Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20](S(C)(=O)=O)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[OH:49].S([O-])(O)(=O)=O.[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:34])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([O:49][C:43]4[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=4[F:41])[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cc(F)ccc1F
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Oc2cc(F)ccc2F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
To a solution of 100 mg [4-(5-methanesulfonyl-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethyl-phenoxy]-acetic acid tert-butyl ester in 1.5 ml of N,N-dimethylformamide were added 62 mg of potassium carbonate and 32 mg of 2,5-difluoro-phenol. The mixture was stirred at room temperature for 12 h. Then the mixture was poured onto water, neutralized by addition of a 10% aqueous solution of sodium hydrogensulfate, and extracted twice with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. After filtration the solvent was distilled off in vacuo and the residue purified by preparative HPLC to yield 69 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31](OC)=[O:32])[CH2:27][CH2:26]2)=[CH:19][CH:18]=1>O1CCCC1.CCCCCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:31]([CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:26][CH2:27]1)=[O:32]
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Temperature: -78 °C

Procedure:
Dissolve freshly distilled benzothiazole (3.41 g, 25.24 mmol) in anhydrous tetrahydrofuran (60 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, n-butyllithium (15.14 mL of a 2.5M solution in hexane, 37.86mmol) and stir briefly at -78° C. Add, by dropwise addition, a solution of 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (7.0 g, 25.24 mmol) in anhydrous tetrahydrofuran (40 mL). Stir for 1 hour at 78° C., quench with methano 1 (5 mL) and pour into saturated ammonium chloride (100 mL). Filter, separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phase s and wash with water and brine. Dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (ethyl acetate) and recrystallize (cyclohexane) to give the title compound as a pale yellow powder; mp 118°-120° C.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:18]([S-:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Na+]>C(O)C>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:16]([S:25][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCCCCC[S-]
Reactant: CCOC(=O)CCCCCCC1=CCCC1=O
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)OCC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
3.2 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, dissolved in 20 ml. of dry ethanol, is added to a solution of sodium heptanethiolate (producible by dissolving 0.24 g. of sodium in 30 ml. of dry ethanol and adding 1.3 g. of heptylthiol); the reaction mixture is agitated under nitrogen for 24 hours at 40°, then diluted with 150 ml. of ice water and 10 ml. of concentrated HCl, extracted with CH2Cl2, washed with saturated aqueous NaCl solution, dried over Na2SO4, and the solvent is distilled off. After purifying the residue by chromatography, 2-(6-carbethoxyhexyl)-3-heptylthio-cyclopentanone is obtained. Rf = 0.7 (silica gel/chloroform).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COCCOC.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22](=O)[C:23]([N:25]2[CH2:30][CH2:29][N:28]([N:31]=O)[CH2:27][CH2:26]2)=O)=[CH:14]1>O>[NH2:31][N:28]1[CH2:29][CH2:30][N:25]([CH2:23][CH2:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:13][CH:14]=2)[CH2:26][CH2:27]1
Reactant: O=NN1CCN(C(=O)C(=O)c2c[nH]c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: NN1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: -5 °C

