Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:27](=[O:28])[CH:26]=[CH:25][C:22]1[CH:23]=[CH:24][C:19]([S:16](=[O:18])(=[O:17])[NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:20][CH:21]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.21 g, 3.01 mmol) in tetrahydrofuran (4.0 ml) a saturated NaHCO3 solution (2.6 ml) was added and the resultant mixture was stirred at ambient temperature for 25 min. To the reaction mixture a 3-(4-phenylsulfamoyl-phenyl)-acryloyl chloride (44a) (0.19 g, 0.59 mmol) solution in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, and the solvent was removed. The residue was washed with diethyl ether to give the title compound (0.074 g, 39%) as white crystals, m.p. 176-177.5° C. 1H NMR (DMSO-d6, HMDSO), δ:6.54 (1H, d, J=−16.0 Hz); 6.96-7.32 (5H, m); 7.47 (1H, d, J=16.0 Hz); 7.76 (4H, s); 9.14 (1 H, br s); 10.29 (1H, br s); 10.86 (1H, s). Anal. Calcd for C15H14N2O4S, %: C 56.59, H 4.43, N 8.80. Found, %: 55.82, H 4.38, N 9.01.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: Fc1cccc(CBr)c1
Product: Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Yield: 62 %

Procedure:
Prepared in analogy to example 8 from 2-methyl-4-nitrophenol and 3-fluoro-benzylbromide. Colorless oil. Yield=62%. MS: m/e=261.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccccc1Cl
Yield: 52.3 %

Procedure:
Prepared according to Procedure A using 2-amino-5-chlorobenzoic acid (2.0 g, 11.7 mmol) and SOCl2 (2.2 mL, 29.2 mmol) in benzene (50 mL), followed by 2-chloroaniline (2.5 mL, 23.3 mmol) and CHCl3 (50 mL). The product was purified by recrystallization from MeOH to provide 1.72 g of a dark yellow solid (52%). 1H NMR (CDCl3) δ: 8.37 (dd, J=1.5, 8.3 Hz, 1H); 8.22 (br s, 1H); 7.48 (d, J=2.3 Hz, 1H); 7.42 (dd, J=1.5, 8.1 Hz, 1H); 7.31 (dt, J=1.4, 7.8 Hz, 1H); 7.22 (dd, J=2.4, 8.8 Hz, 1H); 7.09 (dt, J=1.5, 7.7 Hz, 1H); 6.67 (d, J=8.8 Hz, 1H); 5.56 (br s, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH3:14])([CH3:13])[CH:11]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:15][OH:16].N1C=CC=CC=1>C(O)C.Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH3:14])([CH3:13])[CH:11]=[N:15][OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C=O)c1ccc2c(c1)OCO2
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C=NO)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a solution of Compound I (511 mg, 2.66 mmol) in ethanol (1 mL), HCl.NH2OH (277 mg, 4.00 mmol) and pyridine (2.2 mL, 26.58 mmol) were added and it was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated to dryness and added 10 mL of ethyl acetate. The organic layer was washed with distilled water, dried over anhydrous sodium sulfate, filtered and evaporated. The crude reaction mixture was purified over silica gel column using 5:1 petroleum ether-ethyl acetate as solvent to afford Compound J (528 mg, 96%) as a white foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].C(OCC)(=O)C.[C:18]12([CH2:28][S:29](O)(=[O:31])=[O:30])[C:25]([CH3:27])([CH3:26])[CH:22]([CH2:23][CH2:24]1)[CH2:21][C:19]2=[O:20]>C(O)C>[CH3:26][C:25]1([CH3:27])[CH:22]2[CH2:23][CH2:24][C@@:18]1([CH2:28][S:29]([O:6][C@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:31])=[O:30])[C:19](=[O:20])[CH2:21]2
Reactant: CNCC[C@H](O)c1cccs1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCC[C@H](OS(=O)(=O)C[C@]12CCC(CC1=O)C2(C)C)c1cccs1
Temperature: 30 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (34.2 g, 200 mmol) and ethyl acetate (400 mL) is heated to 30° C., then a mixture of (+)-camphor-10-sulfonic acid (46.4 g, 200 mmol), ethyl acetate (100 mL) and ethanol (100 mL) is added dropwise at 30° C. in 40 minutes. At the end of the addition, the resulting solution is heated to 50° C., stirred for 15 minutes at that temperature, then cooled to 25° C. Once cold, the reaction mixture is concentrated to dryness and ethyl acetate (500 mL) is added to the residue. The resulting mixture is then heated to reflux, kept at that temperature for 15 minutes, then cooled to 25° C. in 30 minutes while seeding the reaction mixture when the temperature reaches about 40° C. Once cold, the resulting suspension is stirred for 30 additional minutes. Afterwards, the precipitate is filtrated, washed with ethyl acetate (2×50 mL) and dried at 40° C. under vacuum (20 mbar) for 15 h affording a white solid (71.5 g, 89%); 1H-NMR (CDCl3, 400 MHz): 7.2 (1 H, dm), 7.0 (1 H, m), 6.9 (1 H, m), 5.21 (1 H, t), 3.3 (3 H, m), 2.82 (1 H, d), 2.75 (3 H, s), 2.50 (1 H, m, symm.), 2.3 (3 H, m), 2.1 (1 H, m), 2.0 (1 H, m), 1.85 (1 H, d), 1.74 (1 H, m, symm.), 1.4 (1 H, m), 1.04 (3 H, s), 0.82 (3 H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:6]=2[C:5](=[O:27])[NH:4][C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH:35](I)([CH3:37])[CH3:36]>CN(C=O)C.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][N:7]3[C:6]4[C:5](=[O:27])[N:4]([CH:35]([CH3:37])[CH3:36])[C:3](=[O:28])[N:2]([CH3:1])[C:10]=4[N:9]=[CH:8]3)=[CH:17][CH:16]=2)=[O:26])=[CH:20][CH:21]=1
Reactant: CC(C)I
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Yield: 6.3 %

