Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([Cl:13])[CH:6]=1>O.CS(C)=O>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([Cl:13])[CH:6]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Potassium cyanide (587 g) was dissolved in a mixed solution of water (1408 mL) and dimethyl sulfoxide (767 g), and a solution of 4-bromo-2-chlorobenzyl bromide (512 g) of Reference Example 13 in dimethylsulfoxide (1663 g) was added dropwise at an inside temperature of 90° C. After stirring at the same temperature for 1 hr, the reaction mixture was poured into water. After partitioning and extraction with ethyl acetate, the organic layer was washed 4 times with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (383 g) as a brown oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1)/[C:13](=[O:19])[NH:14]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:1]1([C:7]#[C:8][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2/[C:12](=[CH:20]/[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)/[C:13](=[O:19])[NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2cccc(Br)c2/C1=C/c1ccc[nH]1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(C#Cc3ccccc3)c2/C1=C/c1ccc[nH]1

Procedure:
Using general Method D above, phenyl acetylene (32 mg, 0.31 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 9) (46.3 mg, 0.16 mmol) using (Ph3P)4Pd (8 mg) (Aldrich) and CuI (1.5 mg) (Aldrich) as catalyst in DMF (2 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h, yielding (Z)-1,3-dihydro-4-(phenylethynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 41 mg, 83%)
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.Br[CH:13]1[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]1=[O:15]>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:13]2[CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14]2=[O:15])=[CH:7][CH:6]=1
Reactant: O=C1NCCCCC1Br
Reactant: Sc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCCCCC1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
54 g (1.0 mol) of sodium methylate and 144.6 g (1.0 mol) of 4-chlorothiophenol are initially introduced into 500 mL of methanol, and a methanolic solution of 192 g (1.0 mol) of α-bromocaprolactam is added dropwise at room temperature. After the exothermic reaction has ceased, the mixture is stirred for a further 3 hours at room temperature, the precipitated sodium bromide is then filtered off under suction and the mother liquor is evaporated down in vacuo. The precipitated crystals are filtered off under suction.
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:27][CH3:28])(=O)=O>CN(C)C=O>[CH2:1]([N:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:27][CH3:28])=[O:10])[C:6](=[O:12])[C:5]2[CH:13]=[C:14]([CH3:16])[S:15][C:4]1=2)[CH3:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 100 °C

Procedure:
A suspension of 0.237 part of 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylic acid and 0.83 part of pulverized potassium carbonate in 6 parts by volume of dry dimethylformamide is stirred under heating at 100° C for 1 hour. To the mixture is then added 0.3 part by volume of diethyl sulfate. The mixture is stirred under heating at 100° C for 1 hour and filtered to remove insoluble material. The filtrate is concentrated to dryness under reduced pressure and the residue is extracted with chloroform. Evaporation of the solvent from the extract gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno(2,3-b)pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142° C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH:11]([Cl:13])[CH3:12])=[O:9].[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:17])[CH:15]=[CH2:16]>ClCCl>[C:8](=[O:9])([O:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:14](=[O:17])[CH:15]=[CH2:16])[O:10][CH:11]([Cl:13])[CH3:12]
Reactant: C=CC(=O)OCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of 1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 4-hydroxybutyl acrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. under a dry N2 atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. the reaction mixture is transferred to a separating funnel with the aid of dichloromethane (10 ml). The reaction mixture is washed with hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and water (2×10 ml). The organic phase is dried (MgSO4) and the solvent evaporated under reduced pressure to give 2.26 g (90%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.80 (4 H, m, CH2 --CH2), 1.86 (3 H, d, J=5 Hz, CH3), 4.24 (4 H, m, 2×CH2 --O), 5.7-6.6 (4 H, m, CH=CH2 and CH).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:34])[CH:10]([N:16]1[C:20]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=2[N:18]=[C:17]1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:46]([O-])=[O:47].[Na+]>>[CH2:1]([N:8]([N:46]=[O:47])[C:9](=[O:34])[CH:10]([N:16]1[C:20]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=2[N:18]=[C:17]1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a ice-cold solution of 9.50 g (19.79 mmol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-acetamide in 64.53 ml (1128 mmol) acetic acid and 135.84 ml (2395 mmol) acetic anhydride were added in portions over 60 min. 6.83 g (99 mmol) sodium nitrite. The reaction mixture was stirred for 1 h in an ice-bath, then at room temperature overnight. The mixture was evaporated and the residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and solid sodium bicarbonate was added to adjust the pH to 7. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining brown foam was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane and ethyl acetate (100:0 to 50:50). Yellow solid (72%). MS (Turbo Spray): m/z=509.2 [M+H].
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([CH2:15][N:16]=[N+:17]=[N-:18])=[CH:13][C:12]=1[C:21]#[N:22]>C(O)C>[NH2:2][C:1]1[N:16]([CH2:15][C:14]2[CH:19]=[CH:20][C:11]([Cl:10])=[C:12]([C:21]#[N:22])[CH:13]=2)[N:17]=[N:18][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#Cc1cc(CN=[N+]=[N-])ccc1Cl
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(Cn2nnc(C(N)=O)c2N)ccc1Cl
Yield: 32.7 %

