Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]#[N:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1.C(O)C.C[O-].[Na+].[Cl-:27].[NH4+:28]>CO>[ClH:27].[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:28])[NH2:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Reactant: [Cl-]
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cl
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
406.0 g (1.50 mol) of the compound from Example 8 were suspended in 2.08 1 of ethanol. Subsequently, 54.1 g (0.30 mol) of sodium methoxide in methanol (30%) were added and the mixture was stirred at room temperature overnight. 88.4 g (1.65 mol) of ammonium chloride were added, and the mixture was heated to 65° C. and stirred at 65° C. for 3.5 h. The solvents were distilled off and the residue was stirred with 1.6 1 of ethyl acetate overnight. The precipitated solids were filtered off with suction, washed twice with 140 ml each time of ethyl acetate and dried in a vacuum drying cabinet at 50° C. under a gentle nitrogen stream. This gave 441.4 g (90.7% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]=O>C(O)=O>[CH3:14][N:12]=[S:10]([CH3:13])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:11]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C=O
Solvent: O=CO
Product: CN=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
500 mg (2.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide in 4 ml formaldehyde (aqueous, 37%) and 20 ml formic acid (98-100%) are stirred in the open flask at 100° C. After 22 hours, the solvent is evaporated, the mixture is treated again with 4 ml formaldehyde (aqueous, 37%) and 20 ml formic acid (98-100%) and stirred for a further 22 hours at 100° C. Residues of the solvent are removed on the rotary evaporator. The remaining residue is dissolved with 2N HCl and extracted with dichloromethane. The aqueous phase is basified with NaHCO3 and extracted with dichloromethane. The combined organic phases are dried (Na2SO4), filtered and concentrated. 448 mg (2.1 mmol, corresponding to 85% of theor.) of the product is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5]([N:8]=CN(C)C)=[N:6][CH:7]=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[CH:7][N:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc(-c2csc3c(N)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(NC(=O)Nc4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-[4-(7-amino-4-{[(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide and phenyl isocyanate using General Procedure N followed by General Procedure M. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (s, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 8.06 (d, 1H), 7.73 (m, 2H), 7.60 (d, 1H), 7.49 (d, 2H), 7.36 (s, 1H), 7.30 (m, 4H), 7.14 (m, 2H), 7.00 (t, 1H), 6.10 (br, 2H), 4.04 (s, 3H), 3.93 (s, 3H); MS: (MH)+ 563.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[OH-].[Na+].C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(OCCC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(OCCCN)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
In an argon atmosphere, 3-(4-methoxyphenoxy)propionitrile (5.0 g) was dissolved in tetrahydrofuran (20 mL), and a borane-tetrahydrofuran complex (1.02 mol/L, 30.0 mL) was added dropwise to the resultant solution at 80° C. over 10 minutes. The mixture was stirred for 3 hours at 80° C. Thereafter, the reaction mixture was cooled to room temperature. Under cooling on ice, 4N aqueous sodium hydroxide solution (30 mL) was added thereto over 10 minutes. Ten minutes after, the mixture was stirred at room temperature for 5 minutes, and further stirred at 80° C. for 12 hours. The mixture was cooled to room temperature, and toluene (100 mL) was added thereto, followed by stirring for 1 hour. Subsequently, after removal of insoluble matter through filtration by means of Celite, the organic layer was collected and washed sequentially with water (100 mL×2) and saturated brine (100 mL), followed by drying over sodium sulfate anhydrate (80 g). After filtration, the filtrate was concentrated under reduced pressure, to thereby yield 4.0 g of a white solid (79.0%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:33])[C:8]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]([OH:32])[C@H:28]([OH:31])[CH2:29][OH:30])=[CH:21][C:9]=4[C:10]([CH3:20])([CH3:19])[C:11]=3[N:12]2[CH2:15][C:16]([OH:18])=[O:17])=[CH:4][CH:3]=1.[CH3:34][Si](C=[N+]=[N-])(C)C>CO>[CH3:34][O:17][C:16](=[O:18])[CH2:15][N:12]1[C:11]2[C:10]([CH3:20])([CH3:19])[C:9]3[CH:21]=[C:22]([O:25][CH2:26][C@@H:27]([OH:32])[C@H:28]([OH:31])[CH2:29][OH:30])[CH:23]=[CH:24][C:8]=3[C:7](=[O:33])[C:6]=2[C:5]2[C:13]1=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=2
Reactant: CC1(C)c2cc(OC[C@@H](O)[C@H](O)CO)ccc2C(=O)c2c1n(CC(=O)O)c1cc(Br)ccc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@@H](O)[C@H](O)CO)cc1C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
[3-Bromo-6,6-dimethyl-11-oxo-8-((2R,3R)-2,3,4-trihydroxy-butoxy)-6,11-dihydro-benzo[b]carbazol-5-yl]-acetic acid (Compound T22-6, 15.0 mg, 29.0 μmol) was dissolved in methanol (0.30 mL), added with trimethylsilyldiazomethane (0.10 mL), and then stirred at room temperature for 1 hr. The residues obtained from the reaction solution after concentration under reduced pressure were purified by silica gel column chromatography (methylene chloride/methanol) to obtain the target compound (15.2 mg, 96%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14](I)[CH:13]=2)=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Zn+]>>[C:1]([C:4]1[S:8][C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[CH:13]=2)=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: [Zn+]c1ccccn1
Reactant: CC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(I)c2)s1
Agent: [Br-]
Product: CC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)s1

