Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.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+].Cl[C:56]1[CH:61]=[C:60]([O:62][CH3:63])[N:59]=[C:58]([S:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[C:67]=2[F:73])[N:57]=1.[Cl-].[NH4+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:73][C:67]1[C:68]([F:72])=[CH:69][CH:70]=[CH:71][C:66]=1[CH2:65][S:64][C:58]1[N:57]=[C:56]([NH:14][S:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)(=[O:12])=[O:13])[CH:61]=[C:60]([O:62][CH3:63])[N:59]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)N1CCC2(CC1)OCCO2
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N2CCC3(CC2)OCCO3)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonamide (the product of step i), (0.29 g), tris(dibenzylideneacetone)-dipalladium (0) (61 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (32 mg), cesium carbonate (0.32 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i, 0.20 g) in anhydrous dioxane (8 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 15 min. Saturated aqueous ammonium chloride was added and the resulting mixture extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 1:19 to 2:3 mixture of ethyl acetate and iso-hexane as eluent to give the subtitle compound as a yellow foam. Yield: 0.27 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.[Cl-].[CH3:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1[CH:19]=[N+:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH:19]([C:18]1[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=1[O:16][CH3:15])[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[C:8]([OH:13])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: COc1ccc2c(C(c3ccccc3OC)N3CCOCC3)c(O)ccc2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 6-methoxy-2-naphthol and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 28.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13]>C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)=[O:4])[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(CC(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
4.3 g of 2-Chloro-4′-fluoroacetophenone and 8.0 g of 1-ethoxycarbonylpiperazine were dissolved in 30 ml of chloroform and refluxed with heating for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and 25% aqueous ammonia solution was added, followed by extraction with ether. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give a crude 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-oxoethyl]piperazine, which was then dissolved in 40 ml of ethanol, and a solution prepared by adding 1 drop of 5% potassium hydroxide and 1.0 g of sodium borohydride to 5 ml of water was added, followed by heating at 50° C. for an hour. After concentration of the reaction solution under reduced pressure, water was added, followed by extraction with ether, and the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. To the residue was poured 50 ml of 4M hydrogen chloride/ethyl acetate solution, the solution was concentrated under reduced pressure, and the resulting solid was washed with ether to give 8.3 g of 1-ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-hydroxyethyl]piperazine hydrochloride.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.P(O)([O-])([O-])=O.[Na+].[Na+].[O:21]=[CH:22][C@@H:23]([C@H:25]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[OH:26])[OH:24].[OH:33][CH2:34][C:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43]O)[OH:42])[OH:40])[OH:38])=[O:36]>>[CH2:31]([OH:32])[C@H:29]1[O:30][C@H:22]([O:21][CH2:43][C@H:41]2[O:42][C:35]([OH:36])([CH2:34][OH:33])[C@@H:37]([OH:38])[C@@H:39]2[OH:40])[C@H:23]([OH:24])[C@@H:25]([OH:26])[C@@H:27]1[OH:28]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: OC[C@H]1O[C@H](OC[C@H]2OC(O)(CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
840 units of isomaltase of yeast origin was added to 0.5 ml of a reaction mixture of a citric acid-disodium phosphate buffer (pH 6.0) containing 10% glucose and 30% fructose, and the reaction was carried out at 30° C. overnight. The yield of the isomaltulose formed during the reaction was 17%, in relation the glucose added. Note, the isomaltulose was determined according to the same procedures as described in Example 1.
Reaction SMILES: [F:1][C:2]1([F:15])[CH2:7][C@H:6]2[CH2:8][C@H:4]([C:5]2([CH3:10])[CH3:9])[C@@H:3]1[CH2:11][C:12](Cl)=[O:13].[NH2:16][N:17]1[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:34].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:34])[N:17]([NH:16][C:12](=[O:13])[CH2:11][C@@H:3]3[C:2]([F:15])([F:1])[CH2:7][C@H:6]4[CH2:8][C@@H:4]3[C:5]4([CH3:10])[CH3:9])[N:26]=2)=[CH:28][CH:29]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: CC1(C)[C@@H]2C[C@H]1[C@H](CC(=O)Cl)C(F)(F)C2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)[C@@H]2C[C@H]1[C@H](CC(=O)Nn1nc(-c3ccc(Cl)cc3)c3ccccc3c1=O)C(F)(F)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of the above crude 2-((1S,2S,5R)-3,3-difluoro-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)acetyl chloride (50 mg, 0.211 mmol) and the product from Example 86A (57.4 mg, 0.211 mmol) in 10 mL of CHCl3 was added pyridine (0.051 mL, 0.634 mmol). The reaction is stirred at rt for 12 hours and then reluxed for 16 hours, and quenched with 1M NaHCO3 (10 mL). The aq layer was extracted with EtOAc (2×20 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-40% of EtOAc in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.51 (s, 1H), 8.39-8.43 (m, 1H), 7.94-8.00 (m, 2H), 7.70-7.76 (m, 1H), 7.58-7.70 (m, 4H), 2.92-3.09 (m, 1H), 2.81 (dd, J=15.3, 6.4 Hz, 1H), 2.36-2.45 (m, 3H), 2.11-2.16 (m, 1H), 1.93-2.04 (m, 1H), 1.27 (s, 3H), 1.08-1.20 (m, 2H), 1.01 (s, 3H); MS (ESI+) M/Z 472 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.[CH2:10]([S:12]Cl)[CH3:11].Cl>C1(C)C=CC=CC=1>[CH2:10]([S:12][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])[CH3:11]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: CCSCl
Agent: Cl
Solvent: Cc1ccccc1
Product: CCSc1c(O)cc(C)oc1=O
Temperature: 25 °C