Procedure:
To a stirred mixture of 9.0 g of lithium aluminum hydride in 400 ml. of 1,2-dimethoxyethane is added 10.52 g (0.037 mol) of 1-(indol-3-ylglyoxyloyl)-4-nitrosopiperazine slowly to maintain reaction temperature below 35° C. After all the material is added, the mixture is refluxed for 14-16 hours. The reaction mixture is cooled to -5° C. and a solution of 50 ml. of water and 50 ml. of 1,2-dimethoxyethane is slowly added while maintaining the temperature below 15° C. Another 50 ml. of water is added, and the mixture is then filtered. The solvent is removed from the filtrate and the residual solid is recrystallized from benzene, producing the pure crystals of 3-[2-(4-aminopiperazin-1-yl)ethyl]indole, m.p. 115°-117° C. Analysis: Calculated for C14H20N4 :68.82% C; 8.25% H; 22.93% N Found:68.70% C; 8.17% H; 22.55% N.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][CH:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[H-].[Na+].Cl[CH2:33][O:34][CH2:35]Cl.COCOC.C(Cl)(=O)C.P(O)(O)([O-])=O.[Na+]>CN(C)C=O.CO>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7](=[O:9])[O:8][CH2:33][O:34][CH3:35])[C@H:3]1[C:10]([O:12][CH:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Reactant: ClCOCCl
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: COCOC
Solvent: CO
Product: COCOC(=O)C#C[C@H]1[C@@H](C(=O)OC(C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3 g of (RS)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(3-hydroxy-3-oxo-1-propynyl)-cyclopropane-carboxylate in 30 ml of anhydrous dimethylformamide was cooled to +10° C. and 300 mg of 61% sodium hydride in oil were added in portions thereto. Then, over 15 minutes, 2.5 ml of chloromethyl ether solution prepared by mixing 4.5 ml of methylal and 0.52 ml of methanol and slowly adding 3.53 ml of acetyl chloride after which the mixture was stirred for 36 hours at room temperature. The mixture was stirred for 2 hours and was then poured into an aqueous solution of monosodium phosphate. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 75-25 mixture of cyclohexane-ethyl acetate to obtain 2 g of (RS)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(3-oxo-3-methoxymethoxy-1propynyl)-cyclopropane-carboxylate.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:6][CH:5]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29](O)=O)[N:23]=2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:6][CH:5]=4)[N:14]=3)[N:23]=2)=[CH:20][CH:21]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(C(=O)O)n1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2nc(-c3ccc(S(N)(=O)=O)cc3)no2)n1

Procedure:
The title compound was prepared from N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (0.16 g, 0.75 mmol) and 4-(4-chloro-phenyl)-6-methyl-pyrimidine-2-carboxylic acid (example D.10) (0.124 g, 0.5 mmol) according to the general procedure V. Obtained as an off-white solid (0.032 g, 15%). MS (ISN) 426.1 [(M−H)−]; mp 297° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[C:12]([CH3:13])=[C:2]([N:24]3[CH2:25][CH2:26][N:21]([C:17]4[S:16][CH:20]=[CH:19][N:18]=4)[CH2:22][CH2:23]3)[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]=2[O:9]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(C)O2
Product: Cc1c(C)c(N2CCN(c3nccs3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 36.5 %

Procedure:
By using 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (404 mg, 1.50 mmol) synthesized in Reference example 4 and 1-(1,3-thiazol-2-yl)piperazine (508 mg, 3.00 mmol), the reaction was carried out in the same manner as Example 21 to synthesis the title compound 196 mg (yield 36%). Melting point was 150 to 151° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:40])S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C.C1(S)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@H:20]4[C@H:19]([O:23][C:22]([CH3:25])([CH3:24])[O:21]4)[C@@H:18]([CH2:26][NH:27][CH3:40])[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C)S(=O)(=O)c3ccccc3[N+](=O)[O-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: CNC[C@H]1O[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A suspension of N-(((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-N-methyl-2-nitrobenzenesulfonamide (0.82 g, 1.2 mmol) and cesium carbonate (0.82 g, 2.5 mmol) in acetonitrile (23 mL, 440 mmol) was degassed by sparging with nitrogen gas for 10 minutes. The solution was treated dropwise with benzenethiol (0.26 mL, 2.5 mmol) and the mixture was allowed to stir at room temperature overnight. After 22 h, LCMS indicated the reaction was complete. The reaction mixture was partitioned between 60 mL 1N NaOH and 120 mL CH2Cl2, the layers separated and the aqueous phase was washed with three 25 mL portions of CH2Cl2. The combined organic phase was dried over MgSO4, filtered, and concentrated to an oil. The material was purified by flash chromatography (80 g silica gel, 0-5% 7N NH3 in CH3OH/CH2Cl2) to yield the title compound (320 mg, 54%) as a foam: MS (ESI+) for C24H31N5O6 m/z 470.1 (M+H)+; (ESI−) for C24H31N5O6 m/z 468.0 (M−H); HPLC purity 99% (ret. time, 2.67 min).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=2)[CH2:19][CH2:18]1)C(=O)OC(C)(C)C>ClCCl>[CH3:8][NH:9][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=2)[CH2:19][CH2:18]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nccn2C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCN(c2nccn2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 ml) was added at 0° C. to a solution of tert-butyl methyl(1-(1-methyl-1H-imidazol-2-yl)piperidin-4-yl)carbamate (241 mg, 0.82 mmol, 1 eq) in dichloromethane (5 ml), and the reaction mixture was stirred for 1 h at room temperature. Concentration under reduced pressure was then carried out. The crude product so obtained was used in the next stage without being purified further.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)=[O:36])=[CH:30][CH:29]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:16][O:15][C:13](=[O:14])[C@H:12]([N:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=4)=[O:36])=[CH:32][CH:33]=3)=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Temperature: 82.5 °C
Reaction time: 1.25 h

