Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:12](=[O:31])[CH2:13][C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1)=O)C.[O-]CC.[Na+]>C(O)C>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:11]2[C@@H:7]3[C@@H:6]([CH2:10][CH2:9][CH2:8]3)[C:4]([OH:3])=[C:13]([C:14]3[NH:19][C:18]4[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][C:17]=4[S:16](=[O:30])(=[O:29])[N:15]=3)[C:12]2=[O:31])=[CH:34][CH:35]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Yield: 59.2 %

Procedure:
To a solution of cis-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.044 g, 0.076 mmol) in ethanol (10 mL) was added a 21% w/w solution of sodium ethoxide in ethanol (0.0981 g, 0.303 mmol) and the reaction mixture was heated at 60° C. for 16 h. Upon cooling the reaction mixture was quenched with a 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the crude product, which was further purified by prep-HPLC to afford cis-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.0241 g, 0.045 mmol, 59.4%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.48-1.55 (4H, m), 1.95-2.10 (4H, m), 3.07 (3H, s), 3.34 (1H, bs), 3.86 (1H, bs), 4.48 (1H, d, J=14.7 Hz), 4.91 (1H, d, J=14.8 Hz), 7.16 (2H, t, J=8.9 Hz), 7.40 (2H, t, J=6.6 Hz), 7.52 (1H, d, J=10.7 Hz), 7.59 (2H, d, J=8.4 Hz), 10.18 (1H, s). LC-MS (ESI) calcd for C23H23FN4O6S2 534.10, found 535.4 [M+H+].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O-])=[O:14])[CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH2:13][OH:14])[CH:2]=1
Reactant: O=C([O-])C=Cc1cnc2ccccc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCC=Cc1cnc2ccccc2c1
Temperature: -57 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
The 3-(3-quinolyl)-2-propenoate (141 g, 0.621 moles) was dissolved in 2.0 L anhydrous methylene chloride in a 5-L round-bottom flask with overhead stirring and cooled to −57° C. with isopropanol/dry ice bath. Diisobutylaluminum hydride (1.55 L, 1.0 M in methylene chloride) was added in a slow stream, keeping the temperature of the reaction mixture below −40° C. After 30 minutes, the starting ester is consumed. While cooling with dry ice/acetone, 434 mL MeOH was added dropwise and the mixture was allowed to warm to room temperature. Then, 2 L of 10% sodium potassium tartrate was added portionwise to the solution and the mixture was stirred for 1 h at room temperature. The layers were separated. The organic layer was washed with 2 L aq. NaCl solution and dried over MgSO4. Evaporation gave a solid which was recrystallized from EtOAc to afford a yield of 71 g (62%) of a pinkish solid.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[C:8]([O:12][NH:13][C:14]([C@:16]1([OH:45])[C@H:21]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C.C(OCC)=O>CO>[C:8]([O:12][NH:13][C:14]([C@:16]1([OH:45])[C@H:21]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:37]=[C:36]([CH3:44])[CH:35]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:20][CH2:19][N:18]([CH:3]=[O:4])[CH2:17]1)=[O:15])([CH3:11])([CH3:10])[CH3:9]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(O)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 46 °C
Yield: 61.3 %

Procedure:
(3R,4R)-N-tert-Butoxy-3-hydroxy-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide trifluoroacetic acid salt (250 mg, 0.32 mmol) was dissolved in methanol (1 mL) and diisopropylethylamine (0.23 mL, 1.3 mmol, 4 eq) was added, followed by ethyl formate (5 mL, excess). The reaction was heated at 46° C. for 5 h, and then concentrated in vacuo. The residue was triturated with ether to yield 112 mg (62%) of (3R,4R)-N-tert-butoxy-1-formyl-3-hydroxy-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide as white waxy solid. MS: (M+H)+=571.1.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH:15]([CH:21]([CH3:23])[CH3:22])[C:16]([O:18]CC)=[O:17].O>C(O)C>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH:15]([CH:21]([CH3:23])[CH3:22])[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
To 0.60 grams of sodium hydroxide dissolved in 10 ml of ethanol was added 3.30 g of the above ester. The mixture was stirred at room temperature for 4 hours, after which water was added, and the mixture was washed with toluene. The organic phase was discarded. The product was acidified, extracted into ether, washed with water, dried and solvent removed to yield 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid, m.p. 132°-135°, in 90% yield.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=1[C:33]([NH:35][O:36][CH3:37])=[O:34]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=3[C:33](=[O:34])[NH:35][O:36][CH3:37])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CONC(=O)c1ccccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NOC)n2)c(OC)c1)OCC
Yield: 73.4 %