Procedure:
5-Acetyl-N-(4-chloro-3-iodophenyl)thiophene-2-carboxamide (202 mg, 0.5 mmol) was used in Procedure B with 2-pyridylzincbromide (2.5 mL, 1.25 mmol, 0.5 M in THF). Purified by silica gel chromatography (10-100% ethyl acetate/hexanes) to yield 5-acetyl-N-(4-chloro-3-(pyridin-2-yl)phenyl)thiophene-2-carboxamide as a yellow solid: TLC Rf=0.19 (50% ethyl acetate/hexanes); 1H NMR (CDCl3, 400 MHz) δ 8.96 (bs, 1H), 8.67 (d, 1H), 7.79 (dt, 1H), 7.68 (m, 3H), 7.61 (d, 1H), 7.58 (d, 1H), 7.37 (d, 1H), 7.32 (m, 1H), 2.58 (s, 3H); MS (Q1) 357.0 (M)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](=[S:16])[NH:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]N(C=O)C.C([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([S:16][CH3:19])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(=S)[nH]c(=O)c1-2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(SC)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(thioxo) pyrazolo[3,4-d]pyrimidin-4-one (5.2 g, 19.6 mmol), DMF (50 mL) and K2CO3 (2.76 g, 20 mmol) was stirred at ambient temperature for 25 minutes and then dimethyl sulfate (3.88 mL, 40 mmol) was added. The reaction mixture was stirred for 2 hours, then was poured into cold water. The product was collected by filtration, washed with water, recrystallized from cyclohexane/ether and dried at 70-75° C. in vacuo to afford 4.6 g of 1-cyclopentyl-3-ethyl-6-(methylthio) pyrazolo[3,4-d]pyrimidin-4-one, m.p.200-202° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[N:7]([CH:10]([CH3:18])[C:11]([O:13]C(C)(C)C)=[O:12])=[N+:8]=[N-:9]>C1(C)C=CC=CC=1>[CH3:6][O:5][C:1]([C:2]1[N:9]=[N:8][N:7]([CH:10]([CH3:18])[C:11]([OH:13])=[O:12])[CH:3]=1)=[O:4]
Reactant: C#CC(=O)OC
Reactant: CC(N=[N+]=[N-])C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(C(C)C(=O)O)nn1
Temperature: 100 °C