Procedure:
The compound of example 329 (288 mg, 0.886 mmol), compound of example 327 (300 mg, 0.738 mmole) and Pd(dppf)Cl2: CH2Cl2 (18 mg, 0.022 mmol) were taken in DMF (5 mL) under an argon atmosphere. To this reaction mixture, 2M solution of Na2CO3 (234 mg, 2.214 mmole, 1.1 mL) was added. The reaction mixture was stirred at 80-85° C. for 1 to 1.5 h. After completion of the reaction, water was added and the product obtained was extracted with ether. The ether layer was washed with water, brine and dried over anhydrous Na2SO4 or anhydrous MgSO4. The solvent was evaporated and the residue obtained was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=4)=[O:25])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CCCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (110 mg, 0.27 mmol) and methyl 4-amino-2-methoxybenzoate (48 mg, 0.27 mmol) in dichloromethane (15 mL) were added the solution of 1-methyl-1H-imidazole (87 mg, 1.1 mmol) and EDCI (203 mg, 1.1 mmol) in dichloromethane (5 mL), the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed in vacuo, then methanol (5 mL) was added, the precipitate was collected by filtration and washed with methanol (5 mL) to afford methyl 4-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxamido)-2-methoxybenzoate (126 mg, 80.8%) as an orange solid. LC-MS: 579 [M+H]+, tR=1.58 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][C:27]1([C:31]([O:33][CH3:34])=[O:32])[CH2:30][NH:29][CH2:28]1>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:29]4[CH2:30][C:27]([OH:26])([C:31]([O:33][CH3:34])=[O:32])[CH2:28]4)=[CH:18][C:17]=3[F:24])=[CH:13][C:12]=2[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1(O)CNC1
Reactant: O=Cc1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(F)c1
Product: COC(=O)C1(O)CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B1 and general procedure I from 4-(5-benzylbenzofuran-2-yl)-3-fluorobenzaldehyde (0.100 g, 0.30 mmol) and methyl 3-hydroxyazetidine-3-carboxylate (0.058 g, 0.30 mmol) to give methyl 1-((4-(5-benzylbenzofuran-2-yl)-3-fluorophenyl)methyl)-3-hydroxyazetidine-3-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.91 (t, J=7.9 Hz, 1H), 7.40-7.61 (m, 2H), 7.15-7.36 (m, 8H), 6.26 (s, 1H), 4.04-4.10 (m, 1H), 4.04 (s, 2H), 3.70 (s, 3H), 3.68-3.69 (m, 1H), 3.63 (d, J=7.9 Hz, 1H), 3.12-3.18 (m, 4H). MS (ESI) m/z: Calculated: 445.2 Observed: 446.1 (M++1).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([CH:9]2[CH2:11][N@@:10]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[O:6][C:5]1=[O:24])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][CH2:35][C:34]1=[O:41]>C1(C)C=CC=CC=1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[N:33]1[C:34](=[O:41])[CH2:35][N:36]([CH2:11][C@H:9]([NH:10][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[C@@H:7]2[CH2:8][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[O:6]2)[C:37]([CH3:40])([CH3:39])[CH2:38]1
Reactant: CC1(C)CN(c2cc(F)ccc2Cl)C(=O)CN1
Reactant: CC(C)[C@@H]1C[C@@H](C2C[N@@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Agent: CC(C)[C@@H]1C[C@@H](C2C[N@]2S(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3cc(F)ccc3Cl)CC2(C)C)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Yield: 89.1 %