Procedure:
A stirred suspension of 2-cyanoacetamide (790 mg, 9.40 mmol) in absolute ethanol (40 ml) was treated with sodium methoxide (495 mg, 9.16 mmol) and refluxed 10 minutes. The mixture was cooled slightly, a solution of 4-chloro-3-cyanobenzyl azide (1.35 g, 7.01 mmol) in absolute ethanol (10 ml) was added in one portion, and the mixture was refluxed 2.5 hours. The mixture was filtered hot, the solid was washed with absolute ethanol, and the combined filtrate and wash were evaporated to dryness under vacuum. The residue was triturated with diethyl ether, filtered, and washed twice with diethyl ether. The solid was recrystallized from methanol (6 ml) and dried at 65° C. under vacuum to provide 635 mg (24%) 5-amino-1-(4-chloro-3-cyanobenzyl)-1,2,3-triazole-4-carboxamide, m.p. 172°-175° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[O:2]1.[CH3:13][N:14]([C:18](=[O:20])[CH3:19])[CH2:15]CO>>[CH3:13][N:14]([CH2:15][CH2:1][O:9][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[OH:2])[C:18](=[O:20])[CH3:19]
Reactant: CC(=O)N(C)CCO
Reactant: O=[N+]([O-])c1ccc2c(c1)OCO2
Product: CC(=O)N(C)CCOc1ccc([N+](=O)[O-])cc1O
Temperature: 100 °C

Procedure:
0.1 mol (16.7 g) of 3,4-methylenedioxynitrobenzene is introduced into 67 ml of N-methyl-N-acetylethanolamine. The mixture is heated to the region of 100° C., with stirring, and 11 ml of 15N potassium hydroxide solution are then added. After stirring for 4 hours at 100° C., the reaction medium is poured onto 200 g of crushed ice. The unreacted starting material, which is insoluble in an alkaline medium, is removed by filtration. The filtrate is then brought to a pH of 5 with hydrochloric acid. The expected nitro product which has precipitated is filtered off. After washing with water, drying and recrystallization from a 50/50 ethyl acetate/ethanol mixture, the product melts at 158° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][S:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:17]([C:16]1[CH:19]=[CH:20][C:13]([S:12][CH3:11])=[CH:14][CH:15]=1)[OH:18]
Reactant: c1cscn1
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2nccs2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of thiazole (5.0 g, 58.7 mmol) in THF (250 mL) was added n-butyllithium (2.5M in hexanes, 23.5 mL, 58.7 mmol) dropwise and the resulting solution was stirred at −78° C. for 10 min. 4-(Methylthio)benzaldehyde (7.1 mL, 53.4 mmol) was then added at −78° C. The resulting mixture was stirred until completion, and quenched with a saturated aqueous solution of NH4Cl. The mixture was then diluted with EtOAc and HCl 10%, extracted and washed (NaHCO3 (sat.), brine). The organic phase was dried over MgSO4 and concentrated. The residue was then purified by flash chromatography (80% CH2Cl2/20% EtOAc) to yield (1,3-Thiazol-2-yl)[4-(methylthio)phenyl]methanol.
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1>C(#N)C>[CH3:11][C@H:1]1[CH2:2][C@@H:3]([OH:10])[C@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6]1
Reactant: CC1CCC(C(C)C)C(O)C1
Solvent: CC#N
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 5 °C
Yield: 59.3 %

