Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH3:23])[C:16]=1[CH2:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21].[OH-].[Na+]>ClCCl>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][CH2:17][C:16]1[C:15]([CH3:23])=[C:14]([CH:3]=[O:4])[NH:13][C:12]=1[CH3:11]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c(C)c1CCCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
To the ice-cooled solution of N,N-dimethylformamide (6.0 mL, 76 mmol) in dichloromethane (30 mL) was added phosphorus oxychloride (7.0 mL, 76 mmol) dropwise. Upon addition of phosphorus oxychloride, the reaction mixture was stirred at room temperature for 15 minutes and a solution of [3-(2,4-dimethyl-1H-pyrrol-3-yl)-propyl]-dimethyl-amine (6.8 g, 38 mmol) in dichloromethane (20 mL) was added dropwise at 0° C. The final reaction mixture was refluxed at 60° C. for 4 hours and cooled with ice bath. Ice cube was added to the reaction mixture slowly followed by addition of 2 N sodium hydroxide to adjust pH to 12. The reaction mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic-layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude product which was purified on a silica gel column eluting with dichloromethane-methanol-ammonium hydroxide (9:1:0.01) to give 5 g (63%) of 4-(3-dimethylamino-propyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde as a dark red oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH:9]=[CH:10][O:11][C:6]=2[CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])([CH3:35])[CH3:34]>C(Cl)Cl>[O:8]1[C:7]2[CH:12]=[CH:13][C:4]([C:2]3[O:3][C:44](=[O:45])[C:43]([S:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[CH:33]([CH3:34])[CH3:35])=[C:47]([OH:48])[CH:1]=3)=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: CC(=O)c1ccc2c(c1)OC=CO2
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc3c(c2)OCCO3)oc1=O

Procedure:
The title compound was prepared by Method A using 1,4-benzodioxin-6-yl methyl ketone (2 g, 11.22 mmol), trimethylsilyl triflate (2.5 g, 11.22 mmol), triethylamine (2.27 g, 22.44 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio)propanedioic acid (1.73 g, 5.61 mmol). m.p. 246°-248° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.4 (m, 1H), 4.32 (m, 4H), 6.72 (s, 1H), 6.89 (d, 1H), 7.01 (d, 1H), 7.06 (t, 1H), 7.11 (t, 1H), 7.26 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:14][CH:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]2)=[N:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:23][N:15]([CH:13]1[CH2:14][N:11]([C:5]2[C:6]3[N:7]([N:8]=[N:9][N:10]=3)[C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][N:4]=2)[CH2:12]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(Br)n3nnnc23)C1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(-c3cccs3)n3nnnc23)C1
Temperature: 80 °C
Reaction time: 14 h
Yield: 69.5 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl (1-(5-bromotetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)(methyl)carbamate (50 g, 0.13 mol), thiophene-2-boronic acid (22 g, 0.17 mol), tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol), Cs2CO3 (50 g, 0.15 mol), 1,4-dioxane (1.5 L) and water (500 mL). After the air was purged by bubbling N2 into the solution, the resulting solution was stirred at 80° C. under N2 for 14 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 0-25% ethyl acetate in CH2Cl2, and then crystallized from methanol, to afford 35 g (70%) of the product as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[S:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(CC)C(=O)c1cccc(F)c1
Product: CCN(CC)C(=S)c1cccc(F)c1
Yield: 142 %

Procedure:
A mixture of N,N-diethyl-3-fluorobenzamide (4.69 g, 24 mmol) (cf Mills, et al., "Directed Ortho Metalation of N,N-Diethylbenzamides. Silicon Protection of Ortho Sites and the o-Methyl Group," J. of Organic Chemistry 54: 4372-4385, 1989), Lawesson's reagent (6.47 g, 16 mmol) and xylenes (150 mL) was refluxed overnight, then was concentrated and kugelrohr distilled (105°-110° C. at 0.25 torr) to yield 4.8 g N,N-diethyl-3-(fluoro)thiobenzamide as a yellow oil, a 95% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CSC(=O)N1
Reactant: CN1CCCN(c2ccn3ncc(C=O)c3n2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCCN(c2ccn3ncc(C=C4SC(=O)NC4=O)c3n2)CC1
Temperature: 70 °C