Procedure:
A solution of 1.15 g of (3S,5S)-3-isopropyl-5-[(S)-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]dihydrofuran-2-one obtained in Example (1g) (3.25 mmol) and 889 mg of 1-(2-chloro-5-fluorophenyl)-5,5-dimethylpiperazin-2-one obtained in Example (62d) (3.9 mmol) in toluene (32 ml) was stirred at 110° C. for one hour. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: toluene/acetone=10/1) to obtain 1.77 g of the title compound (yield: 91%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]4[N:26]=[C:25]([CH2:27][CH2:28][CH:29]5[NH:35][C:34](=O)[CH2:33][CH2:32][CH2:31][CH2:30]5)[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]4[N:26]=[C:25]([CH2:27][CH2:28][CH:29]5[NH:35][C:34](=[S:46])[CH2:33][CH2:32][CH2:31][CH2:30]5)[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)CC1
Solvent: C1COCCO1
Product: CCN1CCN(S(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=S)N5)nc4c3)cc2)CC1
Yield: 93 %

Procedure:
The title compound is analogously synthesized as described for 7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione (compound A2) from 170 mg of 7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B7) and 142 mg of Lawesson's reagent at 100° C. for 2.5 hours in 20 ml of dioxane. Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 163 mg of the title compound as a waxy solid. ESI-MS: 527.3 (MH+). TLC: Rf=0.34 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:25])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12]([S:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13])=[O:4].[Li+].[OH-].OS([O-])(=O)=O.[K+].C(OCC)(=O)C>CO.O>[CH2:23]([O:22][C:20]([NH:19][C@@H:11]([C:12]([S:15][CH:16]([CH3:17])[CH3:18])([CH3:13])[CH3:14])[C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC)C(C)(C)SC(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)(C)SC(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A mixture of 1-[2-(R)-ethoxycarbonylamino-3-isopropylsulfanyl-3-methyl-butyryl-]-pyrrolidine-2-(S)-carboxylic acid methyl ester (0.45 g) and 0.06 g of LiOH in 6 mL of methanol and 1 mL of water was stirred for 16 h at ambient temperature. KHSO4 was added, the volatiles were pumped off followed by addition of water, extraction with ethyl acetate and concentration of the organic layer to give 0.34 g (79%) of the title compound as a colorless oil. (+)-APCI-MS: 361 (MH+).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]([CH3:26])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[CH3:26][N:16]1[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:27])=[O:5])=[CH:8][N:9]=2)=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[N:17]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
A solution of lithium hydroxide monohydrate (40 mg, 0.96 mmol) in water (1.2 mL) was added dropwise to a suspension of 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid methyl ester (156 mg, 0.96 mmol) in THF (1.2 mL) and MeOH (0.3 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (129 mg, 86%) as a white solid. MS: m/e=309.4 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CN1CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.2 %

Procedure:
Benzyl bromoacetate (500 mg, 2.18 mmol) was added to a mixture of pyrrolidine (171 mg, 2.40 mmol) and sodium carbonate (254 mg, 2.40 mmol) in tetrahydrofuran (7 ml). The mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The residue was mixed with water (200 ml) and extracted with dichloromethane (3×100 ml). The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography eluting with 0-10% (v/v) methanol in dichloromethane afforded pyrrolidin-1-yl acetic acid benzyl ester (230 mg, 1.05 mmol).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][C:7](Cl)=[CH:6][N:5]=1)([OH:3])=[O:2].P(Cl)(Cl)(Cl)=[O:12]>>[C:1]([C:4]1[CH:9]=[N:8][C:7]([OH:12])=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(O)c1cnc(O)cn1

Procedure:
For example the compound 2-carboxy-5-chloro-pyrazine can be prepared by treating with an excess of phosphorus oxychloride, at the reflux temperature, the 2-carboxy-5-hydroxy-pyrazine compound in its turn obtained in the manner described in Helv. Chim. Acta 47, 873 (1964).