Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C12BC(CCC1)CCC2.FC(F)(F)S(O[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[N:37]([CH3:39])[C:36]([C:40](=[O:59])[NH:41][C:42]1[CH:47]=[C:46]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:45]=[C:44]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[C:43]=1[O:57][CH3:58])=[CH:35]2)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C=O.O.C(OCC)(=O)C.ClCCl>[C:48]([C:46]1[CH:45]=[C:44]([NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[C:43]([O:57][CH3:58])=[C:42]([NH:41][C:40]([C:36]2[N:37]([CH3:39])[C:38]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[O:59])[CH:47]=1)([CH3:51])([CH3:49])[CH3:50]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1c(NC(=O)c2cc3cccc(OS(=O)(=O)C(F)(F)F)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(NC(=O)c2cc3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
A mixture of 620 mg tert-butyl 4-methylene-piperidine-1-carboxylate and 6.3 ml of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran is heated for one hour to 80° C. under argon. The solution thus prepared is added under argon to a mixture of 1.8 g 2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-yl trifluoro-methanesulphonate, 3.5 g potassium carbonate and 253 mg [1,1′-bis(diphenylphosphino)-ferrocen]dichloropalladium(II) complex with dichloromethane (1:1) in 12 ml N,N-dimethylformamide and 1.2 ml of water. The mixture is heated for 3 hours to 60° C., the solvents are eliminated in vacuo, taken up in ethyl acetate and the insoluble ingredients are filtered off. The filtrate is washed twice with water and once with saturated aqueous sodium chloride solution. After drying with magnesium sulphate the solvent is eliminated in vacuo and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate 80:20 to 20:80.
Reaction SMILES: CCC(NC(C(NC(C(NC(C=O)CCCN=C(N)N)=O)CC(C)C)=O)CC(C)C)=O.CC(CC(NC(C)=O)C(NC(C(NC(C=O)CCCN=C(N)N)=O)CC(C)C)=O)C.[Mn]([O-])(=O)(=O)=O.[K+].CC(C[C@H](NC(C)=O)C(N[C@H](C([NH:83][C@H:84]([C:92]([OH:94])=[O:93])[CH2:85][CH2:86][CH2:87][N:88]=[C:89]([NH2:91])[NH2:90])=O)CC(C)C)=O)C.N[C@H](C=O)CCCNC(=N)N>>[NH2:83][C@H:84]([C:92]([OH:94])=[O:93])[CH2:85][CH2:86][CH2:87][NH:88][C:89](=[NH:90])[NH2:91]
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: CC(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N
Agent: CCC(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N
Product: N=C(N)NCCC[C@H](N)C(=O)O

Procedure:
The leupeptins under test were brought into an aqueous solution and oxidized with potassium permanganate to leupeptin acids (the argininal portion of leupeptin had been oxidized to form arginine). The resulting acids were purified and isolated by activated charcoal chromatography and acidic alumina chromatography. The isolated acids were hydrolyzed with 6N hydrochloric acid at 110° C for 24 hours. The total arginine content of the hydrolyzate was determined by means of an amino acid analyzing instrument. On the other hand, the L-arginine content of the hydrolyzate was determined by bioassay using lactic-acid bacteria. The L-arginine content (%) of the total arginine was assumed to be equal to the L-leupeptins content (L-form percantage) in the total leupeptins. The L-form content of the standard sample was 100% and that of the DL-leupeptins obtained by conventional fermentation methods was 52%.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][Si](C=[N+]=[N-])(C)C.N#N.CCCCCC>CO.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:12])=[O:8])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.0 eq of 4-(bromomethyl)benzoic acid in 20 ml of methanol and 50 ml of toluene; was added dropwise 2.05 eq of trimethylsilyldiazomethane while stirring at room temperature. The reaction was titrated until a persistant pale yellow color existed from the addition of excess trimethylsilyldiazo- methane. Let stir at room temperature for 1 hr to insure the complete evolution of N2. Thin layer chromatography in 1:1 hexane:ethyl acetate indicated the disappearance of starting material and the appearance of desired ester with an Rf of 0.7.
Reaction SMILES: [OH:1][CH:2]1[CH2:23][NH:22][CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[OH:1][CH:2]1[CH2:23][N:22]([S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][C:25]([F:24])([F:37])[F:38])(=[O:35])=[O:34])[CH2:21][CH2:20][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2O
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2O

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 2 step A) and 2-trifluoromethoxy-benzenesulfonyl chloride. Colourless solid. MS (ESI): 555.2 (MH+)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4cccc(C(F)(F)F)c4)cc(C(F)(F)F)n3)ccn2)c1

Procedure:
N-tert-Butyl-3-{4-[4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (example E.59) (0.17 g, 0.42 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.14 g, 0.54 mmol) according to the general procedure VI. Obtained as an off-white solid (0.22 g), which was subsequently deprotected.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[CH:17]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH:18]=O>C(O)(CC)(C)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][C:12]3[N:13]([C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[CH:18][N:15]=3)[N:14]=2)=[CH:7][CH:8]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)nn1
Reactant: COc1ccc(CC(Cl)C=O)cc1
Agent: Cl
Solvent: CCC(C)(C)O
Product: COc1ccc(Cc2cnc3ncc(-c4ccc(F)cc4)nn23)cc1
Temperature: 130 °C

Procedure:
A mixture of 6-(4-fluorophenyl)-1,2,4-triazin-3-amine hydrochloride (50 mg, 0.2 mmol) and 2-chloro-3-(4-methoxyphenyl)propanal (48 mg, 0.24 mmol) in tert-amyl alcohol (1 mL) was heated at 130° C. for 4 h. After cooling, the mixture was purified by preparative HPLC to afford the desired product. (7.1 mg) LCMS: (M+H)=335.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:18]([O:17][C:16]([NH:15][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
A mixture of (S)-tert-butyl ((3-hydroxyphenyl)(phenyl)methyl)carbamate (3.20 g, 10.7 mmol), methyl 4-(bromomethyl)benzoate (2.70 g, 11.8 mmol) and potassium carbonate (2.20 g, 16.1 mmol) in acetonitrile (54 mL) was stirred at RT for 16 hours. The reaction mixture was concentrated at reduced pressure and the residue partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts combined, dried with anhydrous magnesium sulfate, filtered and the solvent evaporated at reduced pressure. The residue was recrystallised from ethyl acetate and iso-hexane to afford the title compound as a white solid (3.25 g, 68%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:33])[C:9]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:10][O:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]([CH3:33])[C:9]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:10][O:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C(=NOCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(=NOCCN)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A mixture of [N,N′-di(tert-butoxycarbonyl)] 2-(benzyloxycarbonylamino)ethoxy-N-methylguanidine (700 mg, 1.5 mmol), as prepared in the preceding step, 10% Pd/C (70 mg) in methanol (20 mL) and chloroform (5 mL) was hydrogenated under hydrogen (balloon) for 1 h. The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless foam (250 mg, 50%). 1H-NMR (300 MHz, CDCl3) δ 4.14 (t, J=5.0 Hz, 2H), 3.09 (s, 3H), 3.06 (q, J=5.0 Hz, 2H), 1.50 (s, 9H), 1.46 (s, 9H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:8]([NH:10][C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[CH3:12])=O)(=[O:4])=[O:3].B>C1COCC1>[Cl:23][C:22]1[CH:21]=[CH:20][C:7]([CH2:8][NH:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH3:12])=[CH:6][C:5]=1[S:2]([NH2:1])(=[O:3])=[O:4]
Reactant: C[C@@H](NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1cccc(Cl)c1
Agent: B
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(S(N)(=O)=O)c1)c1cccc(Cl)c1
Yield: 39.2 %

Procedure:
To a solution of 3-(aminosulfonyl)-4-chloro-N-((1R)-1-(3-chlorophenyl)ethyl)benzamide 38 (0.558 g, 1.49 mmol) in THF (10 mL) at room temperature was added borane (0.138 g, 9.97 mmol) (10 mL, 1 M in THF). The reaction mixture was heated to reflux for 24 h, quenched with 1 M NaOH, and diluted with EtOAc. The organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 40% to 80% EtOAc in hexanes) gave (R)-2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)benzenesulfonamide 39 (0.210 g, 39.1% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.5 Hz, 3H), 3.64 (s, 2H), 3.76 (q, J=6.6 Hz, 1H), 5.20 (s br, 2H), 7.19-7.31 (m, 5H), 7.44-7.46 (m, 2H), 8.01 (s, 1H). Mass spectrum: calculated for C15H16Cl2N2O2S 358.0. found 359.1 (M++1).
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]2[N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]2[N:35]([CH3:36])[CH2:34][CH2:33][N:32]([CH3:37])[C:31]2=[O:38])[CH:27]=[CH:28][CH:29]=1>>[CH3:36][N:35]1[CH2:34][CH2:33][N:32]([CH3:37])[C:31](=[O:38])[CH:30]1[C:26]1[CH:25]=[C:24]([NH:23][C:2]2[N:7]=[CH:6][C:5]3=[CH:8][CH:9]=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[N:4]3[N:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)c2)C1=O

Procedure:
N-(2-{2-[3-(1,4-Dimethyl-3-oxo-piperazin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide was prepared from N-[2-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a brown foam (72 mg, 46%). LCMS (m/e) 520 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.72 (s, 1H), 7.89-7.82 (m, 1H), 7.54-7.45 (m, 4H), 7.38 (s, 1H), 7.20-7.12 (m, 1H), 7.02-6.92 (m, 2H), 6.89-6.81 (m, 2H), 3.70-3.60 (m, 1H), 3.52 (s, 1H), 3.24-3.15 (m, 1H), 3.11 (s, 3H), 3.01-2.92 (m, 1H), 2.97 (s, 3H), 2.68-2.55 (m, 1H), 2.62 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([CH3:28])=[C:10]([C:25]([OH:27])=[O:26])[S:11][C:12]=1[NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[CH3:28][C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:12]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])[S:11][C:10]=1[C:25]([OH:27])=[O:26]
Reactant: CCCCCCCCNC(=O)Nc1sc(C(=O)O)c(C)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCNC(=O)Nc1sc(C(=O)O)c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.6 %

Procedure:
(7.1) To a stirring solution of 3-methyl-5-(3-octyl-ureido)-thiophene-2,4-dicarboxylic acid 4-tert-butyl ester (50.0 mg, 0.13 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL). The reaction was stirred at RT for 2 h, and then solvent was removed under reduced pressure to give a solid. The product was dissolved in EtOAc, washed with sat. NaHCO3 (aq.), and brine. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure to give 10.0 mg of a solid (22%): 1H NMR (CDCl3) δ 10.45 (bs, 1H), 6.27 (bs, 1H), 5.00 (bs, 1H), 3.50-3.20 (m, 2H), 2.37 (s, 3H), 1.70-1.40 (m, 2H), 1.26 (bs, 10H), 0.88 (t, 3H, J=6.2 Hz). MS (EI): 312.9 (m+—COOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.C(O)C.Cl[CH:16]([CH3:20])[C:17](=O)[CH3:18]>CCOCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:16]([CH3:20])=[C:17]([CH3:18])[N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N)=S)cc1
Reactant: CC(=O)C(C)Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(-c2nc(C)c(C)s2)cc1
Yield: 87.3 %

Procedure:
To a stirred mixture of 65.1 g (4-methoxy)thiobenzamide and 156 ml ethanol was added dropwise 50.1 g 3-chloro-2-butanone, and the reaction mixture was heated at reflux for 3 hours. An additional 6.1 g 2-chloro-3-butanone was added and heating was continued for an additional hour. The reaction mixture was cooled, 300 ml ether added, and the solid which precipitated was collected and dried to give 74.5 g 2-(4-methoxyphenyl)-4,5-dimethylthiazole in the form of its hydrochloride monohydrate, m.p. 166°-170° C.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:9][C:10]1[C:11]([C:31]([O:33][CH3:34])=[O:32])=[N:12][C:13]([C:17]2([CH3:30])[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][NH:18]2)=[N:14][C:15]=1[OH:16])(=O)C1C=CC=CC=1.[BH3-][C:36]#N.[Na+].C(O[Na])(C)=O.C=O>CO>[C:26]([O:25][C:23]([N:21]1[CH2:20][CH2:19][N:18]([CH3:36])[C:17]([C:13]2[N:12]=[C:11]([C:31]([O:33][CH3:34])=[O:32])[C:10]([OH:9])=[C:15]([OH:16])[N:14]=2)([CH3:30])[CH2:22]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2)nc(O)c1OC(=O)c1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: CC(=O)O[Na]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2C)nc(O)c1O
Temperature: 25 °C

Procedure:
Crude material methyl 5-(benzoyloxy)-2-[4-(tert-butoxycarbonyl)-2-methylpiperazin-2-yl]-6-hydroxypyrimidine-4-carboxylate (C-44) obtained in step 1 was dissolved in MeOH, and NaCNBH3 (2.8 eq), AcONa (3.2 eq) and HCHO (37% in H2O, 4 eq) were added. The reaction mixture was stirred at room temperature. After 30′, the solvent was evaporated and the crude solid (C-45) obtained washed with Et2O.
Reaction SMILES: [OH:1][C@H:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10].C([O-])(=O)C.[Na+].C(OCC)(=O)C>O.C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[O:1]=[C:2]1[CH2:27][C@@H:26]2[C@:13]([CH3:30])([CH2:14][CH2:15][C@H:16]3[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]3([CH3:29])[CH2:18][CH2:19][C@H:20]([OH:28])[CH2:21]2)[C@H:3]1[C@H:4]([CH3:12])[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10]
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1[C@@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Cr+6]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](CO)CCC[C@@H](C)[C@H]1C(=O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
A solution of chromium trioxide (80 mg) in water (0.4 ml) and acetic acid (0.8 ml) is added dropwise to a solution of (25R)-16β,26-dihydroxycholesterol (2) (0.500 g), and sodium acetate (2.48 g) in glacial acetic acid (90 ml), and is stirred for 18 hours at room temperature. The excess reagent is then destroyed with methanol (15 ml), and solvent is evaporated under reduced pressure. The resulting residue is diluted with water, and extracted with methylene chloride. The organic layer is washed with 5% K2CO3 and water, dried over sodium sulfate, and evaporated under reduced pressure to yield 0.48 g of crude product. The mixture is resolved by silica flash column chromatography (hexanes:ethyl acetate) to afford 0.313 g of (25R)-16-oxo-26-hydroxycholesterol (9). M.pt. 167°-169° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:28])[CH2:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[CH2:14][C:15]=1[OH:16])[CH2:8][CH3:9])[CH3:4].[Cl-].[Ca+2:30].[Cl-]>>[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:28])[CH2:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[CH2:14][C:15]=1[O-:16])[CH2:8][CH3:9])[CH3:4].[Ca+2:30].[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:28])[CH2:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)[CH2:14][C:15]=1[O-:16])[CH2:8][CH3:9])[CH3:4]
Reactant: CCON=C(CC)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Product: CCON=C(CC)C1=C([O-])CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O

Procedure:
Into 20 ml of an aqueous solution containing 2% of sodium hydroxide was dissolved 1.9 g of 2-[1-(ethoxyimino)propyl]-5-(4-methanesulfonamidophenyl)-3-hydroxy-2-cyclohexen-1-one and to the solution was added 3 cc of an aqueous solution containing 10% of calcium chloride at room temperature. The water was removed under a reduced pressure and the residue was dissolved in ethanol and an insoluble sodium chloride was separated with a filtering step. The ethanol was distilled off under reduced pressure and 1.5 g of white powder having a melting point of 250° C. or more was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:17][OH:18]>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:17]=[O:18]
Reactant: Cc1[nH]c(-c2cccc(C(F)(F)F)c2)nc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(-c2cccc(C(F)(F)F)c2)nc1C=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 88.5 %

Procedure:
A mixture of 5-methyl-2-(α,α,α-trifluoro-m-tolyl)-4-imidazolemethanol (30.0 g), manganese dioxide (200 g) and chloroform (1000 ml) is stirred at room temperature for 7 hours, and then filtered, and the solution allowed to stand over the weekend. Ethyl acetate is added to dissolve precipitated material and the solution is filtered. The solution is then evaporated to dryness in vacuo to afford 26.34 g solid, m.p. 179.5°-180° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)#[N:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:8])#[N:2]
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(C(=O)O)c(F)c1C#N
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc(OC)c(C#N)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A mixture of the above benzoic acid derivative (360 mg, 1.85 mmol), p-anisidine (315 mg, 2.56 mmol), N,N-diisopropylethylamine (1.34 mL, 7.68 mmol) and PyBop (1.6 g, 3.1 mmol) in dry DMF (7 mL) was stirred at room temperature overnight and then diluted with water (40 mL). The precipitates were filtered, washed with water three times, and dried in vacuo to give 3-cyano-2-fluoro-4-methoxy-N-(4-methoxy-phenyl)-benzamide (540 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH2:6])=O.Cl.[OH-].[Na+]>C1COCC1>[NH2:6][CH2:4][C:3]1[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[C:9]([Cl:11])=[CH:10][C:2]=1[NH2:1]
Reactant: NC(=O)c1cc([N+](=O)[O-])c(Cl)cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1cc([N+](=O)[O-])c(Cl)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a solution of 2-amino-4-chloro-5-nitrobenzamide (3.0 g, 13.7 mmol) in dry THF (50 mL), borane dimethyl suphide complex (1.56 g, 20.6 mmol) was added at RT and the reaction mass was refluxed for 24 h. The reaction mass was cooled to RT and dilute HCl was added till it became acidic. Further, the reaction mixture was stirred for 1 h and then the reaction mixture was basified with dilute NaOH and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated to afford 2.0 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.58 (s, 2H), 6.72 (br s, 3H), 8.04 (br s, 1H); MS (m/z): 200.28 (M−H).