Procedure:
A mixture of 37.2 g. (0.295 mole) of 4-hydroxy-6-methyl-2-pyrone and 28.4 g. (0.295 mole) of ethanesulfenyl chloride in 900 ml. of toluene was heated under reflux with stirring at 75°C. for two hours, during which time hydrogen chloride evolved. The reaction mixture was cooled to room temperature and filtered to remove 24.2 g. of a solid (m. 170°-172°C. - probably a mixture of starting pyrone and an unknown substance). The filtrate was concentrated to give 13.3 g. (25 percent) of the product as a white solid, m. 94°-95°C. Recrystallization from cyclohexane gave the pure product as white crystals, m. 101°-102°C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:16])[NH:12][CH2:13][CH2:14][OH:15])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:6]([O:10][C:11]([NH:12][CH2:13][CH2:14][O:15][S:2]([CH3:1])(=[O:4])=[O:3])=[O:16])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.60 mL, 7.76 mmol) was added to a solution of (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (1.04 g, 6.46 mmol) and triethylamine (1.35 mL, 9.70 mmol) in dichloromethane (35 mL) cooled to 0° C. The solution was stirred for one hour, after which time it was diluted with ethyl acetate, washed with saturated NaHCO3 (2×), brine, dried over Na2SO4 and concentrated to a thick colorless liquid (1.37 g, 89%).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1.C(Cl)Cl>CC(N(C)C)=O.[Zn].[Cu]I>[Cl:22][C:23]1[C:28]([CH:19]2[CH2:20][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18]2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Clc1nccnc1Cl
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 34.9 %

