Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N+]1([O-])CCOCC1.[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[NH:23][C:22](=[O:24])[C:21]2([CH2:29][CH2:28][N:27]([S:30]([CH2:33][CH2:34][C:35]3[C:40]([CH3:41])=[CH:39][C:38]([N:42]([CH3:46])[C:43]([NH2:45])=[O:44])=[CH:37][C:36]=3[CH3:47])(=[O:32])=[O:31])[CH2:26][CH2:25]2)[N:20]=1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:41][C:40]1[CH:39]=[C:38]([N:42]([CH3:46])[C:43]([NH2:45])=[O:44])[CH:37]=[C:36]([CH3:47])[C:35]=1/[CH:34]=[CH:33]/[S:30]([N:27]1[CH2:28][CH2:29][C:21]2([N:20]=[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[O:9])[NH:23][C:22]2=[O:24])[CH2:25][CH2:26]1)(=[O:31])=[O:32]
Reactant: Cc1cc(N(C)C(N)=O)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(CCCCCCCCCO)NC2=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1cc(N(C)C(N)=O)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(CCCCCCCCC=O)NC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
NMO (22.0 mg, 0.192 mmol), Molecular Sieves 4A (25.0 mg) and TPAP (0.700 mg, 0.00213 mmol) were added to a solution of 1-(4-{2-[2-(9-hydroxy-nonyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3,5-dimethyl-phenyl)-1-methyl-urea (24.0 mg, 0.0426 mmol) in CH2Cl2 (850 μl) at room temperature. The mixture was stirred at room temperature for one hour and then filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 1-(3,5-dimethyl-4-{(E)-2-[4-oxo-2-(9-oxo-nonyl)-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-vinyl}-phenyl)-1-methyl-urea (17.0 mg, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 30 cm3 of dimethyl sulphoxide and 5 g of piperazine is heated at a temperature close to 100° C., with stirring, for 2 hours. The solution obtained at about 100° C. is poured, with stirring, into a mixture of 150 cm3 of water and 50 g of ice. The solution is extracted with 3 times 40 cm3 of trichloromethane. The combined organic phases are extracted with twice 50 cm3 of 0.1 N methanesulphonic acid. 10 g of potassium carbonate are added to the combined aqueous phases. The mixture is extracted with 3 times 40 cm3 of trichloromethane. The combined organic extracts are washed with twice 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is recrystallized from 25 cm3 of ethanol. 0.8 g of 3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine is obtained in the form of a yellow solid melting at 221° C.
Reaction SMILES: [OH:1][CH:2]([CH2:30][N:31]1[C:44](=[O:45])[C:34]2([CH2:39][C:38]([CH3:41])([CH3:40])[NH:37][C:36]([CH3:43])([CH3:42])[CH2:35]2)[O:33][C:32]21[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:3][N:4]1[C:17](=[O:18])[C:7]2([CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]([CH3:16])([CH3:15])[CH2:8]2)[O:6][C:5]21[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2>C(OC(=O)C)(=O)C>[C:2]([O:1][CH:2]([CH2:3][N:4]1[C:17](=[O:18])[C:7]2([CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([C:17](=[O:18])[CH3:7])[C:9]([CH3:16])([CH3:15])[CH2:8]2)[O:6][C:5]21[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:30][N:31]1[C:44](=[O:45])[C:34]2([CH2:35][C:36]([CH3:42])([CH3:43])[N:37]([C:5](=[O:6])[CH3:19])[C:38]([CH3:40])([CH3:41])[CH2:39]2)[O:33][C:32]21[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)(=[O:1])[CH3:3]
Reactant: CC1(C)CC2(CC(C)(C)N1)OC1(CCCCCCCCCCC1)N(CC(O)CN1C(=O)C3(CC(C)(C)NC(C)(C)C3)OC13CCCCCCCCCCC3)C2=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC(CN1C(=O)C2(CC(C)(C)N(C(C)=O)C(C)(C)C2)OC12CCCCCCCCCCC2)CN1C(=O)C2(CC(C)(C)N(C(C)=O)C(C)(C)C2)OC12CCCCCCCCCCC2