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.060 g, 0.13 mmol) and 2-amino-N-methoxybenzamide (Compound 259A, 0.0242 g, 0.145 mmol). The crude material was purified on an Isco Combiflash unit using 0→5% MeOH in DCM as eluent to afford 55.7 mg of the title compound (72%). 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.70 (br. s., 1H), 8.79 (br. s., 1H), 8.38 (s, 1H), 7.48-7.57 (m, 2H), 7.42 (t, J=7.71 Hz, 1H), 7.09 (t, J=7.33 Hz, 1H), 7.01 (s, 1H), 6.83 (td, J=2.02, 8.08 Hz, 1H), 3.91-4.04 (m, 4H), 3.76 (s, 3H), 3.70 (s, 3H), 3.18-3.28 (m, 2H), 1.19 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 585.1915 [MH+]. HPLC: tR=1.41 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=[C:33]([CH3:41])[CH:32]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:5])C.[OH-].[Li+]>C1COCC1.CO.O>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH:7]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[C:33]([CH3:41])[CH:32]=3)=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CN(C(=O)OC(C)(C)C)CCC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.6 g, 1.03 mmol) and lithium hydroxide (0.148 g, 6.18 mmol) in THF:methanol:water (3:2:2 mL) was stirred at 25° C. for 19 h. The solution was then concentrated in vacuo to provide 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester as a crude solid (0.55 g, 96%). MS: 556 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:21]>ClCCl.CCOCC>[ClH:21].[ClH:21].[O:17]1[CH2:16][CH2:15][N:14]([C@H:11]2[CH2:10][CH2:9][C@H:8]([NH2:7])[CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: N[C@H]1CC[C@H](N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of trans-tert-butyl-4-morpholinocyclohexylcarbamate (19.2 g, 67.5 mmol) in dichloromethane (100 ml) was added HCl (100 ml, 400 mmol) (4M in dioxane) and the reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted with ether and solid salt was filtered off, and dried in an oven.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:55]1[C:63]2[CH:62]=[CH:61][S:60][C:59]=2[CH:58]=[C:57]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH:56]=1)(=O)=O>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([O:3][C:1]([NH:2][C:55]1[C:63]2[CH:62]=[CH:61][S:60][C:59]=2[CH:58]=[C:57]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH:56]=1)=[O:8])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)c2ccsc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(NC(=O)OC(C)(C)C)c2ccsc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Tert-butyl carbamate (81 mg), palladium acetate (4 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl biphenyl (17 mg), and cesium carbonate (340 mg) were added to a solution of ethyl 4-(trifluoromethylsulfonyloxy)benzo[b]thiophene-6-carboxylate obtained in the above-described Step 2 (120 mg) in dioxane (2 ml), and the reaction solution was stirred at 100° C. for 3 hours. The reaction solution was diluted with ethyl acetate, and washed successively with a saturated aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain ethyl 4-(tert-butoxycarbonylamino)benzo[b]thiophene-6-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22]>>[OH:23][C:21]([CH3:24])([CH3:22])[CH2:20][NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: CC(C)(O)CNC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 1-amino-2-methylpropan-2-ol (CAN 2854-16-2) as starting materials and isolated (28 mg, 34%) as a yellow oil; MS (ESI, m/z): 333.5 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:8]=[CH2:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(Cl)(Cl)[Cl:12]>>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:10])([CH3:1])/[CH:8]=[CH:9]/[Cl:12])[CH3:7]
Reactant: ClC(Cl)Cl
Reactant: C=CC(C)(C)C(=O)OCC
Product: CCOC(=O)C(C)(C)/C=C/Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A five liter four neck round bottom flask equipped with thermometer, cold bath, mechanical stirrer and inlet tube for subsurface gas introduction was charged with 470 g of ethyl 2,2-dimethylbut-3-enoate (prepared according to the procedure of J. L. Hermann, G. R. Kiecgykowski, and R. H. Schessinger, Tetr. Lett., 2425 (1973)) and 2500 mL of chloroform. The solution was cooled to 0° C. and chlorine was bubbled into the solution at a rate that kept the internal temperature below 10° C. (3 hours total addition time). After removal of solvent, the residue (703 g) was taken up in 2500 mL of DMF and cooled to -5° C. Potassium t-butoxide (636 g) was added to the stirred solution at a rate such that the temperature remained below 0° C. (2.3 hours total addition time). After the addition was complete, the solution was stirred an additional 1 hour, then poured onto 3 L of ice and water and extracted into 2× 2 L of hexane. The combined hexane fraction was washed with 2×200 mL of saturated brine solution, dried over Na2SO4 and stripped to give 422 g of (E)-ethyl-4-chloro-2,2-dimethylbut-3-enoate an oil. This was then added over 1/2 hour to a stirred, cooled (-5° C.) solution of KOH (280 g) in methanol (1 L). Stirring was continued for 16 hours at ambient temperature, then the solution was poured into 3 L of ice water and extracted with 2×2 L of ether. The aqueous layer was then acidified to pH 2 using concentrated HCl, and extracted with 2×2 L of ether. The combined acid extracts were dried over Na2SO4 and stripped of solvent to give 222 g of an oil.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[C:6]([OH:13])(=[O:12])/[CH:7]=[CH:8]/[C:9]([OH:11])=[O:10].C1(O)C(=CC(=CC=1)O)C.C(O)C(O)C.C(O)(=O)/C=C/C(O)=O.[OH-].[K+]>>[CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[C:6]([O-:13])(=[O:12])/[CH:7]=[CH:8]/[C:9]([O-:11])=[O:10]
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cc1cc(O)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CC(O)CO
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 193 °C