Procedure:
A 12 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (745 g, preactivated according to the above Preparation 1, 11.4 mol, 2 eq.) and DMA (2 L, anhydrous). 1,2-dibromoethane (71 mL, 0.855 mol, 0.15 eq, Aldrich) was then added over 10 min, followed by TMSCl (108 mL, 0.855 mol, 0.15 eq, Acros) over 20 min. The reaction mixture was stirred for 25 min at RT. A solution of N-Boc-3-iodoazetidine (2) (2420 g, 8.55 mol, 1.5 eq, CNH Technologies) in DMA (5 L, anhydrous) was added via a 2 L addition funnel over 2 h keeping the internal temperature below 65° C. using a water bath. The suspension was stirred for 1 h at RT at which point it was degassed with nitrogen. Stirring was stopped and the suspension was allowed to stand. A 22 L 3-neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dichloropyrazine (6) (850 g, 5.70 mol, 1.0 eq, AK Scientific), PdCl2dppf.CH2Cl2 (140 g, 171 mmol, 0.03 eq, Aldrich), CuI (67.3 g, 353 mmol, 0.062 eq, Aldrich), and DMA (5 L, anhydrous). The solution was degassed with nitrogen. The clear zinc reagent solution above the residual solid zinc was poured into the 22 L flask under nitrogen. The brown solution was degassed with nitrogen and heated to 80° C. for 16 h at which point LCMS indicated complete conversion of 2,3-dichloropyrazine (6). The reaction mixture was transferred to brine (8 L) in 50 L reparatory funnel. Water (8 L) and EtOAc (15 L) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 L). The combined organics were washed with water (3×10 L) and brine (5 L), dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=10:1) to obtain 536 g of pure tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7) and 121 g of mixed fractions. The impure material was distilled under high vacuum to remove the impurity (N-Boc-azetidine) to give 81 g of pure tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(F)=C(C(F)(F)F)C=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:27][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][N:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(C(F)(F)F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Fc1ccc(NCC2CCCC2)cc1C(F)(F)F
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(C(F)(F)F)c2)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-fluoro-3-trifluoromethylphenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-fluoro-3-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:24]([O:26][CH2:27][CH2:28][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)(=[O:25])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCN1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1

Procedure:
20 Grams of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril and 3 ml of ethyl 2-bromoacetate and 1.5 ml of triethylamine are mixed with 20 ml of dimethyl formamide at 50°-60° C. for 8 hours under stirring conditions. The reaction mixture is concentrated under reduced pressure and to the viscous residue thus obtained are added 30 ml of 2% sodium hydrogencarbonate aqueous solution followed by extraction with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue is purified by silica gel chromatography and recrystallized from isopropanol to obtain 5-{3-[4-(2-acetyloxyethyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 131°-132° C.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][O:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12](=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[H][H]>C(O)C.[Pd].[C]>[F:33][C:31]([F:32])([F:34])[C:29]1[CH:28]=[C:5]([CH:4]=[CH:3][C:30]=1[C:31]([F:34])([F:33])[F:32])[CH2:6][O:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1
Reactant: O=C(C=Cc1ccncc1)NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CCc1ccncc1)NCC(COCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)c1ccccc1
Yield: 131.1 %

Procedure:
Compound 45 (4.00 g, 7.8 mmol) was dissolved in ethanol (100 mL), a 5% Pd-carbon catalyst (0.5 g) was added thereto and the mixture was stirred for 20 hours in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was evaporated in vacuo and the crystals separated out therefrom were filtered after addition of petroleum ether to give the Compound 48 (2.61 g, 66%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[O:15]1[CH2:29][CH:16]1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CC(C)=O>CO>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[OH:15][CH:16]([CH2:29][NH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH2:17][O:18][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)NCCN)cc1
Reactant: COC(=O)c1ccccc1OCC1CO1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1OCC(O)CNCCNS(=O)(=O)c1ccc(C)cc1

Procedure:
A solution of 2.15 g of N-(2-aminoethyl)-p-toluenesulfonamide (0.1 mole) and 2.08 g of methyl 2-(2,3-epoxypropoxy)benzoate (0.01 mole) in 100 ml of methanol was stored at 25° C. for 4 hours. The methanol was then removed under reduced pressure, leaving an oil (NMR indicated only mono-alkylated product). The oil was then dissolved in 50 ml of methanol and an equimolar quantity of oxalic acid was added to the solution. 50 Ml of acetone was added, and the product crystallized upon refrigeration. The product was recrystallization from acetone/methanol (1:1) to yield 1.4 g of product which had a melting point of 165°-166° C. The elemental analysis (CHN) and NMR spectrum were consistent with the assigned structure.
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:23][CH2:24][CH3:25])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:6][CH:5]=1.COC1C=C(C#C)C=CC=1OC.[NH2:38][C:39](N)=[O:40]>>[OH:1][N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:23][CH2:24][CH3:25])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:8][CH:9]=1)[C:39]([NH2:38])=[O:40]
Reactant: CCOC(C#Cc1ccc(OC)c(OC)c1)c1ccc(CNO)cc1
Reactant: NC(N)=O
Agent: C#Cc1ccc(OC)c(OC)c1
Product: CCOC(C#Cc1ccc(OC)c(OC)c1)c1ccc(CN(O)C(N)=O)cc1