Procedure:
54 g of crude menthol (content of (L)-menthol: 95.7%; optical purity: 97% e.e.; content of isomer of isomenthol: 2.5%; content of isomer of neoisomenthol: 1.8%; content of isomer of neomenthol: trace) was dissolved in 150 ml of acetonitrile at 30° C., and this solution was cooled to 5° C., followed by filtration to obtain 32 g of purified (L)-menthol. GC (gas chromatography) analysis revealed that no isomers (isomenthol, neoisomenthol, and neomenthol) were detected with the purified (L)-menthol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:21][C@H:4]2[CH2:5][CH2:6][O:1][C:2](=[O:7])[C@H:3]2[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CCCO1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
To a stirred solution of 5,6-dihydro-2H-pyran-2-one* (136 g, 1.39 mole) in dichloromethane (2 L) at -20° C. was added N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethyl amine (80% pure) (D12, 450 g, 1.5 mole). To this solution was added trifluoroacetic acid in dichloromethane (140 ml, 1 molar solution) at -20° C. The reaction was then transferred at -20° C. under a small positive pressure of nitrogen via a double ended needle to a second flask on a water bath at 30° C. As the cold mixture warmed up an exothermic reaction occurred and the rate of addition was controlled to maintain gentle reflux. When addition was complete and the reaction had subsided the solution was allowed to stand at room temperature for 2 h. The reaction was then washed with saturated aqueous potassium carbonate solution, dried (Na2SO4) and concentrated in vacuo to a gum. Vacuum distillation afforded the title compound as a single main fraction b.p. 180°-190° C. 0.5mmHg (D20, 180.9 g, 0.73 mole, 56%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.CCN(CC)CC.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:29](=[O:30])[C:28]2[CH:27]=[C:26]([C:25]([F:40])([F:39])[F:24])[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1
Reactant: CNc1cnccc1-c1cc(F)cnc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-chloro-5-fluoro-[3,4′]bipyridinyl-3′-yl)-methyl-amine (80 mg, 0.34 mmol) in CH2Cl2 (10 mL) were added Et3N (0.187 mL, 1.35 mmol) and 3,5-bis(trifluoromethyl)-benzoyl chloride (0.061 mL, 0.34 mmol, CAS RN 1271-19-8) at 25° C. and the resulting reaction mixture was stirred for 4 hours at 25° C. The mixture was diluted with CH2Cl2 (20 mL), the organic layer was washed with saturated aqueous NaHCO3 solution (2×20 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude product which was purified using preparative HPLC. Off-white solid (22 mg, 14%). MS (ESI): m/z=478.4 [M+H]+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)[N:18]=1.[Br:38]Br>CCCCCC.O1CCCC1>[Br:38][C:22]1[C:17]([F:16])=[N:18][C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:24]=2)=[CH:20][N:21]=1
Reactant: CCCCCCCCOc1ccc(-c2cncc(F)n2)cc1
Reactant: BrBr
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(Br)c(F)n2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
3.50 g (24.8 mmol) of 2,2,6,6-tetramethylpiperidine and 15.50 ml (24.80 mmol) of 1.6 M n-butyllithium solution in hexane are stirred at 0° C. for 0.5 hour in 80 ml of tetrahydrofuran, 250 ml of tetrahydrofuran are added, and the mixture is cooled to -78° C. 5.00 g (16.5 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyrazine in 150 ml of tetrahydrofuran and, after the mixture has been stirred for one hour, 0.85 ml of bromine are subsequently added dropwise at -78C. The reaction mixture is stirred overnight, during which it warms to room temperature, and is partitioned between ether and aqueous sodium chloride solution, the aqueous phase is washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from the solvent, and the residue is purified by chromatography (silica/hexane: ethyl acetate = 9:1). 4.68 g of 2-bromo-3-fluoro-5-(4-octyloxyphenyl)pyrazine are obtained. ##STR16## 1d
Reaction SMILES: [OH:1][C@@H:2]([C@H:45]([OH:52])[C@@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48][OH:49])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C@H:9]([NH:14][C:15](=[O:44])[C@@H:16]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:17][CH2:18][C:19](=[O:32])[NH:20][CH2:21][C@@H:22]([OH:31])[C@H:23]([OH:30])[C@@H:24]([OH:29])[C@@H:25]([OH:28])[CH2:26][OH:27])[C:10]([O:12]C)=[O:11])=[O:6].[OH-].[Li+]>O1CCCC1.CO>[OH:1][C@@H:2]([C@H:45]([OH:52])[C@@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48][OH:49])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C@H:9]([NH:14][C:15](=[O:44])[C@@H:16]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:17][CH2:18][C:19](=[O:32])[NH:20][CH2:21][C@@H:22]([OH:31])[C@H:23]([OH:30])[C@@H:24]([OH:29])[C@@H:25]([OH:28])[CH2:26][OH:27])[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC[C@H](NC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)OCc1ccccc1)C(=O)O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