Procedure:
39.2 g of 20,20'-(2-hydroxy-1,3-propanediyl)bis[2,2,4,4-tetramethyl-7-oxa-3,20-diazadispiro[5.1.11.2]heneicosan-21-one] were dissolved in 400 cm3 of acetic anhydride and heated so strongly that about 200 cm3 of liquid distilled off over the course of 6 hours. The batch was then evaporated to dryness in vacuo, the residue was taken up in toluene and washed by shaking with dilute hydrogencarbonate solution and water, and the organic phase was dried. After evaporation, the target compound crystallized as a colorless solid during stirring with hexane. 36.9 g having a melting point of 122° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[NH:13][CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28]2)=[O:26])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CNCCNC.Cl.CCOCC>C(Cl)Cl.[Cu]I.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:17][C:11]3[C:12](=[O:16])[N:13]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([CH:27]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28]5)=[O:26])=[CH:21][CH:20]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CN1CCC(C(=O)c2ccc(Br)cc2)C1
Reactant: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Agent: [Cu]I
Agent: CNCCNC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1CCC(C(=O)c2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2)C1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 151.8 %

Procedure:
Combine 2-(4-chloro-phenyl)-6H-thieno[2,3-c]pyridin-7-one (0.15 g, 0.57 mmol), (4-bromo-phenyl)-(1-methyl-pyrrolidin-3-yl)-methanone (0.16 g, 0.60 mmol), Cs2CO3 (0.37 g, 1.15 mmol), 1,4-dioxane (6 mL), and CuI (0.044 g, 0.23 mmol). Purge the mixture with nitrogen for 10 min. Add sym-dimethylethylene diamine (0.040 g, 0.46 mmol). Heat the mixture at 100° C. overnight. Cool the mixture to RT, dilute with CH2Cl2 (200 mL), and wash with a solution of 5% NH4OH/H2O (2×30 mL). Dry the organic layer over Na2SO4, filter, and concentrate. Filter the crude with H2O (200 mL) and Et2O (100 mL). Prepare the HCl salt by dissolving the solid in CH2Cl2 and adding 1 eq 1M HCl/ether. Allow the solution to stir for 15 min and concentrate to give 0.21 g (77%) of the title compound. LC-MS/ES m/z (35Cl) 449.0 [M+H]+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]=[C:7]([CH2:14][CH2:15][CH3:16])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(Cl)(Cl)Cl>[Cl:4][CH:8]([C:7](=[O:6])[CH2:14][CH2:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCC(=O)CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCCC(=O)C(Cl)C(=O)OCC

Procedure:
Sulphuryl chloride (175 ml) was added to a rapidly stirred and cooled solution of ethyl 3-oxohexanoate (300 ml) in chloroform (150 ml) whilst maintaining the temperature at 10°-15°. The mixture was stirred overnight at room temperature, then heated under reflux for 0.5 h. The cooled reaction mixture was washed with water (0.5 l), 2N sodium bicarbonate (0.5 l) and water (0.5 l), dried and concentrated in vacuo. Fractionation gave the title compound (341.8 g) as a pale yellow liquid b.p. 106°-108°/ca. 10 mmHg, t.l.c. (ether:hexane 1:1), Rf 0.60.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.N12CCCN=C1CCCCC2.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>O1CCCC1.CN(C)C=O>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:52]([CH3:51])(=[O:54])=[O:53])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 23 %