Procedure:
To 5-(4-methyl-1,4-diazepan-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (36 mg, 0.138 mmol) in EtOH was added 2,4-thiazolidinedione (16 mg, 0.138 mmol) and piperidine (14 μL, 0.138 mmol). The mixture was heated at 70° C. and purified by HPLC to yield 5-((5-(4-methyl-1,4-diazepan-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=359)
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:3]1.[NH3:21].Cl>C(O)(C)C>[ClH:1].[NH2:21][C:17]([CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH:4]1[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:2][CH2:3]1)=[O:19]
Reactant: N
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Agent: Cl
Solvent: CC(C)O
Product: NC(=O)CCNCCC1COc2ccccc2C1
Reaction time: 12 h

Procedure:
3 g (100 mmol) of N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride (example 4) are added to 20 ml of 5.5N methanolic ammonia solution. The mixture is stirred in a bomb tube for 12 hours at 60°. Subsequently, the reaction mixture is concentrated by evaporation, the resulting residue is dissolved in 2N hydrochloric acid, and the acidic solution is extracted with diethyl ether. The acidic aqueous phase is rendered alkaline with 2N sodium hydroxide solution and extracted with diethyl ether. The combined ethereal phases are washed in succession with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated by evaporation, yielding the crude base in the form of an oil. The crude base is dissolved in a small amount of isopropanol. Ethereal hydrochloric acid is added to the isopropanol solution until the mixture gives a weakly acidic reaction. The precipitate is filtered off and recrystallized from isopropanol/diethyl ether, yielding 0.6 g of N-(2-aminocarbonylethyl)-N-[2-(chroman-3-yl)ethyl]amine hydrochloride melting at 220° to 222°.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCC(c3ccccn3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C2CCNCC2)nc1
Reaction time: 24 h
Yield: 100.3 %

Procedure:
To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 mL), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 mL EtOAc and 50 mL water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane: EtOAc, 4. 5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 mL), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution was refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL chloroform and 5 mL water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate:methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ 1.45 (s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 ( s, 1 H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 0.098 g (100%) of 3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[N:10][C:9]([C:17]([O:19]C)=[O:18])=[CH:8]2>O.O.O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH:11]=[N:10][C:9]([C:17]([OH:19])=[O:18])=[CH:8]2
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cnc(C(=O)O)cc2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of sodium hydroxide (4.38 g, 109.4 mmol) in 70 ml of water was added to a solution of 6,7-dimethoxy-3-isoquinolinecarboxylic acid, methyl ester (22.54 g, 91.2 mmol) in 1800 ml of water:tetrahydrofuran 1:1. After stirring overnight at room temperature, the tetrahydrofuran was distilled off in vacuo and the pH of the remaining aqueous solution was brought to 3 with 3N hydrochloric acid. The resulting precipitate was filtered off with suction, washed with water and dried in vacuo. Yield: 19.57 g; melting point 228.2° C.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:27]=1[C:28](N(OC)C)=[O:29]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:28](=[O:29])[C:27]3[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:26]=3[O:25][CH3:24])=[N:3][CH:4]=[C:5]([Cl:23])[CH:6]=2)[CH2:20][O:21][CH3:22])(=[O:11])=[O:10])=[CH:13][C:14]=1[CH3:19]
Reactant: COc1cccc(C)c1C(=O)N(C)OC
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C)c1
Product: COCN(c1cc(Cl)cnc1C(=O)c1c(C)cccc1OC)S(=O)(=O)c1ccc(Cl)c(C)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-methyl-benzenesulfonamide was prepared from N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-methyl-benzenesulfonamide and 2,N-Dimethoxy-6,N-dimethyl-benzamide according to previously described procedure example 29. The product was purified by chromatography on silica gel using ethyl acetate-hexane. MS m/z: 509.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[N:4]=[C:5]([S:26][CH3:27])[C:6](=[N:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9](O)[C:8]=1[F:16].FC1C([CH2:38][O:39][CH2:40][CH2:41][O:42][Si](C(C)C)(C(C)C)C(C)C)=CC(OC)=CC=1C=O>>[CH3:1][O:2][C:3](=[O:28])[N:4]=[C:5]([S:26][CH3:27])[C:6](=[N:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([CH2:38][O:39][CH2:40][CH2:41][OH:42])[C:8]=1[F:16]
Reactant: COc1cc(C=O)c(F)c(COCCO[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(O)c1F
Product: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(COCCO)c1F

