Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH2:7][OH:8])([CH2:5][OH:6])[CH2:3][OH:4].[CH2:9]([OH:11])C>C(=O)(OCC)OCC>[OH:4][CH2:3][C:2]1([CH2:7][OH:8])[CH2:5][O:6][C:9](=[O:11])[NH:1]1
Reactant: NC(CO)(CO)CO
Reactant: CCO
Solvent: CCOC(=O)OCC
Product: O=C1NC(CO)(CO)CO1
Temperature: 25 °C

Procedure:
A suspension of 2-amino-2-(hydroxymethyl)propane-1,3-diol (51.37 g, 424.1 mmol) in diethyl carbonate (55 ml) was heated to 140° C. for 14 h, during which approximately 50 ml of ethanol was collected in a Dean-Stark trap. The reaction mixture was cooled to RT and the resulting thick, clear syrup was used without further purification. LRMS (ESI/APCI): 148 [M+H]+.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C@H:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[OH:3].[C:12](=[O:15])([O-:14])[O-:13].[Cs+].[Cs+].C(=O)=O.[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:15][C:12](=[O:14])[OH:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:1]([O:10][CH3:11])(=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[OH:3]
Reactant: ClCc1ccccc1
Reactant: COC(=O)C[C@H](O)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(O)C(=O)OC
Product: O=C(O)OCc1ccccc1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Dimethyl (S)-(−) malate (0.27 mL, 2 mmol) is dissolved in anhydrous N,N-dimethylforamide (8 mL), and powdered cesium carbonate (1.95 g, 6 mmol, 3 eq) is added. The suspension is then stirred at room temperature while passing carbon dioxide gas for 1 hour before benzyl chloride (0.69 mL, 6 mmol, 3 eq) is added to the solution. Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed. The reaction is quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc) to yield 384 mg of the desired dimethyl malate benzyl carbonate (65%): IR (thin film) 3034, 2957, 1746, 1439, 1383, 1216, 1042, 909, 756, 699 cm−1; 1H NMR (360 MHz, CDCl3) d 2.93 (d, 2H, J=6.26 Hz), 3.71 (s, 3H), 3.78 (s, 3H), 5.22 (s, 2H, J=6.08 Hz), 7.34-7.38 (m, 5H); 13C NMR (90 MHz, CDCl3) d 35.60, 51.97, 52.55, 70.00, 71.13, 128.17, 128.43, 153.94, 168.80, 169.10.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C@@H:8]1[CH2:16][C@@H:11]2[O:12][C:13](=[O:15])[CH2:14][C@@H:10]2[C@H:9]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClCCl>[CH2:17]([C@@H:9]1[C@@H:10]2[C@@H:11]([O:12][C:13](=[O:15])[CH2:14]2)[CH2:16][C@H:8]1[O:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: CCCCCCCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Dihydropyran (60 μL, 0.66 mmol) and PPTs (11 mg, 0.045 mmol) were added to a solution of 5-3 (81 mg, 0.32 mmol) in dichloromethane (1.2 mL). After overnight stirring, the reaction was washed with 1 M HCl, saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Isco Combiflash unit) gave the title compound (100 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:19][CH:20]=O>CO.O>[Cl:12][C:4]1[N:3]2[CH:19]=[CH:20][N:1]=[C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1N
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Cl)n2ccnc12
Reaction time: 16 h
Yield: 58.5 %

Procedure:
To a stirred suspension of methyl 2-amino-6-chloro-3-pyridinecarboxylate (2 g, 10.72 mmol) and sodium bicarbonate (900 mg, 10.72 mmol) in a mixture of methanol (40 mL) and water (20 mL) was added chloroacetaldehyde (50% wt. solution in water, 2.9 mL, 22.51 mmol). The resultant mixture was heated at reflux for 5 hours when more chloroacetaldehyde (50% wt. solution in water, 1.45 mL, 11.25 mmol) was added and heating at reflux continued for 16 hours. The majority of the solvent was then removed in vacuo and the residue was partitioned between ethyl acetate (150 mL) and saturated aqueous sodium bicarbonate (150 mL). The organic phase was separated and the aqueous phase was back extracted with ethyl acetate (150 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100 g) using a 0-100% ethyl acetate-cyclohexane+0-20% methanol gradient over 60 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow solid (1.32 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH2:1]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18]2)=[O:16])=[CH:13][CH:14]=1)[S:31]([N:30]([CH3:35])[CH3:29])(=[O:33])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(NCc2ccccc2)cc1)N1CCOC(c2ccccc2)C1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)N(Cc1ccccc1)c1ccc(C(=O)N2CCOC(c3ccccc3)C2)cc1
Yield: 34.8 %

