Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]([C:21]([O:23][CH3:24])=[O:22])=[CH:16][C:15]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:42]Br>C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[CH:16][C:17]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([O:20][CH2:42][C:41]2[CH:44]=[CH:45][C:46]([F:47])=[C:39]([F:38])[CH:40]=2)[N:19]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an oven-dried round bottom flask was added DMF (5 mL), the product of Step E (0.500 g; 1.27 mmol), Cs2CO3 (0.910 g; 2.79 mmol), and 3,4-difluorobenzyl bromide (0.162 mL; 1.27 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aq. NaHCO3 solution (3×), and brine. The organic portion was dried (Na2SO4), filtered, and concentrated in vacuo. Purification done by MPLC (silica gel; 0-10% ethyl acetate/hexane gradient) afforded the desired product: m/e=518 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:17]=[C:16]([CH3:18])[C:15](I)=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH2:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>O1CCCC1.CCCCC>[CH2:32]([O:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]([C:15]2[C:16]([CH3:18])=[CH:17][C:9]([N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:10]3[C:14]=2[CH2:13][CH2:12][CH2:11]3)[OH:45])=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)c1cc(C=O)ccc1OCc1ccccc1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1I)CCC2
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c2c(c1C(O)c1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
To a solution of dibenzyl(7-iodo-6-methylindan-4-yl) amine (583 mg) in dry tetrahydrofuran (10 mL) was added a 1.48 mol/L solution of tert-butyllithium in n-pentane (1.30 mL) at −100° C. The mixture was stirred for 15 min. Adding dropwise 4-benzyloxy-3-isopropylbenzaldehyde (320 mg) in tetrahydrofuran (5 mL), the reaction mixture turned orange solution. The reaction mixture was stirred at ambient temperature for 15 min, and then warmed to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride to quench the reaction. Adding brine, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=3/1−1/1) to give the title compound (497 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C1COCC1>O>[CH2:28]([O:27][C:25]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH2:17][CH3:18])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Yield: 99.2 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-amino-3-propoxypiperidine-1-carboxylate obtained in Example (113d) (3.41 g, 13.2 mmol), sodium bicarbonate (1.26 g, 15 mmol), benzyl chloroformate (2.81 g, 16 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 5.14 g of the title compound as a colorless oily substance (99%).
Reaction SMILES: [CH:1]1([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[C:12]2S)[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[N+:21]([O-:24])([OH:23])=[O:22].N([O-])=O.[Na+].[OH-].[Na+]>O>[N+:21]([O-:24])([OH:23])=[O:22].[CH:1]1([N:11]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=[CH:12]2)[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cnc(S)n1C1CCCC2CCCCC21
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC(=O)c1cncn1C1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 39.4 %

Procedure:
A mixture of 77.7 parts of methyl 1-(decahydro-1-naphthalenyl)-2-mercapto-1H-imidazole-5-carboxylate, 157 parts of nitric acid, 300 parts of water and 0.2 parts of sodium nitrite was stirred for 1.5 hours at room temperature. The reaction mixture was poured into crushed ice and treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was converted into the nitrate salt in 1,1'-oxybisethane. The salt was filtered off and dried, yielding 33.9 parts (39.4%) of methyl 1-(decahydro-1-napthalenyl)-1H-imidazole-5-carboxylate mononitrate; mp. 148.6° C. (compound 1.03).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11](N4CCN(CCC(OC)=O)CC4)[CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1>C(O)(=O)C.O.S(=O)(=O)(O)O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[CH:11][CH:12]=3)[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2ccc(F)cc2c1=O

Procedure:
2.9 g of the compound of Example 9 are dissolved in a mixture of 14 ml of acetic acid and 9.5 ml of water, and 1.4 ml of concentrated sulphuric acid are added. The mixture is heated at 150° to 160° C. for 1.5 hours and poured into 90 ml of water. The precipitate is filtered off with suction, washed with water and methanol and dried. 2.3 g (72% of theory) of 7-]4-(2carboxyethyl)-1-piperazinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid semisulphate semihydrate of decomposition point 258° to 261° C. are isolated.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][NH:4][C:5]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27]>>[F:1][C:2]([F:22])([F:23])[CH2:3][N:4]([C:5]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=1[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8])[C:26](=[O:27])[C:25]([Cl:30])([Cl:29])[Cl:24]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1NCC(F)(F)F
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1N(CC(F)(F)F)C(=O)C(Cl)(Cl)Cl

