedure:
A solution of 49.3 g (0.3 mol) of (S)-(+) 2-phenyl-3-methylbutanol in 400 ml of absolute methylene chloride was treated with 80 g (0.3 mol) of triphenylphosphine. Thereafter, 53.4 g (0.3 mol) of N-bromosuccinimide were added portionwise while stirring vigorously. After 16 hours, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in hexane and purified by chromatography on silica gel, to obtain in this manner 34.9 g (51%) of (S)-(-)-2-phenyl-3-methylbromobutane as a volatile oil, [α]D20 =-19.6° (c=1%. chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].CCN(CC)CC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:1]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)c(O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1=Cc2ccc(C)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 46.2 %

Procedure:
A mixture of 2-hydroxy 4-methyl benzaldehyde (50.0 g, 0.367 mole) and ethyl 4,4,4-trifluorocrotonate (308.8 g, 1.84 mole) was dissolved in anhydrous DMF (10 mL) and Et3N (20 mL) warmed to 60° C. and treated with anhydrous K2CO3 (81 g, 0.58 mole). The solution was maintained at 90° C. for 2 hours, LCMS indicated 60% converting. Additional Et3N (10 mL) was added to the mixture and the reaction was heated for another 2 hr. The reaction was cooled to room temperature, and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford a brown oil, solidify upon standing. The crystalline solid was collected and washed with hexane and dried to give 40.2 g off white crystalline solid. The mother liquor was concentrated to give crude, which was recrystalized from EtOH and water to give 48.5 g offwhite solid (totally yield 84%): LCMS m/z 287.15 (M+H). 1H NMR (CDCl3/300 MHz) 7.70 (s, 1H), 7.11 (d, 1H, J=8.1 Hz), 6.80 (m, 2H), 5.67 (q, 1H, J=6 Hz), 4.29 (in, 2H), 1.33 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11].[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:18]=1[CH2:19][SH:20].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11])/[CH:13]=[CH:14]\[CH:19]([S:20][CH:19](/[CH:14]=[CH:13]\[C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10](=[O:12])[CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:18]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[C:18]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15]
Reactant: C#Cc1ccc(OC(C)=O)c(OC)c1
Reactant: COc1cc(OC)c(OC)cc1CS
Agent: [Na]
Product: COc1cc(OC)c(C(/C=C\c2ccc(OC(C)=O)c(OC)c2)SC(/C=C\c2ccc(OC(C)=O)c(OC)c2)c2cc(OC)c(OC)cc2OC)cc1OC

Procedure:
A solution of 3-methoxy-4-acetoxyphenylacetylene (0.02 mol), 2,4,5-trimethoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to General Procedure 2 to form (Z)-3-methoxy-4-acetoxystyryl-2,4,5-trimethoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to General Procedure 2.
Reaction SMILES: [OH-:1].[Na+].O.BrBr.[Br:6][C:7]1[S:11][C:10]([C:12](=[O:14])C)=[CH:9][C:8]=1[Cl:15]>O1CCOCC1>[Br:6][C:7]1[S:11][C:10]([C:12]([OH:14])=[O:1])=[CH:9][C:8]=1[Cl:15]
Reactant: CC(=O)c1cc(Cl)c(Br)s1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)c(Br)s1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium hydroxide (50% in water) (5.82 ml, 110 mmol) was added to water (15 ml), and the mixture was chilled to 0° C. Bromine solution (1.669 ml, 32.6 mmol) was added, followed by dropwise addition of a solution of 1-(5-bromo-4-chlorothiophen-2-yl)ethanone (2.4 g, 10.02 mmol) in dioxane (18 ml). The mixture was stirred for 1.5 hours at room temperature, washed with dichloromethane, and then the aqueous phase was adjusted to pH 1 using 4N aqueous HCl. The precipitated solid was collected by filtration to give the title compound.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH3:23])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1.FC1(F)CCCN(C2CCN(C3C=CC(N)=C(OC)C=3)CC2)C1>>[F:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:22][CH3:23])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3]1
Reactant: COc1cc(N2CCC(N3CC[C@H](F)C3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC(N3CCCC(F)(F)C3)CC2)ccc1N
Product: COc1cc(N2CCC(N3CC[C@H](F)C3)CC2)ccc1N
Yield: 86.9 %

