Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=1.[C:16](C1NC=CN=1)(C1NC=CN=1)=[S:17]>C(#N)C>[N:6]1[NH:5][N:4]=[N:3][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:16](=[S:17])[NH:15][C:10]=2[CH:9]=1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccc(-c2nn[nH]n2)cc1N
Agent: Cl
Solvent: CC#N
Product: S=c1[nH]c2ccc(-c3nn[nH]n3)cc2[nH]1
Reaction time: 5 h
Yield: 61.4 %

Procedure:
To 4-(2H-tetrazol-5-yl)-benzene-1,2-diamine dihydrochloride (6.40 g, 25 mmol) in acetonitrile (100 ml) was added thiocarbonyl di-imidazole (4.86 g, 28 mmol). A further 100 ml of acetonitrile was added. The reaction was then stirred for 5 hours and the reaction analyzed by HPLC. The solvent was removed under reduced pressure and water added (100 ml). The pH of the reaction mixture was adjusted to pH 2.0 and the solid filtered and washed with water (50 ml). The material was dried to give 5-(2H-tetrazol-5-yl)-1,3-dihydrobenzimidazole-2-thione (3.35 g, 61% yield). The material was suspended in water (300 ml) and the pH adjusted to 11.0 with 40% (v/v) NaOH. Methanol (15 ml) was then added followed by Activated carbon (0.38 g) and the mixture stirred for 1 hour. The mixture was filtered and the solvent removed, under reduced pressure, to half its volume. The pH was adjusted to 2.0 with 50% (v/v) hydrochloric acid to yield an off white solid. The solid was filtered off and washed with water. The purity was >98% by hplc Rt=7.8 mins. The material was dried to yield 5-(2H-tetrazol-5-yl)-1,3-dihydrobenzimidazole-2-thione (2.37 g). 1H NMR (d6-DMSO, 400 MHz) 12.88 ppm (1H, s), 12.84 ppm (1H, s), 7.82 ppm (1H, dd, 8.4 Hz, 1.6 Hz), 7.78 ppm (1H, m), 7.30 ppm (1H, d, 8 Hz). MS (high resolution EI). Found 218.036514 m/z C8H6N6S to +4 ppm mass accuracy.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([Br:11])[N:10]=1)=O)C.[CH3:12][NH2:13]>CO>[CH3:12][NH:13][C:4]([C:6]1[S:7][CH:8]=[C:9]([Br:11])[N:10]=1)=[O:3]
Reactant: CCOC(=O)c1nc(Br)cs1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromothiazole-2-carboxylic acid ethyl ester (500 mg, 2.13 mmol) is dissolved in methanol (1 mL) and methyl amine in methanol (10 mL) is added. The mixture is stirred overnight at room temperature. Evaporation of the solvent under reduced pressure affords the title compound as yellow solid. LCMS: Rt 0.92 min (100%) m/z (ESI) 219/221 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[C:33]=2[CH2:38][O:39]C2CCCCO2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:19])([F:18])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:46])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[C:33]=4[CH2:38][OH:39])[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)c1CO

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M60) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (64 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[H-].[Na+].[O:28]1CCC[CH2:29]1>CO.ClCCl>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:6][CH:5]=[C:4]([O:28][CH3:29])[N:3]=1
Reactant: C1CCOC1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2Cl)o1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2nnc(-c3c(-c4ccccc4)noc3C)o2)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,6-dichloro-3-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (316 mg, 0.85 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added sodium hydride (55% dispersion in mineral oil, 41 mg, 0.93 mmol) and the reaction mixture was stirred for 4 h at ambient temperature. The resulting suspension was diluted with dichloromethane (10 mL) and was washed brine (half saturated, 10 mL). The aqueous layers were extracted with dichloromethane (10 mL) and dried over sodium sulfate. The filtrate was treated with tert-butylmethylether (20 mL) and the dichloromethane was distilled off. The resulting suspension was stirred for 5 min, filtered off and washed with tert-butylmethylether affording the title compound (51 mg, 16%) which was obtained as a white solid. MS: m/e=369.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[N:6][C:5](Cl)=[CH:4][CH:3]=1.[NH:9]1[CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10]1>CN1C(=O)CCC1.C(N(C(C)C)CC)(C)C>[C:13]([CH:12]1[CH2:11][CH2:10][N:9]([C:5]2[N:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:19][CH2:18]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cc1ccc(Cl)nn1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2ccc(C)nn2)CC1
Yield: 44 %

Procedure:
55 mmoles of 6-methyl-3-chloropyridazine was added to 75 mmoles of ethyl isonipecotate in 5 mL NMP and 20 mL diisopropylethylamine (DIPEA) and refluxed for 6 hours. The product was isolated as described in Example 1a above to give a 44% yield of 3-(4-carboethoxy-1-piperidinyl)-6-methylpyridazine. Reduction of 18.8 mmol of this compound using 56.6 mmol DIBAL in 100 mL THF with a Rochelle's salt quench gave 3-(4-hydroxymethyl-1-piperidinyl)-6-methylpyridazine (Formula IV: R1 =CH3 ; Y=CH2) which was used unpurified in the final step. Reaction of 5 mmol of the product described in Example 1b with 4.5 mmol of the 3-(4-hydroxymethyl-1-piperidinyl)-6-methyl pyridazine according to the procedure of Example 1c afforded after recrystallization from ethyl acetate at -70° C. the compound of formula I (R1 =R4 =CH3, Y=CH 2, R2 =R3 =hydrogen) in 12% yield, m.p. 180°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:10]=[C:11]([CH2:18][OH:19])[N:12]([CH3:17])[C:13]=2[CH:14]([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.ClC(Cl)(Cl)[C:22]([N:24]=C=O)=[O:23].C(=O)([O-])O.[Na+]>O1CCCC1>[C:22]([O:19][CH2:18][C:11]1[N:12]([CH3:17])[C:13]([CH:14]([CH3:16])[CH3:15])=[C:9]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=1)(=[O:23])[NH2:24]
Reactant: CC(C)c1c(Sc2cccc(Cl)c2)nc(CO)n1C
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1c(Sc2cccc(Cl)c2)nc(COC(N)=O)n1C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
In 5 ml of dry tetrahydrofuran was dissolved 200 mg (0.67 mmol)of [4-(3-chlorophenylthio)-5-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-38), and 190 mg (1.0 mmol) of trichloroacetylisocyanate was added to the mixture with cooling at -40° C. After 10 minutes, the mixture was warmed to 0° C., and stirred at the same temperature for 10 minutes To the reaction mixture, ice-water was added, and then, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and to the residue was added 5 ml of methanol, 0.5 ml of water and 0.5 ml of triethylamine. The mixture was stirred at 50° C. for 30 minutes. To the reaction mixture was added water, extracted with methylene chloride, the extract was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate). The product was recrystallized from ethyl acetate/isopropyl ether to give 180 mg of the target compound (Compound I-59)(yield 79%). mp 145-146° C.
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].S(Cl)([Cl:25])=O>N1C=CC=CC=1.C(Cl)Cl>[C:1]([Cl:25])(=[O:22])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)Cl
Yield: 94.4 %

Procedure:
Under a nitrogen atmosphere, one drop of pyridine was added to 2.0 g of phytanic acid and 10 ml of methylene chloride, and 1.14 g of thionyl chloride was added dropwise at room temperature. After the completion of dropwise addition, the mixture was refluxed for 1 hour, and then concentrated under reduced pressure to obtain about 2 g of phytanic acid chloride.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:18][NH3+:19].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]1([CH2:7][C:8](=[N:19][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH3+]O
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 1,3-diphenyl-2-propanone (5.0 g, 24 mmol) and hydroxylammonium chloride (3.3 g, 48 mmol) in a mixture of absolute ethanol (30 ml) and water (10 ml) was carefully added a solution of sodium carbonate (13.2 g, 96 mmol) in water (30 ml). The resulting mixture was stirred at room temperature for 16 h. The precipitated compound was collected and washed with water (3×15 ml) and dried to give 4.9 g of 1,3-diphenyl-2-propanone oxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]Cl.[C-]#N.[Na+].[CH3:18][N:19](C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:18]#[N:19])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: COc1cc(CC#N)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
3,4,5-trimethoxy benzyl chloride 7.0 g and sodium cyanide 6.3 g were dissolved into 50 ml of N,N-dimethylformamide and they were then stirred at 80° C. for 45 minutes. The temperature of the reactive liquid was then lowered down to the room temperature, 200 ml of water was added thereto and then extraction was made thrice by means of 100 ml of ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 2-bromopyridine according to the general procedure C. Obtained as a yellow solid (407 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13].[H-].