Procedure:
A solution of 3-methyl-7-[4-(4-chlorobenzoyl)-benzyl]xanthine (544 mg), potassium carbonate (202 mg) and isopropyl iodide (356 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:1) and recrystallized from acetone-hexane to provide the title compound as colorless solid (38 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([OH:13])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54]>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:47][C:48]1[CH:49]=[C:50]([NH:55][C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:64])([F:65])[F:66])[CH:58]=2)[CH:51]=[CH:52][C:53]=1[CH3:54])=[O:13]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: Nc1c(C(=O)O)sc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1sc2nccnc2c1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
A solution of 7-aminothieno[2,3-b]pyrazine-6-carboxylic acid 8 (32 mg, 0.164 mmol), HATU (74.8 mg, 0.197 mmol) and DIPEA (0.054 mL, 0.328 mmol) in DMF (2 mL) was stirred for 15 at rt. N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide 67 (48.2 mg, 0.164 mmol) was added and stirred overnight at 80° C. The reaction mixture was poured in cold citric acid solution and the resulting precipitate was collected. Purification by HPLC gave the title compound 7-amino-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 70 (14 mg, 18%). NMR (400 MHz, DMSO-d6) 2.23 (s, 3H), 7.07 (s, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.62 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.31 (s, 1H), 8.78 (dd, J=5.1 Hz and 2.3 Hz, 2H), 9.48 (s, 1H), 10.49 (s, 1H). (m/z)=472 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26]C)[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:11]=2)[CH:9]=1)=[O:4].C([O:48]C(C1C=NN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)CC)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C=1)=O)C.[N:92]1[CH:97]=[CH:96][CH:95]=[CH:94][C:93]=1CN.CN>>[N:92]1[CH:97]=[CH:96][CH:95]=[CH:94][C:93]=1[CH2:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[C@@H:19]3[CH2:23][C@H:22]([NH:24][C:25](=[O:28])[CH2:26][OH:48])[C@@H:21]([OH:29])[C@H:20]3[OH:30])=[C:12]([NH:31][CH2:32][CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:11]=2)[CH:9]=1)=[O:4]
Reactant: NCc1ccccn1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Reactant: CCOC(=O)c1cnn(-c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Agent: CN
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(-n4cc(C(=O)NCc5ccccn5)cn4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid methylamide (Example 173), by substituting 1-[9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(2-hydroxy-acetylamino)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate ZS) for 1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 173, step 1) and C-pyridin-2-yl-methylamine for methylamine.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].[Br:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1N.O.C(Cl)(Cl)[Cl:24]>CC(N(C)C)=O>[ClH:24].[Br:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2]
Reactant: CCN(CC)CCO
Reactant: ClC(Cl)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Br
Product: Cl
Reaction time: 4 h