Procedure:
4-[(3S)-3-fluoro-1-pyrrolidinyl]-1-[3-(methyloxy)-4-nitrophenyl]piperidine (4 mmol) was reduced in a manner analogous to 4-(3,3-difluoro-1,4′-bipiperidin-1′-yl)-2-(methyloxy)aniline (Intermediate B38). The filtrate was washed with water, dried over MgSO4 and concentrated to give 4-{4-[(3S)-3-fluoro-1-pyrrolidinyl]-1-piperidinyl}-2-(methyloxy)aniline (1.02 g, 86% yield). 1H NMR (400 MHz, d6-DMSO) δ 6.48-6.45 (m, 2H), 6.26 (dd, J=8.4 and 2.4 Hz, 1H), 5.24-5.07 (m, 1H), 4.16 (s, 2H), 3.70 (s, 3H), 3.33-3.30 (m, 2H), 2.88-2.76 (m, 2H), 2.69-2.56 (m,1H), 2.54-2.46 (m under DMSO peak, 2H), 2.37-2.31 (m, 1H), 2.14-1.99 (m, 2H), 1.90-1.75 (m, 3H), 1.51-1.41 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[NH3:10]>>[CH3:9][C:3]1[C:2]([NH2:10])=[N:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: N
Reactant: Cc1cnc(C)c(Cl)n1
Product: Cc1cnc(C)c(N)n1
Temperature: 150 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
A 100 mL autoclave vessel was charged with 3-chloro-2,5-dimethylpyrazine (25.0 g, 176 mmol), NH3 (aq. 25˜28% w/w, 80 mL) and Cu powder (1.69 g, 26.4 mmol) and the autoclave vessel was sealed. The resulting mixture was heated to 150° C. and stirred vigorously for 48 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with brine (100 mL) and extracted with EtOAc (4×100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was washed with PE to render the title compound as a light yellow solid (17.6 g, yield 81%). ESI MS: m/z 124 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1.[CH2:12](B([O-])OC(C(C)(C)C)C)[CH:13]=[CH2:14].[F-].[Cs+]>O1CCCC1.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: COc1cc(Br)cc(F)c1F
Reactant: C=CCB([O-])OC(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCc1cc(F)c(F)c(OC)c1

Procedure:
3.06 g of 1-bromo-3,4-difluoro-5-methoxybenzene (D2), 4.54 ml of pinacolyl allylboronate, 3.04 g of tetrakis(triphenylphosphine)palladium(0) and 7.62 g of caesium fluoride are suspended in 115 ml of tetrahydrofuran under an argon atmosphere. The reaction mixture is subsequently heated under reflux for 48 h. For work-up, the mixture is diluted with 400 ml of diethyl ether and extracted with 100 ml of water and 100 ml of saturated NaCl solution. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent: cyclohexane), giving 1.59 g of the title compound as a colourless oil; MS: 184.0 (M+); TLC: Rf=0.69 (cyclohexane/ethyl acetate 8:1 parts by volume).
Reaction SMILES: N[C:2]1([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([O:10]CC)=[O:9])[CH2:6][S:5][CH:4]=[N:3]1.[OH-].[Na+].C[N:26]1C=CN=C1.CO>O1CCCC1>[NH2:26][C:4]1[S:5][CH:6]=[C:2]([C:7](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:8]([OH:10])=[O:9])[N:3]=1
Reactant: Cn1ccnc1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1)C1(N)CSC=N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2)C(=O)O)cs1
Yield: 261.6 %

Procedure:
Ethyl 2-(4-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetate (syn isomer, 21.15 g.), 1 N sodium hydroxide aqueous solution (94 ml.), 1-methylimidazole (1.02 g.), methanol (220 ml.) and tetrahydrofuran (150 ml.) were treated in a similar manner to that of Example P-(4) to give 2-(2-aminothiazol-4-yl)-2-(4-chlorobenzyloxyimino)acetic acid (syn isomer, 10.13 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:33]4[CH2:34][CH2:35][N:30]([C:27](=[O:29])[CH3:28])[CH2:31][CH2:32]4)=[O:26])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(C(=O)c2cc(C(=O)NCCc3ccc(-c4ccc(Cl)c(Cl)c4)o3)[nH]n2)CC1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-acetylpiperazine. The crude product was triturated in CH2Cl2 at room temperature to afford the product. 1H NMR (400 MHz, CDCl3): 2.15 (3H, s), 3.01 (2H, t), 3.58 (2H, m), 3.72 (2H, m), 3.78 (2H, q), 3.84 (4H, m), 6.21 (1H, d), 6.59 (1H, d), 7.04 (1H, s), about 7.28 (1H, broad s), 7.41 (2H, m), 7.74 (1H, s), 11.35 (1H, broad s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:30])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([NH:28][OH:29])=[NH:27])=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[C:35](OC(=O)C)(=O)[CH3:36]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]5[N:27]=[C:35]([CH3:36])[O:29][N:28]=5)=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[CH:15][CH:16]=2)=[O:30])=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: N=C(NO)c1ccc2c(ccn2-c2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc3c(ccn3-c3ccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)c2)no1
Temperature: 80 °C
Reaction time: 14 h
Yield: 36.4 %

Procedure:
In 0.2 mL of pyridine, 10.5 mg (0.022 mmol) of 1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-N-hydroxy-1H-indole-5-carboxamidine was dissolved, and 10 mg (0.098 mmol) of acetic anhydride was added thereto, and the mixture solution was stirred at 80° C. for 14 hours. The reaction solution was concentrated under reduced pressure, and then the obtained residue was purified by Megabond Elute Silica Gel (a product of Varian, 1 g, methylene chloride:methanol=20:1) to obtain 4.1 mg (37%) of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-{4-[5-(5-methyl-[1,2,4]oxadiazol-3-yl)indol-1-yl]phenyl}urea (Table 1, Compound No. 26).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCc1c[nH]c2ccccc12
Temperature: 110 °C
Yield: 55.4 %

Procedure:
A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (124.5 mg, 0.44 mmol), tryptamine (70.7 mg, 0.44 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 100 mg (55%) of yellow solid mp 278-280° C.; HRMS (ESI) m/z calcd for C20H16BrN3O2 408.03531. found 408.03493 (M+H)+1, Analysis for C20H16BrN3O2; Calcd: C, 58.55; H, 3.93; N, 10.24. Found: C, 58.34; H, 3.63; N, 10.21.