Procedure:
A solution of (4-benzylamino-phenyl)-(2-phenyl-morpholin-4-yl)-methanone (80 mg, 0.21 mmol) and N,N-dimethylsulfamoyl chloride (0.3 ml, 2 mmol) in pyridine (5 ml) was heated to 70° C. for 16 hours. The reaction was cooled then filtered and the filtrate diluted with dichloromethane (20 ml). The resulting solution was washed with hydrochloric acid 2N (20 ml), the organics collected and dried over magnesium sulfate. The solvent was removed in vacuo and the residue purified by preparative thin layer chromatography eluting with 50% ethylacetate/hexanes to afford the title compound as a colourless oil (35 mg, 35% yield). HPLC retention time 6.1 min. Mass spectrum (ES+) m/z 480 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:10][N:9]=1.B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C:25](=[O:34])[NH:26][CH2:27][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:10][N:9]=1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)NCc2ncccn2)cc1Cl
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ncccn1)c1cnc(N2CCC[C@H]2CO)nc1NCc1ccc(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43.3 %

Procedure:
To a solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]-pyrimidine (307 mg) obtained in Example 1-(5) in methylene chloride (6 ml) is added dropwise boron bromide (300 μl) under ice-cooling. The reaction mixture is stirred at 0° C. for 4 hours, and thereto is added methanol, and then a saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran, and the organic layer is washed successively with water and brine. The mixture is dried over sodium sulfate, and concentrated under reduced pressure to give a slightly brown amorphous (227 mg). The resultant is suspended in chloroform, and the resulting insoluble materials are removed by filtration. The filtrate is subjected to silica gel column chromatography, and further purified by NH-silica gel column chromatography to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-hydroxybenzylamino)-5-[N-(2-pyrimidylmethyl)carbamoyl]pyrimidine (129 mg) as a colorless foam, MS (m/z): 470 (MH+), IR (Nujol): 3279, 1632, 1593, 1569, 1518, 1463 cm−1.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C@@H:9]2[N:12]([C:13](=[O:15])[CH3:14])[C:11](=[O:16])[C@H:10]2[CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH:33]C(OCC2C=CC=CC=2)=O)=[N:22]C(OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:44]>[Pd].CO.C(OCC)(=O)C>[ClH:44].[C:1]1([CH2:7][CH2:8][C@@H:9]2[N:12]([C:13](=[O:15])[CH3:14])[C:11](=[O:16])[C@H:10]2[CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:33])=[NH:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=N)N)[C@@H]1CCc1ccccc1
Yield: 76 %

Procedure:
A methanol/ethyl acetate (3 ml/1mL) solution of compound 27 (470 mg, 0.82 mmol) and 1N HCl (0.9 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material (about 30 min). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 220 mg (76%) of the title product.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16]([NH2:17])=[C:15]3[CH:18]=[CH:19][O:20][C:14]3=[N:13][CH2:12]2)=[CH:7][CH:6]=1)(=O)C>[OH-].[K+].CCO.O>[NH2:17][C:16]1[N:11]([C:8]2[CH:7]=[CH:6][C:5]([NH2:4])=[CH:10][CH:9]=2)[CH2:12][N:13]=[C:14]2[O:20][CH:19]=[CH:18][C:15]=12
Reactant: CC(=O)Nc1ccc(N2CN=c3occc3=C2N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC1=c2ccoc2=NCN1c1ccc(N)cc1
Temperature: 60 °C
Yield: 57.7 %