Procedure:
To a solution of the product of Example 345 (15 mg, 0.032 mmol) in tetrahydrofuran (0.4 mL) was added triethylamine (0.018 mL, 0.129 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.018 mL, 0.129 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride was added (0.003 mL, 0.032 mmol). The mixture was stirred at 0° C. for 2.5 hours and then warmed to 23° C. and stirred for 2.5 hours. Additional 1,8-diazabicyclo[5.4.0]undec-7-ene (0.010 mL 0.064 mmol) and methane sulfonyl chloride (0.003 mL, 0.032 mmol) were added and the mixture was stirred at 23° C. for 15 hours. A few drops of N,N-dimethylformamide were added to increase solubility. Additional methane sulfonyl chloride (0.003 mL, 0.032 mmol) was added and the reaction mixture was stirred at 23° C. for 3 hours. A few drops of N,N-dimethylformamide and methane sulfonyl chloride (0.003 mL, 0.032 mmol) were added and the reaction mixture was stirred at 23° C. for 1 hour. Additional methane sulfonyl chloride (0.006 mL, 0.064 mmol) was added and the reaction mixture was stirred at 23° C. for 72 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was diluted with diethyl ether and 1 N hydrochloric acid was added until no further precipitation was observed. The precipitate was then washed with water followed by diethyl ether. The solid was dissolved in 1% triethylamine/dichloromethane and purified by preparative thin layer chromatography eluting with 5% (5% triethylamine/methanol)/dichloromethane. The silica gel was washed with 10% (5% triethylamine/methanol)/dichloromethane to give the triethylamine salt of the title compound (4.7 mg, 23%). 1H NMR (500 MHz, DMSO-d6) δ 1.16 (t, J=6.71 Hz, 9H) 2.94 (s, 3 H) 3.08 (bs, 6 H) 4.26 (d, 2 H) 5.40 (bs, 2 H) 7.06 (m, 2 H) 7.12 (d, J=8.54 Hz, 1 H) 7.23 (m, 5 H) 7.40 (t, J=7.32 Hz, 1 H) 7.50 (t, J=6.41 Hz, 1 H) 8.10 (d, J=6.10 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[NH:11]C(=O)OCCCC)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)NC1CC1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CC1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 9 (560 mg, 2.2 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic acid (15 mL). The reaction mixture was stirred at room temperature for 30 min. The solvent was removed by rotary evaporation. The yellow oil was put under vacuum for 24 h to give crude amine 4b (579 mg, 2.2 mmol, 100%) as a yellow oil, which was used in the next step without further purification: 1H NMR (500 MHz, CDCl3) δ 1.10-1.30 (br s, 1H), 1.40-1.60 (br s, 1H), 2.30-2.50 (br s, 1H), 2.70-2.90 (br s, 1H), 6.70-6.72 (m, 1H), 6.72-6.77 (m, 1H), 6.89-7.00 (m, 1H), 7.10-7.30 (m, 1H), 7.80-8.20 (br s, 2H), 10.8-11.8 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 13.2, 21.5, 31.6, 113.5, 113.7, 114.2, 114.4, 122.29, 122.31, 130.4, 130.5, 140.1, 140.2, 162.2, 164.1; LCQ-MS (M+H+) calcd for C9H11FN 152. found 152; LC-TOF (M+H+) calcd for C9H11FN 152.08755. found 152.08703.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([CH:13]3[C:21](=[O:22])[CH:20]4[CH:15]([CH:16]5[O:23][CH:19]4[CH2:18][CH2:17]5)[C:14]3=[O:24])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:25][CH3:26])=[C:11]([C:13]3[C:14](=[O:24])[CH:15]4[CH:20]([CH:19]5[O:23][CH:16]4[CH2:17][CH2:18]5)[C:21]=3[O:22][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C2C3CCC(O3)C2C1=O
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C2CC2)C2C3CCC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 124.3 %

Procedure:
To a solution of 4-[2-(4-chloro-phenyl)-5-ethyl-thiazol-4-yl]-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (100 mg, 0.18 mmol) in DCM (5 ml) and triethylamine (140 μl, 1 mmol) is added the cyclopropane carbonyl chloride (91 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give cyclopropanecarboxylic acid-4-[2-(4-chloro-phenyl)-5-ethyl-thiazol-4-yl]-5-oxo-10-oxa-tricyclo[5.2.1.0*2,6*]dec-3-en-3-yl ester (102 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:6]([OH:7])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1>[CH3:19][C:2]1([CH3:1])[CH:6]([O:7][C:20](=[O:22])[CH3:21])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(COCc2ccccc2)CC(O)C(C)(C)O1
Solvent: c1ccncc1
Product: CCC1(COCc2ccccc2)CC(OC(C)=O)C(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The alcohol of Example 3 (800 mg) was added to pyridine (20 ml) and acetic anhydride (5 ml) and the mixture was stirred at room temperature over two days. The mixture was then evaporated down under vacuum and the residue was dissolved in diethyl ether. The solution was decolourised over charcoal, and the ether was removed to give 860 mg of the desired product. NMR showed that the product was a mixture of geometric isomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 95.4 %

Procedure:
3-Bromoaniline (1.72 grams, 10 mmol) was reacted with 4-chloro-6-nitroquinazoline (523 mg, 2.5 mmol), in iso-propylalcohol, as is described hereinabove, to give 4-[(3-bromophenyl)amino]-6-nitroquinazoline (823 mg, 95% yield), which was thereafter reacted (590 mg, 1.7 mmol) with hydrazine hydrate, according to the procedure described hereinabove, to give 4-[(3-bromophenyl)amino]-6-aminoquinazoline (332 mg, 62% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:15])([F:14])[C:11](O)=O>>[F:9][C:10]([F:15])([F:14])[C:11]1[N:1]=[C:2]2[NH:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1
Reactant: Nc1cccnc1N
Reactant: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nc2ccc[nH]c-2n1
Yield: 76 %