[Na+].O>C1COCC1>[Br:1][C:2]1[C:3]2=[N:8][S:12](=[O:14])(=[O:13])[CH2:11][CH2:10][N:4]2[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 3-bromopyridin-2-amine (3 g) in dehydrated THF (30 mL) was added to a mixture of 2-chloroethanesulfonyl chloride (7.07 g) and sodium hydride (60%, 3.47 g) in dehydrated THF (30 mL) at room temperature, and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and THF was removed under reduced pressure. The resulting precipitate was collected by filtration, and washed with water and diethyl ether to give the title compound (3.41 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([CH3:31])([CH3:30])[CH2:11][C:12]([OH:29])([C:25]([F:28])([F:27])[F:26])[CH2:13][N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[CH:16]=[CH:15]2)[CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:39][O:40][NH2:41]>CO>[OH:29][C:12]([C:25]([F:26])([F:27])[F:28])([CH2:11][C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[N:41][O:40][CH3:39])[CH3:2])[CH:5]=1)([CH3:30])[CH3:31])[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH:16]=[CH:15]1
Reactant: CON
Reactant: CC(=O)c1cccc(C(C)(C)CC(O)(Cn2ccc(=O)c3ccccc32)C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CON=C(C)c1cccc(C(C)(C)CC(O)(Cn2ccc(=O)c3ccccc32)C(F)(F)F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-quinolin-4-one (55 mg, 0.12 mmol), potassium carbonate (72 mg, 0.52 mmol), and methoxyamine hydrochloride (42 mg, 0.51 mmol) in 1 mL of methanol was heated at 65° C. for 3 hours, cooled to room temperature, and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-(2-hydroxy-4-{3-[1-(methoxyimino)ethyl]phenyl}-4-methyl-2-trifluoromethyl-pentyl)-1H-quinolin-4-one. Yield: 48 mg.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S(Cl)([Cl:28])=O.S(=O)=O.Cl>C(Cl)Cl>[C:1]([NH:20][CH2:21][CH2:22][C:23]([Cl:28])=[O:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCC(=O)O
Agent: Cl
Agent: O=S=O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCC(=O)Cl
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
61.3 g of N-oleoyl-β-alanine was dispersed in 200 ml of methylene chloride. Then, 24.8 g of thionyl chloride was added thereto within 10 minutes under stirring while maintaining the temperature of the mixture at 20° C. After the completion of the addition, the mixture was stirred at the same temperature for 30 minutes so as to complete the reaction. When the reaction solution thus obtained was analyzed by infrared spectroscopy, a peak at 1695 cm-1 due to carboxylic acid (--COOH) disappeared while a new peak due to acid chloride (--COCl) was formed at 1782 cm-1. These facts indicated that an acid chloride was obtained. Then, the methylene chloride employed as the solvent and side products (sulfur dioxide and hydrogen chloride) were distilled off from the reaction mixture under reduced pressure. Thus, 64.1 g of N-oleoyl-3-aminopropionic acid chloride was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:38])[CH2:12][N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27][C:28]([CH3:36])([CH3:37])[C:29]([OH:31])=[O:30])=[CH:25][CH:26]=1)[CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)O)cc2)Cc2ccco2)c(C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
210 mg of tert-butyl 2-[[4-[[[2-[(2,4,6-trimethylphenyl)amino]-2-oxoethyl](2-furanylmethyl)-amino]methyl]phenyl]thio]-2-methyl-propanoate are dissolved in 5 ml of dichloromethane and reacted with 1 ml of trifluoroacetic acid. The mixture is stirred at room temperature for 4 h and then concentrated and purified chromatographically (dichloromethane/ethyl acetate 50+1). This gives 187 mg of the title compound as a solid foam.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[N:23]1[S:24][N:25]=[C:26]2[CH:31]=[C:30]([N:32]=[C:33]=[S:34])[CH:29]=[CH:28][C:27]=12.C(N(CC)CC)C>>[CH3:1][CH2:2][N:3]1[C:9]2[C:8](=[CH:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:33]([NH:32][C:30]4[CH:29]=[CH:28][C:27]5[C:26](=[N:25][S:24][N:23]=5)[CH:31]=4)=[S:34])[CH2:16][CH2:15]3)[N:10]=2)[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1
Reactant: S=C=Nc1ccc2nsnc2c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc5nsnc5c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 2,1,3-benzothiadiazol-5-yl isothiocyanate (15.8 mg, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 7 in Table 1, below (24 mg, 58%). 1H NMR (300 MHz, DMSO) δ 9.26 (s, 1H), 8.98 (s, 1H), 7.98-7.82 (m, 3H), 4.51-4.33 (m, 2H), 4.24-3.99 (m, 8H), 1.42-1.32 (m, 3H) ppm.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][O:23][C:24]1[N:29]=[CH:28][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:25]=1