Procedure:
The same procedure was carried out as in Examples (163a) to (163b), except that 2-fluoro-5-methoxy-3-(2-triisopropylsilanyloxyethoxymethyl)benzaldehyde was used instead of 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde in Example (163a), to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[CH:13][C:12]=1[S:21]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(O)c(Cl)c1
Product: O=S(=O)(Nc1ccc(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3-chloro-4-hydroxy-phenyl)-4-trifluoromethylbenzenesulfonamide was synthesized (92%) from 4-amino-2-chlorophenol (Aldrich) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manner as described in Example 421. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.17 (s, 1H), 8.14 (d, J=1.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 6.88 (dd, J=8.7, 2.5 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H). MS (EI): m/z 384 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[O:22][CH3:23])=[C:4]([CH3:24])[N:3]=1.O=S(Cl)[Cl:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:9]([NH:8][C:6]1[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:27])=[CH:16][C:15]=2[O:22][CH3:23])=[C:4]([CH3:24])[N:3]=[C:2]([NH2:1])[N:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CO)cc1OC
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Temperature: 25 °C

Procedure:
The product from step (iii) (2.2 g) in DCM (100 mL) was cooled to 0° C. and SOCl2 (0.486 ml) was added dropwise. The reaction was allowed to warm up to rt over 1 hr, and poured cautiously into sat. NaHCO3 and the aqueous phase was separated. The organic phase was dried, filtered and the solvent evaporated under reduced pressure to give the subtitle compound as a yellow solid, 2.260 g.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]([O:25]CC)=O)=[O:20])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH3:28]>CO>[C:1]1([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]([NH2:28])=[O:25])=[O:20])[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COC(=O)N1CCC(COc2cccc3ccccc23)CC1
Reactant: N
Solvent: CO
Product: NC(=O)COC(=O)N1CCC(COc2cccc3ccccc23)CC1
Yield: 83.6 %

Procedure:
1.0 g (2.69 mmol) of 2-(ethyloxy)-2-oxoethyl 4-[(1-naphthalenyloxy)methyl]-1-piperidinecarboxylate, prepared in Step 7.3, is dissolved in 12 ml of a 7N solution of ammonia (84 mmol) in methanol. The solution is left to react at ambient temperature for 3 days. It is evaporated to dryness and the residue is purified by chromatography on silica gel, eluting with a 90/10 then 80/20, 70/30 and 50/50 mixture of dichloromethane and ethyl acetate and then with a 95/5 mixture of ethyl acetate and methanol. The eluate is subsequently recrystallized from ethyl acetate, to give 0.77 g of product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[C:11]#[N:12].[I-:13].[Na+].Cl.O>C(#N)C>[I:13][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: [I-]
Reactant: N#Cc1cc2sccc2nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1cc2sccc2nc1I

Procedure:
A solution of 5 g of 5-chlorothieno[3,2-b]pyridine-6-carbonitrile, 10 g of sodium iodide and 1 ml of concentrated hydrochloric acid in 70 ml of acetonitrile was heated at reflux for 65 hours. The mixture was then poured into water and the resulting solid was separated by filtration. The solid was recrystallized from acetone to give 5-iodothieno[3,2-b]pyridine-6-carbonitrile as white needles melting at about 190°-191° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: OB(O)c1cccs1
Product: FC(F)(F)c1cccc(-c2cccs2)c1

Procedure:
3-Bromobenzotrifluoride and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(3-trifluoromethylphenyl)thiophene as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N:10]2[C:17]3[N:13]([N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[CH:12]=[CH:11]2)=[CH:5][C:3]=1[NH2:4].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:40])([F:39])([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([S:35]([F:39])([F:40])([F:36])([F:37])[F:38])[CH:34]=1)[C:29]([NH:4][C:3]1[CH:5]=[C:6]([N:10]2[C:17]3[N:13]([N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[CH:12]=[CH:11]2)[C:7]([CH3:9])=[CH:8][C:2]=1[F:1])=[O:30])#[N:25]
Reactant: Cc1cc(F)c(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: Cc1cc(F)c(NC(=O)c2cc(C#N)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
55 mg (0.18 mmol) of the compound of Example 12A and 58 mg (85% pure, 0.18 mmol) of the compound of Example 23A were reacted and worked up analogously to the procedure of Example 38. This gave 43 mg (42% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[CH:22]([N:25]=[C:26]=[S:27])([CH3:24])[CH3:23]>CC(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[S:27])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(S(N)(=O)=O)c(N)c1
Reactant: CC(C)N=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)NC(=S)NS(=O)(=O)c1ccc(S(C)(=O)=O)cc1N
Temperature: 50 °C