Procedure:
A solution of 2,3-diaminopyridine (1.00 g, 9.16 mmol) in trifluoroacetic acid (10 mL) was stirred for 15 h at 110° C. (microwave). The trifluoroacetic acid was then evaporated under reduced pressure and the residue was co-evaporated with toluene three times. The resulting solid was triturated with water, filtered and dried under reduced pressure to give 1.30 g (6.95 mmol, 76%) 2-(trifluoromethyl)-4H-imidazo[4,5-b]pyridine. Alternatively, the latter can be prepared according to J. Chem. Soc., Perkin 1 1996, (22), 2685-2691.
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:11]2[N:12]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[S:14][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CO.O>[NH:15]([C:13]1[S:14][C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[C:11]=2[N:12]=1)[C:16]([NH2:18])=[NH:17]
Reactant: CCOC(=O)C1CCCc2sc(NC(=N)N)nc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N=C(N)Nc1nc2c(s1)CCCC2C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A suspension of 2-guanidino-4,5,6,7-tetrahydro-benzothiazole-4-carboxylic acid ethyl ester (5 mmol) and sodium hydroxide (20 mmol) in methanol/water (4:1, 10 ml) is stirred overnight at room temperature. The pH is set at 5 by adding 25% hydrochloric acid and the precipitated product is filtered off. In this way the title compound is obtained (671 mg) in a yield of 56%: tR 0.64 min (LC-1); ESI-MS (+/−): m/z 241.49 [M+H]+/239.37 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH2:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH2:17]([NH:21][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN=C=O
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h
Yield: 121.6 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Butyl isocyanate (39 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. An addition amount of butyl isocyanate(100 μL, 0.888 mmol) was added to the reaction mixture and mixing was continued for another 6 days. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 44.4 mg (>100%) of the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]1[N:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28].[H-].[Na+]>CN(C)C=O>[NH2:23][C:21]1[C:22]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[CH:15][N:16]([C:25]3[C:26]([C:27]#[N:28])=[CH:29][CH:30]=[CH:31][N:32]=3)[C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1-n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
5-(4-Phenoxyphenyl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ylamine (906 mg) was reacted with 2-chloronicotinonitrile (510 mg) in the presence of sodium hydride (150 mg) in dimethylformamide (30 ml) at 100° C. for 5 hours to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]pyridine-3-carbonitrile, m.p. 242-242.5° C., after workup.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][S:8][C:9]1[S:10][C:11]([NH:14][C:15]([N:17]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:16])=[N:12][N:13]=1)C.C1(NC2CCCCC2)CCCCC1.C(OC(=O)CCCSC1SC(N)=NN=1)C>>[CH:24]1([N:17]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:15](=[O:16])[NH:14][C:11]2[S:10][C:9]([S:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[N:13][N:12]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)CCCSc1nnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCOC(=O)CCCSc1nnc(N)s1
Product: O=C(O)CCCSc1nnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
4-[5-(3,3-Dicyclohexyl-ureido)-[1,3,4]thiadiazol-2-ylsulfanyl]-butyric acid ethyl ester was pre-pared as described in general procedure (A) using dicyclohexylamine and 4-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-butyric acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([S:22][CH3:23])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[Na].I([O-])(=O)(=O)=[O:32]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([S:22]([CH3:23])=[O:32])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanyl-pyrazin-2-yl)-propionamide (prepared as in Example 4, 0.20 g, 0.441 mmol) in tetrahydrofuran (3 mL) was added dropwise to a solution of sodium-meta-periodate (0.189 g, 0.882 mmol) in water (1.5 mL). The resulting reaction mixture was stirred at 25° C. for 72 h. The reaction mixture was then concentrated in vacuo, and the residue was then diluted with chloroform (25 mL). The organic layer was washed with water (25 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methane-sulfinyl-pyrazin-2-yl)-propionamide (96 mg, 46%) as a white foam: mp 88–95° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H24ClN3O4S2 (M+H)+ 470.0970 found 470.0976.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:33][CH2:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([C:43](O)=[O:44])[CH2:39][CH2:38]1)=[O:36].CCOC(OC(OCC)=O)=O>CN(C=O)C.O>[OH2:7].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][N:13]([C:43]([CH:40]3[CH2:41][CH2:42][N:37]([C:35](=[O:36])[CH2:34][OH:33])[CH2:38][CH2:39]3)=[O:44])[CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:24][CH:25]=1
Reactant: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)CO)CC1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)CO)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a solution of the compound obtained in step 3 (200 mg), triethylamine (313 μL) and 1-(hydroxyacetyl)piperidine-4-carboxylic acid (101 mg) in DMF (4.5 mL) was added DEPC (87 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 40→95% ethyl acetate/hexane) to give the title compound (135 mg, 49%) as a white crystal powder.