Reactant: COCCOc1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: COCCOc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(2-methoxy-ethoxy)-pyridin-3-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-(2-methoxy-ethoxy)-pyridin-3-ylamine. LCMS calcd for C19H16F3N3O4 (m/e) 407, obsd 408 (M+H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:11][CH2:12][CH3:13].C(=O)([O-])O.[Cs+]>CN1C(=O)CCC1>[C:4]([O:6][CH2:16][C:15](=[O:18])[NH:14][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:5])/[CH:3]=[CH:2]/[C:1]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CCCCNC(=O)CCl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCCCNC(=O)COC(=O)/C=C/C(=O)OC
Yield: 20.3 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-butyl chloroacetamide (0.69 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.19 g (21% yield) of the title compound (4) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.92 (m, 2H), 6.09 (br s, 1H), 4.68 (s, 2H), 3.82 (s, 3H), 3.34-3.29 (q, 2H, J=6.4 Hz), 1.54-1.48 (m, 2H), 1.38-1.32 (m, 2H), 0.956-0.920 (t, J=7.6 Hz, 3H). MS (ESI): m/z 244.04 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][C:7]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: COc1ccc(Br)cc1OC
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc(Br)c(S(=O)(=O)Cl)cc1OC
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a cooled (0° C.) solution of 4-bromoveratrole (15 mL, 100 mmol) in dichloromethane (100 mL) was added dropwise chlorosufonic acid (26 mL, 400 mmol). The reaction was allowed to slowly warm to ambient temperature and maintained for 3 hours, at which time it was concentrated and diluted with ether (300 mL). The resultant solution was then washed with ice cold water (2×250 mL) and brine (100 mL), dried over magnesium sulfate, and concentrated to furnish a grayish powder (25 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[ClH:21]>C1C2C(=CC=CC=2)CCC1.CCOCC.[Pd]>[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NCCc3ccccc32)cc1OC
Agent: [Pd]
Agent: Cl
Solvent: c1ccc2c(c1)CCCC2
Solvent: CCOCC
Product: COc1ccc(-c2nccc3ccccc23)cc1OC
Reaction time: 3 h
Yield: 23 %

Procedure:
A sample of 1-(3,4-Dimethoxyphenyl) 3,4-dihydroisoquinoline (A2) from 3.0 g of the hydrochloride (9.9 mmol) was boiled with 10% Pd/C (240 mg) in tetralin (30 ml). After 3 h the reaction was complete by tlc and the cooled mixture was diluted with ether and the catalyst was filtered. The filtrate was treated with HCl gas and the precipitated hydrochloride was collected by filtration. Recrystallization from CH2 /Cl2 /i-PrOH afforded 700 mg (23%) of pure 1-(3,4-dimethoxyphenyl) isoquinoline hydrochloride, mp 208°-228° dec.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([NH:27][CH2:26][CH2:25][N:24]4[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=[C:23]34)[CH2:19][CH2:18]2)=[O:16])=[CH:11][C:10]=1[O:35][CH3:36])([CH3:7])[CH3:6]>N1C=CC=CC=1>[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([N:27]([C:1](=[O:3])[CH3:2])[CH2:26][CH2:25][N:24]4[C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=[C:23]34)[CH2:21][CH2:22]2)=[O:16])=[CH:11][C:10]=1[O:35][CH3:36])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(=O)N2CCC3(CC2)NCCn2c(C(F)(F)F)ccc23)ccc1OC(C)C
Solvent: c1ccncc1
Product: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C(C)=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
Acetyl chloride (158 μL, 2.22 mmol) was added drop-wise to a mixture of (4-isopropoxy-3-methoxy-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone (100 mg, 0.222 mmol) and pyridine (1 mL) at room temperature. The mixture was allowed to stir for 16 h at room temperature before it was partitioned between ethyl acetate and 1N HCl. The layers were separated and the organic layer was washed with 1N HCl, water, and then brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was taken up in DMF and was purified by preparatory-HPLC (10-99% ACN/water with ammonium formate modifier) to give 1-[1′-(4-isopropoxy-3-methoxy-benzoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-2-yl]ethanone (60 mg, 53%) as a white solid. ESI-MS m/z calc. 493.2, found 494.7 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J=1.8 Hz, 1H), 7.05-6.98 (m, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.55 (d, J=3.3 Hz, 1H), 6.15 (d, J=3.9 Hz, 1H), 4.57 (d, J=6.1 Hz, 1H), 4.19-4.10 (m, 2H), 3.88 (m, s, 5H), 3.79 (s, 2H), 3.70-3.52 (m, J=31.5 Hz, 2H), 3.11 (s, 2H), 2.24 (s, 3H), 1.92-1.75 (m, 2H), 1.38 (d, J=6.1 Hz, 6H).