The product of step 11B is dissolved in tetrahydrofuran/methanol (1:1) and treated with excess 3N aqueous lithium hydroxide. The reaction is followed by HPLC for disappearance of starting material. The reaction is concentrated, diluted with additional water, and purified by passage down an acidic ion exchange column. The product fractions are lyophilized to afford the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1ccnc(N)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of ethyl 2-aminoisonicotinate (1.00 g, 6.02 mmol) in anhydrous pyridine (13 mL) was added benzoyl chloride (0.77 mL, 6.63 mmol) dropwise at 0° C. under nitrogen atmosphere. The resulting solution was warmed to ambient temperature, stirred for 18 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate (75 mL), washed with 2 M aqueous hydrochloric acid solution (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 10-50% ethyl acetate in hexanes to give ethyl 2-benzamidoisonicotinate as a colorless solid (1.35 g, 83%): 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 8.84 (br s, 1H), 8.43 (d, J=5.1 Hz, 1H), 7.98-7.93 (m, 2H), 7.70-7.47 (m, 4H), 4.44 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H); MS (ES+) m/z 271.5 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:14])[C:8]([O:12][CH3:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:14][C:7]1[C:8]([O:12][CH3:13])=[C:9]([NH:11][S:23]([CH3:22])(=[O:25])=[O:24])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(N)cc(C(C)(C)C)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To an oven dried 250 mL round bottom flask containing 5.0 g (25.73 mmol) 5-tert-butyl-2-methoxy-benzene-1,3-diamine, 150 mL DCM was added. The reaction mixture was cooled to 0° C. after which triethylamine (5.0 mL, 36.0 mmol) was added followed by the drop wise addition of methylsulfonyl chloride (1.99 mL, 25.7 mmol). The reaction was allowed to stir at 0° C. for 30 min. then warmed to room temperature stirring for an additional 2 h. The reaction mixture was poured over saturated solution of sodium bicarbonate (100 mL) and the layers separated. The aqueous layer was washed twice more with 50 mL dichloromethane and the combined organic layers were dried over magnesium sulfate and concentrated under vacuum to afford a crude oil that was purified by flash chromatography (silica gel, 1:1 EtOAc:Hex) to yield 6.1 g of the desired product (87%). Calculated mass=272. Observed mass=273
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])[CH3:9].C([O:29][C:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:31])C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]([NH:12][C:13]1[C:14]([C:19]2[CH:24]=[CH:23][C:22]([C:36]3[CH:37]=[CH:38][C:33]([CH2:32][C:30]([OH:31])=[O:29])=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)=[N:15][O:16][C:17]=1[CH3:18])=[O:26])[CH3:9]
Reactant: Cc1onc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(B(O)O)cc1
Product: Cc1onc(-c2ccc(-c3ccc(CC(=O)O)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 1, Step 3 using the following starting materials: [3-(4-bromo-phenyl)-5-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and (4-ethoxycarbonylmethylphenyl)boronic acid, pinacol ester. Mass spectometric data [M+H]=491.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccccc2)cn1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: Cn1cc(-c2ccc(S(=O)(=O)Cl)cc2)cn1
Reaction time: 1 h

Procedure:
0.5 g of 1-methyl-4-phenyl-1H-pyrazole (3.16 mmol) were dissolved in 20 ml of dichloromethane. At 0° C., 0.232 ml of chlorosulfonic acid were added and the reaction mixture was stirred for 1 h under ice cooling. Additional 0.7 ml of chlorosulfonic acid were added, the mixture was stirred at 0° C. for 30 minutes and then 90 minutes at 50° C. The two phases were separated and the lower layer put on ice, extracted twice with diethyl ether, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.496 g of the product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCBr
Reactant: CCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Product: CCn1c(=O)n(CCOCCOC)c(=O)c2c1ncn2Cc1ccccc1
Yield: 98 %

Procedure:
14 g (0.037 mol) of 7-benzyl-3-ethyl-1-(2-(2-methoxyethoxy)ethyl)xanthine were prepared from 7-benzyl-3-ethylxanthine (prepared according to Example 5a) and 1-bromo-2-(2-methoxyethoxy)ethane (prepared according to Example 2b) in a yield of 98% of theory (C19H24N4O4 (MW=372.4 g/mol); melting point after recrystallization from diisopropyl ether: 64° C.