Procedure:
A mixture of 3.24 g of 2-(2,2,2-trifluoroethylamino)-5-nitrobenzophenone and 15 ml. of trichloroacetyl chloride was heated at 100° C. (bath temperature) for 5 hours. The volatiles were removed under reduced pressure. The residue was chromatographed on silica gel using benzene as an eluent to give 2-[N-(2,2,2-trifluoroethyl)trichloroacetamido]-5-nitrobenzophenone as an yellow oil.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[C:19]2[N:20]=[CH:21][CH:22]=[N:23][C:24]=2[CH:25]=[CH:26][CH:27]=1)(=[O:17])=[O:16].C1COCC1.Cl>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[C:8]([NH:14][S:15]([C:18]2[C:19]3[N:20]=[CH:21][CH:22]=[N:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH:9]=1
Reactant: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
A solution of LiOH.H2O (0.32 g, 7.7 mmol) in water (5 mL) was added to a solution of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid methyl ester (0.58 g, 1.5 mmol) and THF (10 mL). The biphasic mixture was stirred rapidly at rt for 16 h, then adjusted to pH 5 with 1 M HCl. The resulting precipitate was collected by filtration to afford the acid as a white solid (0.51 g, 92%). MS (ESI+): calcd. for C15H10ClN3O4S, 363.0; m/z found, 364 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.20 (br s, 1H), 11.73 (s, 1H), 9.12 (d, J=1.6, 1H), 9.00 (d, J=1.5, 1H), 8.65 (d, J=7.3, 1H), 8.42 (d, J=8.3, 1H), 8.06 (t, J=7.8, 1H), 7.80 (d, J=8.5, 1H), 7.63 (d, J=2.0, 1H), 7.07 (dd, J=8.4, 1.9, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[N:19]3[CH2:20][CH2:21][CH2:22][CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]3=[N:17][N:16]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[H-].[Na+].[Cl:31]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:31][C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][CH2:20][N:19]2[C:15]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16][N:17]=[C:18]12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)c3)nnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
Under an argon atmosphere, to a mixture of ethyl 3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (1.32 g) in DMF (11 mL) was added sodium hydride (60%, 0.14 g) at 0° C., and the mixture was stirred at room temperature for 30 min. N-Chlorosuccinimide (0.46 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and further recrystallized from ethyl acetate/hexane to give the title compound (0.15 g).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21](=[O:25])[O:22]CC)=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2].[OH-].[Na+].O>C1COCC1>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([NH:19][CH2:20][C:21]([OH:25])=[O:22])=[O:18])=[CH:15][CH:14]=2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)NCC(=O)OCC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCSc2ccc(C(=O)NCC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 1 (500 mg, 1.06 mmoles) was taken up in a mixture of THF (10 ml), 1N NaOH (2.2 ml) and water (7.8 ml). The reaction mixture was stirred at room temperature for three hours, then concentrated in vacuo. The residue was taken up in water, filtered, acidified with dilute HCl and extracted with chloroform. The combined chloroform extracts were dried and concentrated in vacuo to afford the title compound which was recrystallized from ethyl acetate/hexane, m.p. 133°-135° (dec.).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:17])[NH:14][C:13](=[S:15])[NH:12][C:11]1=[S:16]>C(O)C>[CH2:1]([S:15][C:13]1[NH:14][C:10]([CH3:17])([CH3:9])[C:11](=[S:16])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)NC(=S)NC1=S
Solvent: CCO
Product: CC1(C)NC(SCc2ccccc2)=NC1=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 1.91 mL of benzylbromide was added to a solution of 1.6 g of 5,5-dimethyl-2,4-dithiohydantoin in 50 mL of ethanol (EtOH). The reaction mixture was stirred at the room temperature for one hour, and concentrated in vacuo. The residue was treated following the procedure used in Example 62, and purified by column chromatography (CHCl3). Recrystallization from diethyl ether-n-hexane gave 2-benzylthio-5,5-dimethylimidazolin-4-thione in the form of a needle-like crystal. The yield of this compound was 0.87 g with a yield ratio of 34.8%, and the melting point was 133°-134° C.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH2:11][CH2:12][CH2:13][C:14]([CH3:19])([N+:16]([O-])=O)[CH3:15])[C:8](=[O:20])[N:7]([CH3:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[NH2:16][C:14]([CH3:19])([CH3:15])[CH2:13][CH2:12][CH2:11][N:9]1[C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]([CH3:21])[C:8]1=[O:20]
Reactant: [H][H]
Reactant: Cn1c(=O)n(CCCC(C)(C)[N+](=O)[O-])c2c(F)cccc21
Agent: [Ni]
Solvent: CO
Product: Cn1c(=O)n(CCCC(C)(C)N)c2c(F)cccc21