Procedure:
Compound 3-(4-acetamidophenyl)-4-aminofuro[2,3-d]pyrimidine 8 (242 mg) was dissolved in 2 M potassium hydroxide in the mixture of EtOH (16 mL) and water (4 mL). The mixture was heated (60° C.) for 24 h then concentrated in vacuo. Residual oil was triturated with cold water (6 mL) to give precipitation, which was filtrated, washed with water, and dried under the reduced pressure. The compound 9 (118 mg) as pale orange colored was obtained. MS(ES) m/e 227M+H].
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH:18]([Cl:20])C>CN(C=O)C.C(OCC)(=O)C>[Cl:20][CH2:18][CH2:17][CH2:16][CH2:9][N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]1=[O:8]
Reactant: CC(Cl)CCBr
Reactant: Cc1ccc[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccn(CCCCCl)c1=O
Temperature: 90 °C

Procedure:
To a solution of 3-methyl-2(1H)-pyridinone (commercial aldrich) (200 mg, 1.85 mmol), in dry DMF (5 mL), K2CO3 (0.51 g) and 1-bromo-3-chlorobutane (0.32 mL) were added and the resulting mixture was heated at 90° C. for 5 hours. After solvent elimination under reduced pressure, the residue was diluted with ethyl acetate and washed once with water and once with brine. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with cyclohexane/EtOAc 8:2 to give the title compound as colourless oil (0.24 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][Ge:6]([Cl:19])([Cl:18])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9](O)=[O:10]>>[Cl:5][Ge:6]([Cl:19])([Cl:18])[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Product: O=C(Cl)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Yield: 69.1 %

Procedure:
Sixty grams of thionyl chloride was added to 16.4 g (0.05 mol) of β-(trichlorogermyl)hydrocinnamic acid (7), and the mixture was heated under reflux for 2 hours. Then excess thionyl chloride was distilled away in the usual manner. The residue, upon vacuum distillation, gave 12.9 g of a fraction, bp 148°-149° C./4 mmHg. The yield was 69.1%.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[N:20]([CH3:28])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([N:17]([CH3:29])[CH2:18][C:19]2[N:20]([CH3:28])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCN=C=O
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cc3ccccc3n2C)cn1
Reaction time: 144 h
Yield: 24.3 %

Procedure:
Ethyl isocyanate (0.13 mL, 1.68 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (0.27 g, 0.84 mmole) and triethylamine (0.29 mL, 2.1 mmole) in DMF (30 mL) at RT. The reaction was stirred for 6 days, then was concentrated in vacuo, and the residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the title compound (80 mg, 24%) as a light yellow solid: MS (ES) m/e 392 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCCCC2C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 87.2 %