Procedure:
A conventional ten-gallon stainless steel reactor was charged with 17.02 kg of propylene glycol (available from Ashland Chemical Company of Columbus, Ohio) and 12.98 kg of fumaric acid (available from Huntsman Specialty Chemical of Salt Lake City, Utah). For stability, 3.62 g (120 ppm) of toluhydroquinone (THQ) (available from Aldrich Chemical Company of Milwaukee, Wis.) was added into the reactor. The molar ratio of the charge was 2:1 propylene glycol (PG) to fumaric acid (FA). The mixture was heated under a nitrogen atmosphere at 380° F. (193° C.) for five hours. The endpoint of the reaction was determined by the viscosity of the PG-FA product, which was 360 to 450 cps at 120° F. (49° C.) as determined by a cone-and-plate viscometer, such as that made by ICI of Wilmington, Del. The acid value at the reaction endpoint is typically observed to be 10 to 36 Meq KOH/g of alkyd (milliequivalent of potassium hydroxide per gram of alkyd). This material may be used directly as a film former.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[S-:9][C:10]#[N:11].N1C2C(=CC=CC=2)C=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH2:5]([O:4][C:2]([N:11]=[C:10]=[S:9])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: N#C[S-]
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: CC(C)COC(=O)N=C=S
Temperature: 27.5 °C

Procedure:
136.58 grams (1 mole) of 99% isobutyl chloroformate are added to a 50% thiocyanate solution containing 81 grams (1 mole) of NaSCN, 81 grams of water, 4.36 grams of quinoline (catalyst) and 1.8 grams of Na2CO3 (base) while maintaining a reaction temperature of 25-30° C. with agitation. The reaction is monitored for the consumption of the chloroformate during the formation of an upper layer of isobutoxycarbonyl isothiocyanate (approximately 4 hours). The contents of the reaction vessel are filtered to remove solid sodium chloride and the isobutoxycarbonyl isothiocyanate is isolated in the form of a layer that separates from the aqueous layer.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH3:17])=[C:9]([CH:13]=1)[C:10]([NH2:12])=[O:11])(=O)=O.S(=O)(=O)(O)O.C(O)C>[Zn].O>[CH2:15]([O:14][C:8]1[CH:7]=[CH:6][C:5]([SH:2])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])[CH2:16][CH3:17]
Reactant: CCCOc1ccc(S(=O)(=O)Cl)cc1C(N)=O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CCCOc1ccc(S)cc1C(N)=O
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
Finely powdered 5-chlorosulphonyl-2-propoxybenzamide (3.0 g.; prepared from the product described in Reference Example 1) was added to a mixture of concentrated sulphuric acid (12 ml.), water (25 ml.) and ethanol (25 ml.) at -20° C. The mixture was allowed to warm to -5° C. with stirring, and then powdered zinc (6 g.) was added at such a rate that the temperature did not exceed 0° C. After stirring at between -5° C. and +5° C. for 90 minutes, then at room temperature for 90 minutes, water (50 ml.) was added and the resulting dark suspension was finally heated to boiling for approximately 75 minutes, distilling off a mixture of ethanol and water. When the temperature at the distillation head reached 96° C., distillation was stopped and the residue was cooled to room temperature. The precipitated solid was then extracted with chloroform (3 × 25 ml.). The chloroform extract was filtered to remove any remaining zinc, washed with water (2 × 10 ml.) and dried over sodium sulphate. Removal of the solvent gave an off-white solid which was recrystallised from ethanol at -30° C., to give slightly impure 2-propoxy-5-mercaptobenzamide (1.3 g.). This material was sufficiently pure for use in the next stage. Purer 2-propoxy-5-mercaptobenzamide (0.8 g.), m.p. 108° - 111° C., was obtained by further recrystallisation from a small amount of ethanol (only cooling to 0° C. instead of to -30° C.).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.O1CCOCC1.O.C([O:18][C:19]([C:21]1[N:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:22]=1)=[CH2:20])C>O>[Br:1][CH2:18][C:19]([C:21]1[N:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:22]=1)=[O:20]
Reactant: C=C(OCC)c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: O=C(CBr)c1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.3 %