Procedure:
To a solution of 2-(diethylamino)ethanol (0.59 g, 5 mmol) in DMA (5 ml), sodium hydride (0.24 g, 10 mmol) was added in one portion. Fifteen minute later 2-bromo-4-nitroaniline (1.1 g, 5 mmol) was added and the content was stirred for 4 hr. Water (50 ml) was added to the reaction mixture followed by chloroform. The organic layer was separated, washed with saturated sodium bicarbonate follow by brine. The organic layer was dried over sodium sulfate and concentrated to oil. The oil was dissolved in methanol and saturated with HCl gas. The resulting solution was concentrated and diethyl ester was added. The resulting precipitate was washed with ether and dried to yield 0.8 g of 2-[(2-bromo-4-nitrophenyl)Oxy]-N,N-diethylethanamine hydrochloride as a solid. LCMS: m/z 318 (M+H)+.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][C:5]2([O:18][C:19]3[C:24]\1=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[S:32]([O:1]/[N:2]=[C:3]1\[CH2:4][C:5]2([O:18][C:19]3[C:24]\1=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)([C:29]1[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C/C(=N\O)c1ccccc1O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O/N=C2\CC3(CCN(C(=O)OC(C)(C)C)CC3)Oc3ccccc32)cc1
Yield: 81.6 %

Procedure:
A mixture of tert-butyl (4E)-4-hydroxyiminospiro[chromane-2,4′-piperidine]-1′-carboxylate (448 mg, 1.34 mmol) and 4-methylbenzenesulfonyl chloride (514 mg, 2.70 mmol) were stirred in pyridine (2.1 mL) at 0° C. for 6 hours. The reaction mixture was poured over ice and the mixture was extracted with ethyl acetate. The organics were dried over sodium sulfate and evaporated to give (E)-tert-butyl 4-(tosyloxyimino)spiro[chroman-2,4′-piperidine]-1′-carboxylate (532 mg, 81%). ESI-MS m/z calc. 486.2. found 487.5 (M+1)+; Retention time: 2.20 minutes (3 min run).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.[F:21][C:22]1[C:27]([F:28])=[C:26]([C:29]([F:32])([F:31])[F:30])[C:25]([F:33])=[C:24](F)[N:23]=1.CCN(CC)CC>CN(C=O)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:24]3[C:25]([F:33])=[C:26]([C:29]([F:31])([F:32])[F:30])[C:27]([F:28])=[C:22]([F:21])[N:23]=3)=[CH:16][CH:15]=2)=[N:3][CH:2]=1
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Reactant: Fc1nc(F)c(F)c(C(F)(F)F)c1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1nc(Oc2ccc(CCNc3ncnc4nccnc34)cc2)c(F)c(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.6 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (0.27 g, 1.0 mmol), 2,3,5,6-tetrafluoro-4-trifluoromethylpyridine (0.24 g, 1.0 mmol) and DMF (5 mL) were added to a 25 mL round bottom flask equipped with magnetic stirring bar and dry nitrogen line. To the reaction mixture was added Et3N (0.12 g, 1.2 mmol). After stirring 24 h at room temperature, the reaction mixture was concentrated in vacuo, and the residue was partitioned between H2O and EtOAc. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (EtOAc/hexane over SiO2) to afford pteridin-4-yl-{2-[4-(3,5,6-trifluoro-4-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethyl}-amine (110 mg) as a beige solid: mp 103-108° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C@H:19]([NH:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:30]([O:32][CH3:33])=[O:31])[CH2:7][C@@H:6]1[OH:34])(=[O:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)(Cl)Cl.C(O)C.C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[C@H:19]([NH:24][CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C:30]([O:32][CH3:33])=[O:31])[CH2:7][C@@H:6]1[O:34][C:46](=[O:48])[CH3:47])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OC(C)=O)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.33 h

Procedure:
Methyl 2β-acetoxy-3α-hydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (3.069 g) in chloroform (33 ml) containing dry PTSA (2.64 g) was stirred for 20 min then treated with acetic anhydride (6.5 ml) and the mixture left for 5 h. The mixture was diluted with ethanol and evaporated to give an oil. This was dissolved in ethyl acetate, washed with aqueous ammonia solution (2×) and water (1×), dried and evaporated to give an oil (2.867 g). This was purified by preparative t.l.c. in chloroform/methanol (9:1) to give the title compound [α]D +48.6°, νmax 1730 cm-1.
Reaction SMILES: C(N(CC)CC)C.C(O[CH:12]([CH2:17][CH3:18])[CH2:13][N+:14]([O-:16])=[O:15])(=O)C.[CH2:19]([SH:21])[CH3:20].Cl>C(#N)C>[CH2:19]([S:21][CH:12]([CH2:17][CH3:18])[CH2:13][N+:14]([O-:16])=[O:15])[CH3:20]
Reactant: CCC(C[N+](=O)[O-])OC(C)=O
Reactant: CCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCSC(CC)C[N+](=O)[O-]
Reaction time: 1 h
Yield: 86 %