Procedure:
A solution of 2 g (6.7 mmol) 4-fluoro-1-methyl-3-(4-methyl-4-nitro-pentyl)-1,3-dihydro-benzimidazol-2-one in methanol is hydrogenated at 3 bar hydrogen pressure in the presence of Raney nickel. After separation of the catalyst hydrochloric acid in diethyl ether is added. The hydrochloride precipitated is filtered off and dried. Yield: 1.5 g (83%, hydrochloride); melting range=230-232° C.; mass spectroscopy: [M+H]+=303.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28](O)=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:31])[CH:5]=[CH:6][CH:7]=1.C([N:35](C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28]([NH2:35])=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:31])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Cc2ccc(N3CCC[C@H]3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2ccc(N3CCC[C@H]3C(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0-5° C.) and stirred solution of (S)-1-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pyrrolidine-2-carboxylic acid (I-143, 0.15 g, 0.34 mmol) in THF (2 mL) was added diisopropylethylamine (0.05 g, 0.37 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.05 g, 0.37 mmol) was added, stirred at 0-5° C. for 45 min. Ammonium hydroxide (28%, 4.0 mL) was added, the reaction warmed to ambient temperature, stirred for 1.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.074 g (49%) of P-612 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 8.27 (d, J=2.4 Hz, 1H), 7.34-7.46 (m, 4H), 8.2 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 7.4-7.46 (m, 2H), 7.37 (br s, 1H), 7.26-7.38 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 3.92-3.98 (m 3H), 3.93 (s, 2H), 3.73 (s, 3H), 2.55 (t, J=8.4 Hz, 2H), 1.98-2.06 (m, 2H) ppm; MS (APCI+): 441.1 (M+1), LC-MS: 97.0%; HPLC 97.1% pure.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][OH:18])[C:14](=[O:19])[O:13][CH2:12][C@H:11]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:10](=[O:28])[O:9][C@H:8]1[CH3:29])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1.C(Cl)Cl>[C:30]([O:18][CH2:17][CH2:16][C@@H:15]1[C@@H:7]([O:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C@H:8]([CH3:29])[O:9][C:10](=[O:28])[C@@H:11]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:12][O:13][C:14]1=[O:19])(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 107.3 %

Procedure:
To a solution of (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-8-(2-hydroxyethyl)-6 methyl-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (200 mg, 0.479 mmol) in pyridine (0.5 mL) and CH2Cl2 (1 mL) was added benzoyl chloride (195 mg, 0.958 mmol) at room temperature (about 22° C.), and the reaction mixture was stirred at room temperature for 12 h. The solvents were removed under vacuum and the residue was purified by column chromatography (SiO2, hexanes/EtOAc gradient) to give the title compound (268 mg, 74%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, J=8.5, 1.0 Hz, 2H), 7.56-7.40 (m, J=10.6, 3H), 5.39-5.15 (m, 2H), 5.10 (t, J=9.9 Hz, 1H), 4.97-4.73 (m, 2H), 4.42-4.29 (m, 1H), 4.25 (m, 1H), 3.57-3.35 (m, 1H), 2.73 (t, J=9.5 Hz, 1H), 2.62 (dt, J=14.0, 7.0 Hz, 1H), 2.36-2.18 (m, 1H), 1.90-1.71 (m, 1H), 1.46 (s, 9H), 1.28 (d, J=6.4 Hz, 3H), 1.21 (dd, J=7.0, 1.0 Hz, 6H); ESIMS m/z 544 ([M+Na]+).
Reaction SMILES: [BH4-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=O)[C:13](Cl)=[O:14])=[CH:4]1.Cl>COCCOCCOC.O>[CH:8]1[CH:9]=[CH:10][C:11]2[NH:3][CH:4]=[C:5]([CH2:12][CH2:13][OH:14])[C:6]=2[CH:7]=1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: OCCc1c[nH]c2ccccc12