Procedure:
A mixture of 2-amino-4-methanesulfonylbenzenesulfonamide (2.5 g), potassium carbonate (1.66 g) and isopropyl isothiocyanate (1.22 g) in 20 ml of dry acetone was heated at 50° C. for 18 h. Then the reaction mixture was evaporated in vacuo and the residue was dissolved in 25 ml of water. Then the solution was adjusted to pH 2 by dropwise addition of 4 M HCl at 0° C. with stirring. After stirring for 2 h the product was filtered off and dried, yielding the title compound as white crystals; m.p. 151-153° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[NH2:16][C:17]1[S:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1>C(#N)C>[CH3:3][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]=1)=[O:15])[CH3:2]
Reactant: Nc1nc(-c2ccccc2)ns1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CC#N
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1nc(-c2ccccc2)ns1
Yield: 46.4 %

Procedure:
2,6-Diisopropylphenylisocyanate (1.9 g, 9.4 mmol) was added to a refluxing solution of 5-amino-3-phenyl-1,2,4-thiadiazole (1.5 g, 8.5 mmol) in acetonitrile (60 mL). The mixture was refluxed for 18 hours, allowed to cool, filtered, and the filtrate concentrated, taken up in ethyl acetate (150 mL), and washed with water (3×50 mL). The organics were dried over Na2SO4, filtered, concentrated, and the resulting solid washed with hexane and recrystallized from acetonitrile to give a white solid (1.50 g, 46%), m.p. 180°-183° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH2:11])[C:6]([O:9][CH3:10])=[N:7][CH:8]=1.C(#N)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([NH:11][S:16]([CH3:15])(=[O:18])=[O:17])[C:6]([O:9][CH3:10])=[N:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncc(Br)cc1N
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-2-methoxypyridin-3-amine hydrochloride (100 g, 1 wt, 1 eq) is charged to a CLR containing a mixture of acetonitrile (220 mL, 2.2 vols) and pyridine (101 mL, 1.01 vols, 99 g, 0.99 wt) at room temperature. Methanesulfonyl chloride (56.4 g, 0.564 wt, 1.18 eq) is then added to the mixture over 20 minutes whilst maintaining the temperature at 20° C. Having stirred at 20° C. for a further 1.5 hours, the mixture is sampled and analysed by HPLC. The completed reaction is quenched by the addition of water over 1 hour, maintaining the mixture at 20° C. and with increased stirrer speed. The resulting slurry is stirred for 17 hours and then filtered in vacuo. The cake is washed with 3:1 water:acetonitrile (2×50 mL, 2×0.5 vols) and then dried under vacuum at 40-45° C. to afford N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[CH:28](Br)([CH3:30])[CH3:29].O>CN(C)C=O>[CH:28]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20])([CH3:30])[CH3:29]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1sc(-c2ccc(O)c([N+](=O)[O-])c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ccc(OC(C)C)c([N+](=O)[O-])c2)nc1C
Temperature: 70 °C
Yield: 75.7 %

Procedure:
200 mg of Ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate prepared in (1) was dissolved in 3 ml of N,N-dimethylformamide, 540 mg of anhydrous potassium carbonate and 440 mg of isopropyl bromide were added thereto, and the mixture was heated at 70° C. for 18 hours. After the reaction mixture was cooled, 20 ml of water was added thereto. The mixture was extracted twice with 30 ml of ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and the solvent was removed by distillation. The resulting crystal was recrystallized from ethanol to give 172 mg of ethyl 2-(4-isopropoxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylate. This product was hydrolyzed by a conventional process, and the resulting crystal was recrystallized from a 80% aqueous ethanol solution to give 135 mg of 2-(4-isopropoxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid (yield: