Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[C:12]2=[NH:31])[CH:5]=1.[OH-].[Na+]>CO>[F:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:22][CH2:21][CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:32])=[O:2])[C:12]2=[NH:31])=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(Cn2c(=N)n(CCCOc3ccc(F)cc3)c3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.7 %

Procedure:
To a solution of 3-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzoic acid methyl ester (50 mg, 0.12 mmol) in MeOH (2 ml) at rt was added aqueous NaOH (1 ml). The reaction was stirred for 1 h at rt and then it was concentrated under reduced pressure. The material that remained was partitioned between EtOAc and H2O and the 1M KHSO4 was added. The suspension was then filtered and the collected solid was dried to provide 3-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzoic acid (20 mg, 41%). HPLC-MS 420 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=O.C1(C)C=CC=CC=1.Cl>O>[OH:1][C:2]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[C:17]([CH3:25])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1cc(C)c(C(=O)CCCCCCCCC(=O)O)c(O)c1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c(CCCCCCCCCC(=O)O)c(O)c1OC

Procedure:
9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1, wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.254 part), zinc amalgam (0.56 part), toluene (1 volume part), 35% hydrochloric acid (0.5 volume part) and a small proportion of water were refluxed for 5 hours. The toluene layer was separated and the water layer was extracted with diethyl ether. The toluene layer was combined with the ethereal layer, washed with water and dried. The solvents were then distilled off under reduced pressure and the residue was recrystallized from ligroine. The foregoing procedure provided 10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoic acid (formula II-2 wherein R=H3CO, X=H, n=8, in the free form) (0.14 part) as colorless powdery crystals melting at 62.5°-66° C.
Reaction SMILES: O1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C@@H:28]6[CH2:32][CH2:31][CH2:30][O:29]6)[CH:22]=5)[C:17]4=[O:33])=[CH:12][C:11]=3[F:34])[CH2:6]2)[O:4]CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[F:34][C:11]1[CH:12]=[C:13]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:27][C@@H:28]4[CH2:32][CH2:31][CH2:30][O:29]4)[CH:22]=3)[C:17]2=[O:33])[CH:14]=[CH:15][C:10]=1[N:7]1[CH2:8][CH2:9][C:5](=[O:4])[CH2:6]1
Reactant: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(c2ccc(N3CCc4cc(OC[C@@H]5CCCO5)ccc4C3=O)cc2F)C1
Temperature: 70 °C

Procedure:
A mixture of 2-[4-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-3,4-dihydro-2H-isoquinolin-1-one (8.4 g) and p-toluenesulfonic acid (3.4 g) in acetone/water (80 mL/40 mL) was heated for 12 h at 70° C. Then the acetone was removed in vacuum and the aqueous phase was neutralized with sodium hydrogencarbonate solution and then extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 424.47 (C24H25FN2O4); MS (ESI): 425 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.C([N:22](CC)CC)C.O.NN>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:14])[NH:15][NH2:22])=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Reactant: CCN(CC)CC
Agent: NN
Solvent: CCO
Solvent: O
Product: N=C(NN)c1nn(Cc2ccccc2F)c2c1CCC2
Temperature: 0 °C
Reaction time: 72 h

Procedure:
200 mg (0.77 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide were initially charged in 4 ml of ethanol and cooled to 0° C. 310 mg (3.07 mmol) of triethylamine and 48 mg (0.77 mmol) of 80% hydrazine hydrate were added, and the mixture was stirred at room temperature for 72 h. The mixture was concentrated on a rotary evaporator, taken up in ethyl acetate and washed three times with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, concentrated on a rotary evaporator and dried under high vacuum. 209 mg (100% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:24][CH:25]=3)[NH:18][CH:19]=2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][N:2]([CH3:7])[S:3]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[NH:18][CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[N:16]=3)=[CH:25][N:24]=2)[CH2:31][CH2:30]1)(=[O:5])=[O:4]
Reactant: Fc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N1CCN(c2ccc(-c3nc(-c4ccc(F)cc4)c[nH]3)cn2)CC1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
N,N-Dimethylsulfamoyl chloride (0.09 g) was added to a solution of 1-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (0.2 g) and pyridine (0.05 g) in THF. The reaction mixture was held at room temperature overnight and then concentrated in vacuo. The residue was diluted with 1 N NaOH and the resultant mixture extracted with dichloromethane. The organics were extracted with 6N HCl, and the acidic extracts basified with 1 N NaOH. The basic aqueous layer was then extracted with dichloromethane. The organics were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography on silica (20% ethyl acetate in hexanes grading to ethyl acetate grading to dichloromethane) to provide 4-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine-1-sulfonic acid dimethylamide (0.11 g).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]3)=[O:15])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([N:16]3[CH2:20][CH2:19][C@H:18]([NH2:21])[CH2:17]3)=[O:15])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CC(c3cccc(C(F)(F)F)c3)=NO2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCN(C(=O)C2CC(c3cccc(C(F)(F)F)c3)=NO2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the intermediate of step E in methylene chloride (5 mL) was added 4 M HCl in dioxane (5 mL). After stirred at room temperature for 2 h, the resulting solution was concentrated in vacuo to give the HCl salt (350 mg) of the amine as a white solid. LCMS: (M+H)+ 364.4.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccnc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 75.4 %

Procedure:
4-fluoro-3-nitro-toluene (346 mg, 2.2 mmol) and imidazole (299 mg, 4.4 mmol) was dissolved in DMF (5 mL) and the reaction heated to 90° C. for 16 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and 1 M HCl (aq). The aqueous layer was separated and basified with NaOH (s) and extracted with DCM. The DCM was concentrated in vacuo and the residue purified by flash chromatography (Silica, EtOAc:Heptane) to afford the title compound (337 mg, 75%). LC/MS: (00-60% B in A): tR=1.69 min, >90%, m/z (ESI)=204 (MH+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])=O)[CH:2]=[CH2:3].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[F:15])=[N:17][OH:18])[CH:2]=[CH2:3]
Reactant: C=CCOCC(=O)c1cc(Br)ccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCOCC(=NO)c1cc(Br)ccc1F
Temperature: 70 °C

Procedure:
To a solution of 2-(allyloxy)-1-(5-bromo-2-fluorophenyl)ethanone (118 g, 432.1 mmol) in ethanol (1.7 L) is added hydroxylamine hydrochloride (34.5 g, 496.9 mmol) and sodium ethanoate (40.8 g, 496.9 mmol) at 25° C. The reaction is heated at 70° C. for 1 hr. The reaction is cooled and the solvent is removed under reduced pressure. The residue is washed with water (1 L) and is extracted three times with dichloromethane (3×500 mL). The organic phase is dried over magnesium sulfate, filtered, and the solvent is removed under reduced pressure, to obtain the title compound as a mixture of two possible oximes (120 g, 96%). ES/MS m/e (79Br/81Br) 288, 290 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][O:17][C:11]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)COc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A mixture of N-t-butoxycarbonyl-2-hydroxy-5-chlorobenzylamine (730 mg, 2.83 mmol), Cs2CO3 (923 mg, 2.83 mmol) and ethylbromoacetate (0.314 ml, 2.83 mmol) on DMF (5 ml) was stirred for 2 h. The crude reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil which was used for the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:26]=[CH:25][C:8]([C:9]([CH:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[C:12]2=[O:24])=[O:10])=[CH:7][CH:6]=1>C1COCC1.[Pd]>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[CH:11]([C:9](=[O:10])[C:8]1[CH:25]=[CH:26][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][CH:7]=1)[C:12]2=[O:24]
Reactant: O=C(c1ccc(OCCCl)cc1)C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1C(=O)C(C(=O)c1ccc(OCCCl)cc1)C2=O
Reaction time: 8 h
Yield: 97 %

Procedure:
To a suspension of 2-[4-(2-chloroethoxy)benzoyl]-4-nitroindan-1,3-dione (27 g, 72 mmol) in THF (1200 mL) under argon was added 10% Pd/C (2 g, 1.9 mmol). The argon was evacuated and replaced by a balloon of H2. The reaction was stirred overnight and the catalyst removed by filtration. The solvent was evaporated under reduced pressure to give the desired aniline as a yellow solid (24 g, 98% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[CH3:11][C:12]([CH3:14])=O.S(=O)(=O)(O)O>C(O)(=O)C.[Zn]>[CH3:1][C:2]1[NH:3][C:4]([CH:12]([CH3:14])[CH3:11])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(C)=O
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)c1c(C)[nH]c(C(C)C)c1C
Temperature: 45 °C
Reaction time: 1 h

Procedure:
2,4-Dimethyl-3-acetyl-pyrrole (548 mg), 1 ml of acetone and 10 gm of amalgamated zinc (20 mesh) were added to a solution of 1 ml of concentrated sulfuric acid in 20 ml of acetic acid. The mixture was stirred for 1 hour at 45° C. The liquid was decanted from the zinc into 100 ml of water forming a solution from which the crude product separated at 15° C. (174 mg, m.p. 164°-169° C. after the usual solid phase changes). For analysis, it was extracted into ether (thimble) then recrystallized from 3 ml of aqueous ethanol as nearly colourless elongated prisms, m.p. 170°-172° C. (171°-173° when mixed with the product of Example 8) after a solid phase change at 142°. Anal. Calc. for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.60; H, 9.40; N, 7.92.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[C:18]([C:44](=[O:46])[NH2:45])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])[CH2:30][CH2:29]4)=[CH:26][CH:27]=3)[C:18]([C:44](=[O:46])[NH2:45])=[CH:17][CH:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(C(N)=O)c(Nc3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CCC[C@@H](N)C2)nc1Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of ((R)-benzyl 4-(4-(6-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-carbamoylpyridin-2-ylamino)phenyl)piperazine-1-carboxylate) (4.71 g, 7.5 mmol) in CH2Cl2 (5 ml) was treated with 5 mL of TFA and stirred at rt for 5 h. The reaction mixture was concentrated and the residue was partitioned between 1N NaOH and CH2Cl2. The aqueous phase was extracted with CH2Cl2 and the combined organic layers were concentrated. The brown residue was purified by MPLC (ISCO, 8% NH4OH/MeOH/CH2Cl2, 120 g silica gel column) and the fractions containing product were combined and concentrated. The resulting solid was triturated with CH2Cl2 to obtain 1.9 g of (R)-benzyl 4-(4-(6-(3-aminopiperidin-1-yl)-3-carbamoylpyridin-2-ylamino) phenyl)piperazine-1-carboxylate as a white solid. A second trituration gave an additional 320 mg of product as a light yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][O:28]COC)[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][NH2:34]>C1COCC1>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:34][CH3:33])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][CH2:27][OH:28])[CH:25]=3)[C:7]2=[O:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCOCCn1cc(-c2cc3c(C)nc(S(C)(=O)=O)nc3n(C3CCCC3)c2=O)cn1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(C)c2cc(-c3cnn(CCO)c3)c(=O)n(C3CCCC3)c2n1
Temperature: 100 °C
Yield: 70 %

Procedure:
8-cyclopentyl-6-(1-(2-(methoxymethoxy)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (80 mg, 0.17 mmol) was dissolved into 3 ml methylamine in THF (1.0 M). The reaction mixture was then heated to 100° C. in microwave for 30 minutes. The solvent was removed via rot vap and the residue was re-dissolved in 5 ml methanol. A few drops of concentrated HCl was added the mixture was heated to 50° C. for 5 hours. The reaction mixture was cooled down to room temperature. Solvent was removed via rot vap and the residue was triturated with ethylacetate/hexane to give the title compound (45 mg, 70% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C>[CH:1]([NH:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1)=[O:3]
Reactant: COC(=O)Cc1ccnc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccnc(NC=O)n1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of acetic anhydride (32.7 g.) and formic acid (16.2 g.) was stirred at 50° to 60° C. for 30 minutes. The solution was added to a suspension of methyl 2-(2-aminopyrimidin-4-yl)acetate (17.93 g.) in ethyl acetate (300 ml.) at room temperature over 10 minutes, and the solution was stirred at room temperature for 3 hours. After removing the insoluble substance by filtration, water (300 ml.) was added to the filtrate, and then the mixture was adjusted to pH 7 with sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal, and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g.), mp 103° to 107° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=O)=[CH:6][CH:5]=1)[CH3:2].Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[N:29][OH:30])=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CCOc1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ccc([C@@H](CC(=NO)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-ethoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=375.2 ([M+H]+).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([NH2:13])=[O:12].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.ClCCl>[C:17]([N:9]1[CH2:16][CH2:15][CH2:14][C@@H:10]1[C:11]([NH2:13])=[O:12])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@H]1CCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
Under cold conditions (ice bath) and under an inert atmosphere, 10 ml of triethylamine (69.7 mmol) are added to 5 g (33.2 mmol) of prolinamide hydrochloride suspended in chloroform (50 ml), and 9.7 g (34.9 mmol) of trityl chloride are then added portionwise. The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is dissolved in dichloromethane (200 ml) and washed successively twice with HCl solution (1N) (150 ml), with water (150 ml), with saturated NaHCO3 solution (150 ml) and with saturated NaCl solution (150 ml). The organic phase is dried (Na2SO4), filtered and evaporated under reduced pressure. The residue is recrystallized from 20 ml of hot ethanol, to give 11 g of compound in the form of white crystals. Yield=93%. Melting point: 162° C.
Reaction SMILES: N1C=CN=C1.C(=O)([O-])[O-].[Na+].[Na+].[CH:12]1[C:24]2[CH:23](CC3CC(=O)N(O)C3=O)C3C(=CC=CC=3)[C:16]=2C=[CH:14][CH:13]=1.[CH3:34][CH2:35][O:36][CH2:37][CH3:38]>O.CC(C)=O>[CH3:34][CH2:35][O:36][CH2:37][CH3:38].[CH3:14][CH2:13][CH2:12][CH:24]([CH3:23])[CH3:16]
Reactant: O=C1CC(CC2c3ccccc3-c3ccccc32)C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCCC(C)C
Reaction time: 0.33 h

Procedure:
The deprotected imidazole derivative (3.9 g, 14 mmole) was dissolved in water (50 ml), acetone (30 ml) and 1M sodium carbonate (30 ml) and the solution was cooled in an ice bath. 9-Fluorenylmethyl-N-hydroxysuccinimide (4.76 g) in acetone (30 ml) was added dropwise with stirring over a period of 20 minutes (pH maintained at 9 by the addition of 1M sodium carbonate solution) and the stirring was continued overnight. Acetone was removed by evaporation and the aqueous solution was acidified with 1M KHSO4 and the product was extracted into ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over MgSO4, and evaporated to leave an oil. Trituration with ether and ether/isohexane gave a solid [3.66 g, 66%; (M+H)+ 392].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17](Cl)=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1.NC(N)=[S:25].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([SH:25])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Cl)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(S)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (7.50 g), thiourea (7.11 g) in ethanol (50 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, poured into 0.5 M NaOH aqueous solution, stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: chloroform/methanol=10:1) to give 8-(4-bromo-2,6-dimethyl-phenyl)-4-mercapto-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (7.52 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][CH2:16][OH:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.C(=O)=O>CO>[Cl:1][C:2]1[C:3]2[C:4]3[CH2:5][C@@H:6]([CH2:15][CH2:16][OH:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: OCCC1CCc2sc3ncnc(Cl)c3c2C1
Agent: O=C=O
Solvent: CO
Product: OCC[C@H]1CCc2sc3ncnc(Cl)c3c2C1
Yield: 30 %

Procedure:
Purification of compound 154.1. The racemic 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol (2.20 g, 8.19 mmol, 1.00 equiv) was resolute by chiral preparative SFC under the following conditions: column: Chiralpak IA, 2*25 cm, 5 um; mobile phase, CO2 (80%), methanol (domestic, 20%); flow rate: 40 g/min; UV detection at 254 nm. The fractions of the first peak to elute (tR=9.28 min) were collected and evaporated under reduced pressure to give the desired 2-[(12S)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol (compound 154.1, stereochemistry unconfirmed, 660 mg) as an off-white solid with 100% ee. The fractions of the second peak to elute (tR=10.53 min) were concentrated to give 2-[(12R)-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol (compound 154.2, stereochemistry unconfirmed, 790 mg) as an off-white solid with 98.5% ee.