Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH:13]([OH:16])[CH2:14][CH3:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1[N:21]=[CH:20][N:19]([C:22](N2C=NC=C2)=[O:23])[CH:18]=1>C(#N)C>[N:19]1([C:22]([O:16][CH:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH2:14][CH3:15])=[O:23])[CH:18]=[CH:17][N:21]=[CH:20]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(O)c1ccc(-c2ccccc2)nc1
Solvent: CC#N
Product: CCC(OC(=O)n1ccnc1)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 44a (150 mg, 0.70 mmol), CDI (570 mg, 3.52 mmol) and acetonitrile (9 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. White solid. Yield: 116 mg, 54%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.04 (t, J=7.4 Hz, 3H), 2.01-2.15 (m, 1H), 2.22 (dt, J=14.3, 7.2 Hz, 1H), 5.92 (t, J=7.1 Hz, 1H), 7.09 (dd, J=1.6, 0.6 Hz, 1H), 7.41-7.51 (m, 4H), 7.75-7.80 (m, 2H), 7.98-8.03 (m, 2H), 8.17-8.19 (m, 1H), 8.74-8.77 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=9.8, 28.7, 79.8, 117.0, 120.3, 126.9, 128.8, 129.3, 130.8, 132.3, 135.0, 137.0, 138.6, 148.0, 148.3, 158.0; MS (ESI): m/z=308.30 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:19][OH:20])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:19][O:20][CH2:33][C:34]([F:37])([F:36])[F:35])[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCC(=NO)c1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=NOCC(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
To 5.0 g of tert-butyl N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]carbamate in 16.0 ml of N,N-dimethylformamide, 4.3 g of potassium carbonate and 5.4 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of water and extracted with ethyl acetate (100 ml×2), the resulting organic layers were combined, washed with water (50 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 0:10 to 3:7) as the eluent to obtain 4.8 g of the desired product as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH3:26])=[C:10]([C:12]2[C:23](=[O:24])[N:22]([CH3:25])[C:15]3[N:16]=[C:17](SC)[N:18]=[CH:19][C:14]=3[CH:13]=2)[CH:11]=1.OOS([O-])=O.[K+].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH3:26])=[C:10]([C:12]2[C:23](=[O:24])[N:22]([CH3:25])[C:15]3[N:16]=[C:17]([NH:33][CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[N:18]=[CH:19][C:14]=3[CH:13]=2)[CH:11]=1
Reactant: CSc1ncc2cc(-c3cc(-c4ncc[nH]4)ccc3C)c(=O)n(C)c2n1
Reactant: NC1CCOCC1
Agent: O=S([O-])OO
Agent: [K+]
Product: Cc1ccc(-c2ncc[nH]2)cc1-c1cc2cnc(NC3CCOCC3)nc2n(C)c1=O

Procedure:
6-[5-(1H-Imidazol-2-yl)-2-methyl-phenyl]-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 2.5 mg of 6-[5-(1H-imidazol-2-yl)-2-methyl-phenyl]-8-methyl-2-(tetrahydro-pyran-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one: MS (M+H)=417.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>C1CCCCC1.CCOC(C)=O>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(CBr)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOP(=O)(Cc1ccc(OC)cc1[N+](=O)[O-])OCC
Temperature: 120 °C
Yield: 97.4 %

Procedure:
A mixture of 1-(bromomethyl)-4-methoxy-2-nitrobenzene (14.2 g; 57.71 mmol; 1 eq) and triethyl phosphite (9.49 mL; 54.82 mmol; 0.95 eq) is heated at 120° C. for 1 h. TLC analysis using cyclohexane/EtOAc [1/1] as eluent showed that the reaction is complete. The reaction mixture is cooled down to room temperature. The crude is purified by flash chromatography to afford 16.2 g (93%) of an orange oil. Storage at −25° C. allows the product to crystallize. It is then washed with petroleum ether and filtered to afford 14.4 g (82%) of the title compound. 1H NMR (DMSO-d6) δ 7.50 (d, J=3.0 Hz, 1H), 7.45 (dd, J=9.0, 2.0 Hz, 1H), 7.28 (dd, J=9.0, 2.0 Hz, 1H), 3.98-3.89 (m, 4H), 3.84 (s, 3H), 3.64 (s, 1H), 3.57 (s, 1H), 1.14 (t, J=7.0 Hz, 6H). HPLC (max plot) 99%; Rt 3.29 min. LC/MS: (ES+): 304.3, (ES−): 302.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[N:1]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])=[N+:14]=[N-:15]
Reactant: Nc1ccccc1CO
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1CO
Reaction time: 0.75 h
Yield: 72.3 %

Procedure:
To a solution of 2-aminobenzyl alcohol (12.0 g, 97.4 mmol) in 50 mL of trifluoroacetic acid at 0° C. was added sodium nitrite (7.39 g, 107.2 mmol). This solution was stirred for 45 min and then there was added sodium azide (6.33 g, 97.4 inmol) dropwise as a solution in water. The resulting mixture was stirred at 0° C. for 45 min and then was carefully quenched by slow addition of potassium carbonate. The reaction mixture was diluted with ethyl acetate, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated to afford 10.5 g (72%) of the title compound which was used without further purification. 1H NMR (CDCl3) δ7.33 (m, 2H), 7.14 (m, 2H), 4.59 (s, 2H), 2.69 (broad s, 1H).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.[CH3:11][NH+:12]1[C@@H:17]2[CH2:18][C:19]([CH2:21][C@H:13]1[CH2:14][CH2:15][CH2:16]2)=O.S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:15]1[CH2:16][CH:17]3[N:12]([CH3:11])[CH:13]([C:14]2=1)[CH2:21][CH2:19][CH2:18]3
Reactant: Cc1ccc(NN)cc1
Reactant: C[NH+]1[C@@H]2CCC[C@H]1CC(=O)C2
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Temperature: 80 °C

Procedure:
In a 100 mL round-bottom flask were combined p-tolylhydrazine hydrochloride (1.58 g, 10 mmol; Aldrich), pseudopelletierine hydrochloride (2.0 g, 10.5 mmol; Acros), and concentrated sulfuric acid (5 mL) in dioxane (50 mL). The reaction mixture was heated to 80° C. for 2.5 hours, then cooled to room temperature. The solvent was decanted, and the residue was dissolved in water (20 mL) and basified with solid potassium carbonate to pH ˜12. This solution was extracted with dichloromethane (3×50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the resulting solid was recrystallized from ether to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.21-1.41 (m, 2H), 1.60-1.71 (m, 2H), 1.90-2.08 (m, 2H), 2.35 (s, 3H), 2.38 (s, 3H), 2.42-2.52 (m, 1H), 3.16-3.27 (m, 2H), 4.09 (t, J=3 Hz, 1H), 6.86 (dd, J=8, 1 Hz, 1H), 7.10 (s, 1H), 7.17 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 241 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[CH3:30][C@@H:31]1[C@@H:35]([OH:36])[CH2:34][CH2:33][NH:32]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:23][CH2:24][CH:25]([N:32]3[CH2:33][CH2:34][C@H:35]([OH:36])[C@H:31]3[CH3:30])[CH2:26][CH2:27]2)=[O:21])[CH2:3][CH2:2]1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Reactant: C[C@H]1NCC[C@@H]1O
Agent: Cl
Product: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(N2CC[C@H](O)[C@H]2C)CC1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (2R,3S)-2-methyl-pyrrolidin-3-ol hydrochloride (example 187A) in direct analogy to the general procedure used in example 129. MS: 477.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[NH4+].[Cl-].CC(C)=O>[Zn].O>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1cc(Br)cc(F)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cc(Br)cc(F)c1N
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-fluoro-2-nitro-phenylamine (2 g, 8.5 mmol), NH4Cl (6.81 g, 127.6 mmol), acetone (100 mL) and water (20 mL), was added zinc powder portion-wise (three equal portions over 5 minutes) (8.34 g, 127.6 mmol) at 0° C. The mixture was stirred for 2 h then warmed to 23° C. The mixture was filtered through Celite® and the solvents were concentrated under reduced pressure. The mixture was re-dissolved in EtOAc/DCM and filtered a second time through Celite® and the solvents were evaporated. The crude mixture was diluted with EtOAc (200 mL), washed with brine (40 mL), dried, filtered, and concentrated under reduced pressure. The resultant residue was used in the next reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:9]1COCC1.[H-].[Na+].CI>O>[CH3:9][O:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccnc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1cccnc1
Reaction time: 0.25 h

Procedure:
To a mixture of 10.0 g of 3-hydroxymethylpyridine and 200 ml of THF, 3.7 g of 60% sodium hydride (in oil) was added in small portions at room temperature and then stirred for 15 minutes. To the reaction mixture, 13.0 g of methyl iodide was added dropwise, and the reaction mixture was stirred at room temperature for three hours. To the reaction mixture, 25 ml of water was added. Then, the reaction mixture was concentrated under reduced pressure. To the residue, 25 ml of water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 8.17 g of 3-methoxymethylpyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[F:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[C:32]([CH3:39])=[C:33]([CH:37]=O)[NH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>C(O)C.N1CCCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:37]\[C:33]1[NH:34][C:35]([CH3:36])=[C:31]([CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([F:23])[CH2:29][CH2:28]2)[C:32]=1[CH3:39])(=[O:12])=[O:11]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCC(F)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCC(F)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one was condensed with 4-(4-fluoro-piperidin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde in ethanol and piperidine to give the titled compound as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(F)c2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 10 mL was added to the obtained tert-butyl 2-(4-fluoroanilino)-4-(3-fluorophenyl)benzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, hexane was added to the obtained residue, and solid matter was filtrated to give 2-(4-fluoroanilino)-4-(3-fluorophenyl)benzoic acid 56 mg of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
To a chilled solution of 5-chlorothiophene-2-carboxylic acid (0.16 g, 1.0 mmol) in EtOAc (3 mL) and DMF (1 drop) was added neat oxalyl chloride (92 μL, 1.05 mmol). The reaction mixture was stirred cold for 2 hr and concentrated in vacuo to give crude 5-chlorothiophene-2-carbonyl chloride.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.C(=O)(O)[O-].[K+].O.[CH2:32]([OH:34])[CH3:33]>>[CH2:32]([O:34][CH2:14][CH2:13][C:12](=[O:15])[C@@H:11]1[C@:16]2([CH3:25])[C@H:8]([C@H:7]3[C@H:19]([C:18](=[O:24])[CH2:17]2)[C@:20]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[CH2:22][CH2:21]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:33]
Reactant: CCO
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCOCCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane11,20 -dione (250 mg) was dissolved in ethanol (50 ml) and potassium bicarbonate solution (10%; 3 ml) added to the refluxing solution. After 3/4 hour the mixture was poured into water, and extracted into ether. The extract was washed with water, dried (Na2SO4) and evaporated to a white solid (190 mg) which was recrystallised from ether to give title compound (120 mg) m.p. 126°-129.5° C [α]D + 87.5° (c, 1.03).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14](C(=O)C)[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[S:38]([CH3:37])(=[O:40])=[O:39])[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Reactant: CS(=O)(=O)Cl
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)S(C)(=O)=O)c2ccccc21

Procedure:
The titled compound was prepared following the procedures described in Example 1 for the synthesis of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester in step 8, by replacing acetic anhydride with methanesulfonyl chloride. MS (ES+): 553(M+).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:22]3[CH:30]=[CH:31][C:32]([C:34](=[N:36][OH:37])[NH2:35])=[CH:33][C:21]=3[N:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:22]3[CH:30]=[CH:31][C:32]([C:34]4[NH:35][S:1](=[O:2])[O:37][N:36]=4)=[CH:33][C:21]=3[N:20]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=NO)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S1NC(c2ccc3c(c2)nc(-c2ccc(OCc4ccccc4)cc2)n3C2CCCCC2)=NO1
Reaction time: 3 h
Yield: 39.7 %

Procedure:
Thionyl chloride (0.010 mL, 0.14 mmol) was added dropwise to a suspension of 2-[4-(Benzyloxy)phenyl]-1-cyclohexyl-N′-hydroxy-1H-benzimidazole-5-carboximidamide (0.025 g, 0.057 mmol, see above for preparation) and pyridine (0.020 mL, 0.25 mmol) in tetrahydrofuran (2 mL) at 0° C. The resulting solution was stirred for 3 h, and then concentrated on a rotary evaporator. As starting material remained, the residue was resubjected to the reaction conditions (0.020 mL thionyl chloride and 0.040 mL pyridine). The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a yellow solid (0.011 g, 32%). 1H NMR (CD3OD) δ 8.32 (d, 1H, J=8.8 Hz), 8.25 (s, 1H), 8.04 (d, 1H, J=8.8 Hz), 7.77 (d, 2H, J=9.1 Hz), 7.49 (d, 2H, J=6.6 Hz) 7.43-7.35 (m, 5H), 5.27 (s, 2H), 4.55 (m, 1H), 2.45 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H), 1.80 (m, 1H), 1.44 (m, 3H); ESI-MS m/e 487.3 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]1[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=O)[C:15]([CH3:22])=[N:14]1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]1[C:17]([CH3:18])=[C:16]([C:19]([N:31]2[CH2:32][CH2:33][CH:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:29][CH2:30]2)=[O:21])[C:15]([CH3:22])=[N:14]1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1ccc(C(F)(F)F)cc1-n1nc(C)c(C(=O)O)c1C
Product: COc1ccc(C(F)(F)F)cc1-n1nc(C)c(C(=O)N2CCC(N3CCCC3)CC2)c1C
Yield: 27 %

Procedure:
In analogy to the procedure described in Example 18], 1-(2-methoxy-5-trifluoromethyl-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave, after purification on a flash isolute NH2-column (EtOAc:n-heptane 4:1), the title compound in 27% yield as yellow oil. MS: 451.2 (MH+).
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[CH:17][N:16]=1>CO.O>[Cl:14][C:15]1[N:20]=[C:19]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH:18]=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(Sc2ccnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a sodium hydroxide (2.38 g, 59 mmol) solution in methanol (50 mL) and water (5 mL), was added dropwise a solution of methyl 4-mercaptobenzoate (9.00 g, 54 mmol) in methanol (100 mL). The mixture was stirred at room temperature for 1 hour, to this was added methanol solution (100 mL) of 2,4-dichloropyrimidine (8.77 g, 59 mmol) over 5 minutes. The whole was stirred at room temperature for 16 hours. Methanol was removed in vacuo, and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated and dried (Na2SO4). Removal of the solvent in vacuo yielded the product (14.60 g, 97%).
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C@H:10]1[C@H:15]([CH3:16])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH3:16][C@@H:15]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[NH:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1C)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A mixture of trans-benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (0.95 g, 2.5 mmol) and 10% Pd/C (0.13 g, 0.12 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-methylpiperidin-3-ylphosphoramidate (0.63 g, 100%) as an oil.
Reaction SMILES: C(O[C:5]1[C:6]([CH3:24])=[C:7]([CH3:23])[C:8]2[O:12][CH:11](CSC3C=CC=CC=3)[CH2:10][C:9]=2[C:21]=1[CH3:22])(=O)C.[OH-].[Na+].Cl>CO.O>[CH3:22][C:21]1[C:9]2[CH2:10][CH2:11][O:12][C:8]=2[C:7]([CH3:23])=[C:6]([CH3:24])[CH:5]=1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CSc1ccccc1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)c2c(c1C)OCC2
Yield: 149.7 %

Procedure:
To a solution of 5-acetoxy-2-(phenylthiomethyl)-4,6,7-trimethyl-2,3-dihydrobenzofuran [1.2 g (3.5 mmol)] in methanol (8 ml) was added a solution of sodium hydroxide (0.6 g) in water (5 ml). The mixture was heated for one hour under reflux under argon atmosphere. The reaction mixture was, after cooling, diluted with water and, then, neutralized with 2N-HCl and followed by extraction with ethyl acetate. The extract solution was washed with water, and dried, then the solvent was distilled off. The residue was crystallized from isopropyl ether-hexane to obtain 5-hydroxy-2-phenylthiomethyl)-4,6,7-trimethyl-2,3-dihydrobenzofuran (Compound 3) (0.85 g).