Procedure:
2-Ethylthio-1-nitrobutane was prepared by dropwise addition of a solution of triethylamine (16.77 g., 0.166 mol) and acetonitrile (50 ml.) to a stirred solution of 2-acetoxy-1-nitrobutane (26.50 g., 0.164 mol) and ethanethiol (11.20 g., 0.164 mol) over 30 minutes at 0°-5° C. Upon complete addition, the resulting solution was stirred for 1 hour at 0°-5° C., and then was poured into dilute aqueous hydrochloric acid solution (500 ml.). The organics were extracted into methylene chloride (3×150 ml.) and the combined portions were washed with deionized water (2×200 ml.), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled (1.5 Torr., 72°-75° C., internal) yielding a clear oil, 23.03 g., 86% yield. 1H-NMR (CDC13): δ 1.1, t, 3H, --CH3 ; 1.29, t, 3H, SCH2CH3 ; 2.5-2.85, m, 2H, --CH2 --; 2.6, q, 2H, SCH2 --; 3.28, m, 1H, CH; 4.5, d, 2H, --CH2NO2.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:15]#[N:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:24].[Na+].C(O)C.[OH:29]O>O>[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:15]([NH2:16]=[O:29])=[O:24])[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: N#CC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: OO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C([NH2+][O-])C1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1-Benzyl-4-(4-fluoro-phenyl)-4-cyano-piperidine hydrochloride (7.8 g, 26.5 mmol) was combined with aqueous sodium hydroxide (1.2 mL, 50% by weight) and ethanol (130 mL) and the mixture was heated to 50° C. The heating was removed, and a solution of hydrogen peroxide (12.11 mL, 30% by weight in water, 106 mmol) was added at such a rate that the temperature of the reaction mixture does not rise above 50° C. The reaction mixture was then stirred at 50° C. for 4 hours. The reaction mixture was diluted with water (100 mL) and most of the solvent was removed in vacuo before adding water (200 mL) to form a solid which was collected by filtration, rinsed with water, and dried in vacuo to give the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:35]>O.C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:29])[C:19]([C:23]3[N:24]=[C:25]([NH2:28])[S:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:30])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:35]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 0.25 h
Yield: 5.7 %

Procedure:
10 g of the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme-4-carboxylic acid containing 7.2% of ethanol were added to a solution of 2 g of sodium acetate in 7.5 ml of water and 20 ml of absolute ethanol and the mixture was stirred for 15 minutes, was treated with 1.5 g of activated carbon and was filtered. The filter was washed twice with 5 ml of a 9-1 ethanol-water mixture and the filtrate was added dropwise over 50 minutes with stirring at room temperature to 80 ml of ethanol which caused precipitation of the sodium salt. The mixture was stirred for 2 hours at 0° C. and was vacuum filtered. The crystals were washed with ethanol and dried under reduced pressure to obtain 8.45 g of the crystalline D form of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-ceph-3-eme- 4-carboxylate containing 5.7% of water.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5][CH:4]=[C:3]1[C:20]([OH:22])=[O:21].C(Cl)(=O)C(Cl)=O.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CN(C)C=O>[O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([O:22][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH:30]=1)=[O:21]
Reactant: O=C(O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2cnc(-c3ccccc3)n(-c3ccccc3)c2=O)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinecarboxylic acid (i.e. Step B product (B) or the product from Step B1) (1.40 g, 4.8 mmol) in dichloromethane (30 mL) was added oxalyl chloride (1.21 g, 9.61 mmol) at 0° C. followed by catalytic amount (2 drops) of N,N-dimethylformamide. The reaction mixture was allowed to warm to room temperature and stir for 1 h. Then the reaction mixture was concentrated under reduced pressure. To the resulting residue was added dichloromethane (30 mL), 1,3-cyclohexanedione (646 mg, 5.76 mmol), followed by triethylamine (976 mg, 9.60 mmol), and the reaction mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexanes to afford the title product as a white solid (1.1 g).
Reaction SMILES: O.[ClH:2].[CH3:3][N:4]1[CH:8]=[C:7]([CH2:9]O)[N:6]=[N:5]1>S(Cl)(Cl)=O>[ClH:2].[Cl:2][CH2:9][C:7]1[N:6]=[N:5][N:4]([CH3:3])[CH:8]=1
Reactant: Cn1cc(CO)nn1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cn1cc(CCl)nn1
Yield: 101.8 %

Procedure:
1-Methyl-4-hydroxymethyl-1,2,3-triazole hydrochloride hydrate (1.0 g, 6.08 mmol) was suspended in 20 ml thionyl chloride and the mixture was refluxed for 1 hour. Excess thionyl chloride was evaporated off and the residue was triturated with diethyl ether (25 ml). The white solid produced was washed by decantation with diethyl ether and dried in vacuo to give the required product (0.52 g, 51%). 1H NMR (360 MHz, d6-DMSO) 4.04 (3H, s), 4.82 (2H, s), 8.16 (1H, s); MS+131&133.