Procedure:
N-bromosuccinimide (0.55 g, 3.1 mmol) was added to 1,4-dioxane/water (3:1) (20 mL). 2-(1-Ethoxyvinyl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (0.59 g, 1.5 mmol) was then added in small portions at 0° C. Upon completion of addition, the reaction mixture was stirred at room temperature for 20 min. After this time, water was added and the aqueous portion was extracted twice with DCM. The combined organic layers were dried, filtered and evaporated under reduced pressure to yield 2-bromo-1-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)ethanone (600 mg, 69% purity by LCMS), which was used without further purification. LCMS Method Y: retention time 1.996 min, [M+1]=433.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].[F:10][C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Fc1ccc(I)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A 2-Liter 4-neck round-bottom flask, equipped with an overhead mechanical stirrer, a nitrogen inlet, a condenser, placed inside a heating mantle, was charged with 1-ethynyl-4-fluorobenzene (500 g, 4.165 Mol), 1-fluoro-4-iodobenzene (715 g, 3.23 Mol), 22.5 g of dichlorobis(triphenylphosphine)palladium[II] catalyst, 6 g of copper[I] iodide, 8 g of triphenylphosphine, and 800 mL of anhydrous triethylamine. This was heated to reflux (~88° C. ) with stirring. Heating continued for 1 hour after which a gas chromatograph sample showed <1% starting material remained. The reaction mixture was cooled and the copious precipitate was filtered. The solids were washed with dry triethylamine. The combined triethylamine solutions were concentrated on the rotary evaporator and the brown residue was taken up in a minimum of dichloromethane. This was placed on a silica gel plug (about 1.5 kg) and eluted with hexanes (8L). The hexane fractions were concentrated on the rotary evaporator. The solid was recrystallized from methanol. The recrystallized solid, now a pale yellow material, was taken up in portions with hexane and the solution run through another silica gel plug (about 2 kg). The first 8L were clear, the next 16L (using recycled hexane) were yellow. The clear solutions were combined and stripped of solvent to yield a white solid. The yellow solutions were run through another clean silica gel plug to give a clear solution. This was stripped of solvent to give a white solid. The white solids were combined and dried to constant weight in a vacuum oven giving 648 g of the final product. (73% yield, m.p. 95°-97° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24]3[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]4N=N[N:29]=[C:20]4[C:19]=3[N:18]=[C:17]2[CH2:30][CH2:31][CH3:32])(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>[Pt](=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2[C:24]3[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:29])[C:19]=3[N:18]=[C:17]2[CH2:30][CH2:31][CH3:32])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCCS(=O)(=O)c1ccc(F)cc1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCCS(=O)(=O)c1ccc(F)cc1
Reaction time: 48 h
Yield: 37.5 %

Procedure:
A mixture of 7-[5-(4-fluorobenzenesulfonyl)pentyl]-5,6-dimethyl-8-propyl-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine (1.61 g, 3.51 mmol), trifluoroacetic acid (15 mL) and platinum (IV) oxide were added to a Parr vessel and agitated under hydrogen pressure (50 psi, 3.4×105 Pa) for two days. The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure, and the black residue was stirred in concentrated hydrochloric acid (10 mL) for 1.5 hours. The solution was treated with 1 N aqueous sodium hydroxide (100 mL) and solid sodium hydroxide until the solution exhibited a pH of 14. The solution was extracted with chloroform (3×80 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1.8 g of the crude product as a white foam. The crude product was purified by column chromatography on silica gel (eluting with 98:2 chloroform:methanol) and recrystallized from ethyl acetate:hexane. The solid was triturated with ethyl acetate and dried at 70° C. in a vacuum oven overnight to provide 0.57 g of 1-[5-(4-fluorobenzenesulfonyl)pentyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 130.0–132.0° C.