Procedure:
To a solution of 1.87 g (22.3 mmol) of methyl prop-2-ynoate in 40 mL of toluene was added 1.9 g (11 mmol) of tert-butyl 2-azidopropanate. The reaction mixture was heated at 100° C. for 3 h then cooled to ambient temperature. All volatiles were removed under reduced pressure and the crude residue purified by column chromatography on silica gel eluting with a 5 to 25% acetone in hexanes gradient to afford the title compounds.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=2)=[N:8][CH:9]=1.[C:19]([O:22][CH:23]([CH:25]=[CH2:26])[CH3:24])(=[O:21])[CH3:20].C(N)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN1CCCC1=O>[C:19]([O:22][CH:23]([CH3:24])[CH:25]=[CH:26][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][Si:2]([CH3:18])([CH3:17])[CH3:1])=[CH:9][N:8]=2)=[CH:11][CH:12]=1)(=[O:21])[CH3:20]
Reactant: C[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)nc1
Reactant: C=CC(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)(C)N
Solvent: CN1CCCC1=O
Product: CC(=O)OC(C)C=Cc1ccc(-c2ccc(O[Si](C)(C)C)cn2)cc1
Yield: 74.7 %

Procedure:
17 g of 5-trimethylsilyloxy-2-(4-bromophenyl)pyridine, 12 g of 2-acetoxy-3-butene, 10 g of N-tert.-butylamine, 20 ml of N-methylpyrrolidone, 0.12 g of palladium(II) acetate and 0.3 g of triphenylphosphine are reacted in an analogous manner to Example 1(d) to give 14 g of 2-[4-(3-acetoxy-1-butenyl)-phenyl]-5-trimethylsilyloxy-pyridine.
Reaction SMILES: [OH:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>N1C=CC=CC=1>[C:22]([O:1][C@@H:2]([CH3:21])[CH2:3][C@@H:4]([CH3:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)C[C@@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.81 g of the (R,S)-4-[4'-(3"-hydroxy-1"-methylbutoxy)phenyl]benzonitrile prepared in the above Example 1 was mixed with 5.10 g of acetic anhydride and 0.3 g of pyridine. The mixture was stirred at 100° C. for one hour. After cooling, the reaction mixture was carefully poured into 50 ml of 2N hydrochloric acid and extracted with diethyl ether. After washing with water, drying and desolvating, the obtained residue was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (3:1) as a developing solvent. Thus 2.65 g of (R,S)-4-[4'-(3"-acetoxy-1"methylbutoxy)phenyl]benzonitrile was obtained.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.O=[C:7]([CH3:31])[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]([CH3:30])[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:22]=1[CH:21]=[CH:20][C:19]([Cl:23])=[CH:18]2)=[O:13].C([BH3-])#N.[Na+]>CO>[ClH:23].[CH:1]([NH:4][CH:7]([CH3:31])[CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]([CH3:30])[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:17]2[C:22]=1[CH:21]=[CH:20][C:19]([Cl:23])=[CH:18]2)=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(=O)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)NC(C)CCCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.2 ml. of isopropylamine in 25 ml. of methanol is treated with 4 ml. of 5-N methanolic hydrochloric acid. Thereafter, there are successively added under an atmosphere of argon at 20°-25° C. 3.7 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid (4-oxopentyl)amide and 0.4 g. of sodium cyanoborohydride and the mixture is then stirred at room temperature for 48 hours. The mixture is made acidic with concentrated hydrochloric acid while cooling with ice, stirred at room temperature for an additional 0.5 hour and then concentrated to dryness under reduced pressure. The residue is made alkaline with 0.5-N sodium hydroxide with the addition of ice and extracted with 200 ml. of diethyl ether. The extract, dried over sodium sulfate, is concentrated to dryness and the residual oily base crystallized from hot hexane. The thus obtained colorless base, which melts at 102°-105° C. is dissolved in 30 ml. of acetone and treated with excess ethereal hydrochloric acid. The separated hydrochloride is removed by filtration and washed with acetone, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [4-(isopropylamino)pentyl]amide hydrochloride in the form of colorless crystals having a melting point of 216°-218° C. (decomposition). Recrystallization from acetone/methanol does not increase the melting point.
Reaction SMILES: C(OC(N(C[C@@H](C1C=CC=C(Cl)C=1)O)CCC1C=CC([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][C:18]=2OC)=CC=1)=O)(C)(C)C.[OH-].[Na+]>C(O)C>[C:23]([OH:25])(=[O:24])[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylate (220 mg) in ethanol (2.0 ml) was added 1N aqueous sodium hydroxide solution (1.2 ml), and the mixture was stirred at 40° C. for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in tetrahydrofuran (1.5 ml) was added 4N hydrochloride in dioxane (1.0 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]-2-methoxy-1,1′-biphenyl-4-carboxylic acid hydrochloride (83 mg).
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH:4]=[O:5])[CH3:2].[CH2:10]=[O:11].[OH-].[Na+]>CO>[CH3:9][CH2:8][CH2:7][CH2:6][C:3]([CH2:10][OH:11])([CH2:4][OH:5])[CH2:1][CH3:2]
Reactant: CCCCC(C=O)CC
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(CC)(CO)CO

Procedure:
BEPD was prepared by a semi-batch process out of 2-ethylhexanal (2-EH), having a purity of over 90 weight-%, and formaline. The concentration of the formaline aqueous solution was 37 weight-% HCHO and it contained 10 weight-% CH3OH. First, 1207 g (9.225 moles) of 2-EH and 1911 g (23.546 moles) of HCHO were fed into the reactor to make up the reaction mixture, after which 927 g (11.125 moles) in total of sodium hydroxide was fed into the reaction mixture. The concentration of the sodium hydroxide aqueous solution was 48 weight-%, and it was fed for 6 hours at three input rates, namely 93 g/h (1.1161 moles per hour) during the first hour of the reaction (beginning at time T1), 135 g/h of NaOH (1.6201 moles/h; beginning at time T2) during the following two hours and, finally, 188 g/h (2.2562 moles/h; beginning at time T3) during the third to the 6th hour.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:28](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:28][N:16]([C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)[C:13]1[S:14][CH:15]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:12]=1
Reactant: CCOC(=O)c1ccc(Nc2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)c1ccc(N(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Yield: 99.5 %

Procedure:
Under a nitrogen stream, N,N-dimethylformamide (1.05 L, 7.0 v/w) was added to ethyl 4-((4-(4-nitrophenyl)-2-thiazolyl)amino)benzoate hydrobromide (150 g, 0.333 mol) obtained in Example 3(1). With stirring under ice-cooling, potassium carbonate (138 g, 0.999 mol) was added carefully. After stirring at room temperature for 20 min., dimethyl sulfate (63.2 ml, 0.666 mol) was added. After stirring at 60° C. for 2 hr., distilled water (1.05 L, 7.0 v/w) was added with stirring under ice-cooling. After stirring under ice-cooling for 1 hr., the resulting crystal were collected by filtration, washed with distilled water (450 mL) and dried in vacuo to give the title compound (127 g, yield 99.3%) as an orange crystal.
Reaction SMILES: [CH3:1][C:2]([C:15]1[C:16]([CH3:24])=[N:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)(C(OCC)=O)[C:3]([O:5][C:6](C)(C)[CH3:7])=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][C:16]1[C:15]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[N:17]=1
Reactant: CCOC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C

Procedure:
A mixture of tert-butyl ethyl methyl(2-methyl-6-nitropyridin-3-yl)propanedioate (2.8 g, 8 mmol) in a mixed solution of TFA/DCM (30 mL/30 mL) was stirred over night at room temperature. The mixture was concentrated under reduce pressure to give ethyl 2-(2-methyl-6-nitropyridin-3-yl)propanoate.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[S:6]1[C:18]2[N+:9](=[CH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH:17]=2)[CH:8]=[CH:7]1.COC1C=CC(CN2C=CC(C(C3C=CN(CC4C=CC(OC)=CC=4)N=3)=C)=N2)=CC=1>C(O)C.C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[S:6]1[C:18]2[CH2:17][C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:10][N+:9]=2[CH:8]=[CH:7]1
Reactant: c1ccc2c[n+]3ccsc3cc2c1
Agent: C=C(c1ccn(Cc2ccc(OC)cc2)n1)c1ccn(Cc2ccc(OC)cc2)n1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCO
Product: c1ccc2c(c1)Cc1scc[n+]1C2
Temperature: 25 °C

Procedure:
A reaction mixture containing thiazolo[3,2-b]isoquinolinium perchlorate (2.4 g; 8.4 mmol) and 1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)ethylene (4 g; 0.01 mol) in 125 ml of ethanol and 25 ml of acetonitrile was refluxed for 12 h under nitrogen. The reaction mixture was cooled to room temperature, the solid product was filtered, washed with ether, and dried in vacuo to afford 4.65 g (81.6%) of 11,11-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)]-5,10-ethano-5,10-dihydrothiazolo[3,2-b]isoquinolinium perchlorate (Formula I: A=thiazolo; R1 =R2 =R3 =R6 =H; R4 =R5 =1-p-methoxybenzyl-3-pyrazolyl; X- =ClO4-).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH3:23]>>[CH3:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:17]=1[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]1
Reactant: Cc1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Product: Cc1cnccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 72 h

Procedure:
The title compound was prepared from 1-Boc-4-hydroxypiperidine and 4-chloro-3-methylpyridine hydrochloride, using a similar method to preparation 27. The reaction mixture was stirred for 72 hours to afford the title compound the desired product in 87% yield. 1H NMR(CDCl3, 400 MHz) δ: 1.44 (s, 9H), 1.75-1.85 (m, 2H), 1.87-1.97 (m, 2H), 2.18 (s, 3H), 3.42-3.53 (m, 2H), 3.56-3.65 (m, 2H), 4.57-4.65 (m, 1H), 6.72 (d, 1H), 8.29 (s, 1H), 8.35 (d, 1H); LRMS APCI m/z 293 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11][CH2:12][CH2:13][CH2:14]Br.[OH-].[Na+]>O>[Br:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1O
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccccc1OCCCBr

Procedure:
To a stirred and refluxing mixture of 136 parts of 1-(2-hydroxyphenyl)ethanone and 222 parts of 1,3-dibromopropane in 500 parts of water was added dropwise a solution of 40 parts of sodium hydroxide in 140 parts of water. Upon completion, stirring was continued at reflux temperature overnight. The organic layer was separated, dried and distilled, yielding 80 parts of 1-[2-(3-bromopropoxy)phenyl]ethanone; bp. 135° C. at 0.05 mm. pressure (intermediate 77).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:28]=[C:27](F)[CH:26]=[CH:25][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:24])[N:20]3[CH3:23])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([NH:7][C:8]2[N:28]=[C:27]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:26]=[CH:25][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:24])[N:20]3[CH3:23])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(F)nc3NC3CCCCC3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(N4CCCCC4)nc3NC3CCCCC3)cc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A mixture of 2-(cyclohexylamino)-6-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)nicotinamide (150 mg), piperidine (64 mg), potassium carbonate (63 mg) and DMF was stirred at 60° C. for 18 hours. Then, water was added, followed by extraction with ethyl acetate. After drying the organic layer with magnesium sulfate, the solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, hexane:ethyl acetate, 2:1 to 1:1) to obtain 2-(cyclohexylamino)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-6-piperidin-1-ylnicotinamide (138 mg) as a solid.