Procedure:
1-[4-hydroxyaminomethylphenyl]-3-[3,4-dimethoxyphenyl]1-ethoxy-prop-2-yne, prepared from 3,4-dimethoxyphenylacetylene according to Example 5, was converted into the corresponding urea compound following the procedure of Example 8.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([OH:44])=O)=[C:40]([F:48])[CH:39]=3)[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.CS(N)(=O)=O.[CH:54]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:56][CH2:55]1>>[C:26]12([CH2:36][O:37][C:38]3[C:46]([Cl:47])=[CH:45][C:41]([C:42]([NH:60][S:57]([CH:54]4[CH2:56][CH2:55]4)(=[O:59])=[O:58])=[O:44])=[C:40]([F:48])[CH:39]=3)[CH2:33][CH:32]3[CH2:34][CH:28]([CH2:29][CH:30]([CH2:31]3)[CH2:35]1)[CH2:27]2
Reactant: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: NS(=O)(=O)C1CC1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 50 step 5 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid and methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as colorless solid (0.13 g, 49%): 1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.24 (d, J=12.5 Hz, 1H), 3.73 (s, 2H), 3.12-3.03 (m, 1H), 1.99 (s, 3H), 1.75-1.64 (m, 12H), 1.15-1.11 (m, 4H); MS (ES+) m/z 442.1, 444.1 (M+1); MS (ES−) m/z 440.2, 442.2 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1cc(=O)oc2cc(O)ccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(CC(=O)O)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To 9 (1 g, 4.53 mmol) was added 25 ml of acetic anhydride and 5 ml of pyridine, and the reaction was allowed to stir at RT for 30 minutes. Upon removal of solvent in vacuo, the residue was taken into ethyl acetate and washed with 1 N HCl (2×30 ml), water (2×30 ml) and brine (2×30 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to afford 10 (30% yield). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.9 Hz, 1H), 7.23 (d, J=5.6 Hz, 1H), 7.24 (s, 1H), 6.47 (s, 1H), 2.94 (s, 2H), 2.33 (s, 3H). MS (ESI): m/z 263.0 [(M+H)]+.
Reaction SMILES: [CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][CH2:11][C:12](O)=[O:13])[CH2:2]1.S(Cl)([Cl:18])=O>>[CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][CH2:11][C:12]([Cl:18])=[O:13])[CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: CC1CCC(C(C)C)C(OCC(=O)O)C1
Product: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Yield: 107.4 %

Procedure:
0.771 g (3.6 mmol) of (-)-menthoxyacetic acid is stirred under reflux with 2.1 g of thionyl chloride for 4 to 5 h. The thionyl chloride is first removed from the solution by distillation under reduced pressure. 3 ml of dry benzene are then added in order to remove residual thionyl chloride by means of vacuum distillation. 0.9 g of the title compound is obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH:18]([CH2:37][CH2:36][CH3:40])[C:19]([O:21][CH3:22])=[O:20])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2]
Reactant: C1CCOC1
Reactant: CCc1sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c2c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc(CC)c(C)c2c1-c1ccc(C)cc1
Yield: 54.3 %

Procedure:
This compound was prepared according to the procedure C from methyl 2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.196 g; 0.554 mmol), LHMDS 1N in THF (0.635 mL; 0.635 mmol), 1-iodopropane (0.090 mL; 0.923 mmol) in DMF (8 mL) for 3.5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.119 g (54%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:2]3[N:18]=[C:5]4[C:6]([C:10]5[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: COc1ncccc1-c1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: COc1ncccc1-c1cccn2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12

Procedure:
[4-{4-[8-(2-Methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-Chloro-8-(2-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.25 g, 50%). MP=101-103° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.75 (s, 1H), 8.80 (d, J=6.58 Hz, 1H), 8.25 (m, 1H), 8.05 (d, 1H), 7.75 (m, 1H), 7.55 (m, 2H), 7.02 (m, 4H), 4.05 (m, 2H), 3.90 (s, 3H), 2.6-2.8 (m, 3H), 1.65 (m, 2H), 1.40 (m, 11H). MS=501 (MH)+.