Procedure:
1-(1-tert-butoxycarbonylpiperidine-4-carbonyl)-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (75) (1.41 g; 2.39 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15S mL) is added in a slow stream, and the solution is stirred for 2.25 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.02 g) as an oil. ESMS: MH+ 490.4
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:17])[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[C:7]([OH:18])[CH:6]=1)[CH:2]=[CH2:3].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:17])[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[C:7]([O:18][CH3:19])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cc(O)c2c(c1)OC(C)(C)CC2=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: C=CCOc1cc(OC)c2c(c1)OC(C)(C)CC2=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
2.90 g of 7-allyloxy-5-hydroxy-2,2-dimethyl-4-oxochromane was dissolved in 50 ml of N,N-dimethylformamide. Thereafter, 2.42 g of potassium carbonate and 2.32 g of iodomethane were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 days. Thereafter, the reaction solution was diluted with ethyl acetate. The resultant product was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 2.79 g of the subject compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22]([NH:24][C:25]([NH:27][CH3:28])=[O:26])[S:23][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[CH3:28][NH:27][C:25]([NH:24][C:22]1[S:23][C:17]2[CH2:16][NH:15][CH2:20][CH2:19][C:18]=2[N:21]=1)=[O:26]
Reactant: CNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
10% TFA in 60 ml chloroform was added to 2.3 g 2-(3-methyl-ureido)-6,7-dihydro-4H-thiazolo-[5,4-c]pyridine-5-carboxylic acid tert-butyl ester in 28 ml chloroform and stirred for 2 h at RT. The mixture was concentrated, the residue was diluted with chloroform and basified with 2.5 M aqueous potassium carbonate solution and extracted with chloroform. The organic layer was concentrated. The residue was washed with a mixture of 50% ethyl acetate and 50% hexane to yield 1.5 g of the desired product. (M+H)+: 213
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:32][C@H:30]([CH3:31])[CH2:29][NH:28][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C[C@@H](O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 37.4 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ((R)-2-hydroxy-propyl)-amide (30 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (70 mg), (R)-1-amino-propan-2-ol (70 mg), HBTU (200 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 449.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.44-8.41 (t, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.83-7.80 (d, 1H), 7.71 (s, 2H), 7.54-7.52 (d, 1H), 3.84-3.80 (m, 1H), 3.70 (s, 3H), 3.25-3.22 (m, 2H), 1.10-1.08 (d, 3H), —NH and OH proton signal was not observed.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH:5]=1.[Li+].[OH-]>CO.O.C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:25])=[O:2])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester (1.84 g, 5.14 mmol) was dissolved in a mixture of MeOH (15 mL), water (2 mL) and THF (2 mL), and LiOH 308 mg, 12.86 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours and then partitioned between water and 1N aqueous HCl. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.70 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid, Mp=179.5-181.2° C., MS (M+H)=344.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][C:16]1[CH:29]=[CH:28][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:30])[C:18]=2[CH:17]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:46][P-:47]([F:52])([F:51])([F:50])([F:49])[F:48].[K+]>O.ClCCl>[F:46][P-:47]([F:52])([F:51])([F:50])([F:49])[F:48].[C:9]1([S+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:22]2[CH:23]=[CH:24][C:25]3[S:26][C:27]4[C:18](=[CH:17][C:16]([Cl:15])=[CH:29][CH:28]=4)[C:19](=[O:30])[C:20]=3[CH:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=c1c2cc(Cl)ccc2sc2ccc([S+](c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
To 320 ml of dichloromethane were suspended 20.2 g (0.1 mol) of diphenylsulfoxide and 24.6 g (0.1 mol) of 2-chlorothioxanthene-9-one, and 28.2 g (0.1 mol) of trifluoromethanesulfonic anhydride was added dropwise thereto at −70 to −60° C., followed by gradually warming to room temperature and reacting with stirring for 3 hours. After completion of the reaction, the obtained reaction solution was washed with water (320 ml×5 times) and 18.4 g (0.1 mol) of potassium hexafluorophosphate and 200 ml of water were added to the obtained dichloromethane layer, followed by stirring at room temperature for 2 hours and fractionating the solution. Then, 9.2 g (0.05 mol) of potassium hexafluorophosphate and 100 ml of water were further added to the obtained dichloromethane layer, followed by stirring at room temperature for 2 hours and fractionating the solution. Then the obtained dichloromethane layer was washed with 200 ml of water and concentrated to dryness under reduced pressure. The obtained crude product was purified by column chromatography to obtain 4.0 g of objective substance as pale yellow glassy substance (yield: 7%).
Reaction SMILES: [CH2:1]([C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH2:10][NH:11][CH2:12][CH2:13][C:8]=2[C:7](=[O:14])[O:6]1)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41]>C1COCC1>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:14])[O:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]=2[CH2:10]1)=[O:41]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)c1ccc3ccccc3c1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol) and N,N′-diisopropylethylamine (71 mg, 0.552 mmol) in THF (5 mL) at 0° C. was added 2-naphthoylchloride (35 mg, 0.184 mmol) and the reaction mixture was stirred at 0° C. for 30 min, then room temperature overnight. The crude mixture was concentrated to dryness and purified by column chromatography (4 g, SiO2, 0 to 30% ethyl acetate in hexanes) to provide 5-(2-naphthoyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (68 mg, 87%) as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.77-1.08 (m, 6H), 1.63-1.78 (m, 1H), 1.79-1.95 (m, 1H), 2.28-2.59 (m, 3H), 3.28-3.60 (m, 1H), 3.73 (br. s., 1H), 4.09-4.27 (m, 1H), 4.85 (br. s., 1H), 7.29-7.51 (m, 6H), 7.52-7.62 (m, 2H), 7.77-7.98 (m, 4H); MS m/z 426 (M+H)+, 449 (M+23)+, 424 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Product: Cc1ccc(S(=O)(=O)Nc2cccc(COCc3ccc(F)cc3)n2)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 3-chloro-4-methyl-benzenesulfonyl chloride (0.062 g) as a light yellow gum (0.09 g). MS (ESI−): 419.0. ([M−H]−)