Procedure:
A suspension of sodium borohydride (22.6 g.) in diglyme (800 ml.) was stirred in a jacketted flask with water cooling. 3-Indolylglyoxylyl chloride (41.5 g.) was cautiously added in small portions then the mixture was heated to 95°-100° for 5 hours. The cooled reaction mixture was diluted with water (2 l.), acidified with hydrochloric acid and extracted with dichloroethane. The extract was washed with sodium carbonate solution then with water and evaporated to give crude tryptophol as a brown oil. This was distilled at 0.1 mm and the distillate collected at 155°-160° was crystallised from toluene (50 ml.), giving pure tryptophol as white crystals m.p. 57°-59°.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([Cl:14])[C:11]([CH3:15])=[C:10]([C:16]([O:18][CH2:19][CH3:20])=C)[N:9]=1.[Mn]([O-])(=O)(=O)=[O:22].[K+]>O.O1CCOCC1>[Cl:7][C:8]1[N:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:22])[C:11]([CH3:15])=[C:12]([Cl:14])[N:13]=1
Reactant: C=C(OCC)c1nc(Cl)nc(Cl)c1C
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(Cl)nc(Cl)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium metaperiodate (2.111 g, 9.87 mmol) was suspended in water (20 mL) and sonicated until a clear solution was obtained. 2,4-Dichloro-6-(1-ethoxyvinyl)-5-methylpyrimidine (1.15 g, 4.93 mmol) dissolved in 1,4-dioxane (40 mL) was added followed by potassium permanganate (0.117 g, 0.74 mmol). The mixture was stirred at rt for 2 h. The mixture was filtered. The filtrate was diluted with saturated solutions of sodium bicarbonate and sodium chloride and extracted twice with ethyl acetate. The organic phase was dried over sodium sulfate, filtered through a pad of silica gel and concentrated in vacuum. Column chromatography on silica gel using a 0-30% gradient of ethyl acetate in heptane yielded the title product, 0.67 g (58%).
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[N:5]1)([CH3:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[S:16][CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2ccsc2nc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc2c([N+](=O)[O-])csc2nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 3 °C
Reaction time: 3 h

Procedure:
Methyl 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)thieno[2,3-b]pyridine-5-carboxylate (3.94 g, 0.0119 mol) is dissolved in 200 mL concentrated H2SO4 at room temperature. While cooling to 3° C. in an ice bath, 1.5 mL (0.024 mol) concentrated HNO3 is added, then the mixture is allowed to warm to room temperature. After three hours, the reaction mixture is poured onto ice, neutralized with solid NaHCO3 to pH 6 and is extracted with methylene chloride. The extract is filtered, then dried over sodium sulfate, refiltered and concentrated to a yield solid weighing 4.33 g (97%), which upon crystallization from methanol water has mp 201°-202.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C@@H:11]([O:13][CH3:14])[CH3:12])[N:8]=[C:7]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:6]1.[ClH:30].[C:31](=[NH:35])(OC)[CH3:32].C(N(CC)CC)C>CO>[ClH:30].[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C:7]1[S:6][C@@:5]([CH2:4][CH2:3][CH2:2][NH:1][C:31](=[NH:35])[CH3:32])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C@@H:11]([O:13][CH3:14])[CH3:12])[N:8]=1
Reactant: COC(C)=N
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCNC(C)=N)c1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one (Example 5, Steps A-F; 57.5 mg, 0.117 mmol) and methyl acetimidate hydrochloride (192 mg, 1.75 mmol) in methanol was added triethylamine (355 mg, 3.51 mmol). After heating at 50° C. for 16 hours, the mixture was concentrated under reduced pressure. The residue was chromatographed (15:85:1 MeOH/dichloromethane/NH4OH), and the isolated material %% as treated with excess HCl in MeOH then concentrated to afford the product. MS ESI (+) m/z 461 (M+1) detected. 1H NMR (400 MHz, CD3OD) δ 7.65-7.60 (m, 1H), 7.49-7.45 (m, 2H), 7.42-7.38 (m, 2H), 7.35-7.29 (m, 3H), 4.80 (q, 1H, J=7.1 Hz), 3.50-3.40 (m, 2H), 3.36 (s, 3H), 3.28-3.19 (m, 1H), 2.65-2.57 (m, 1H), 2.22 (s, 3H), 2.21-2.12 (m, 1H), 1.75-1.64 (m, 1H), 1.44 (d, 3H, J=7.1 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[Cl-].[Cl:20][CH:21]=[N+:22]([CH3:24])[CH3:23]>ClCCCl>[Cl-:20].[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10]([CH:21]=[N+:22]([CH3:24])[CH3:23])=[C:4]2[CH:3]=1
Reactant: C[N+](C)=CCl
Reactant: COc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(-c2nn3ccc(Br)cc3c2C=[N+](C)C)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of 5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (200 mg, 0.66 mmol) in 1,2-dichloroethane (6 mL) was added N-(Chloromethylene)-N-methylmethanaminium chloride (195 mg, 1.5 mmol). The mixture was stirred at 20° C. for 20 h then heated to 50° C. for 1 h at which time monitoring the reaction by LC indicated all starting material had converted to the title compound. The solids were collected by filtration and dried under reduced pressure to afford the title compound as a solid (260 mg, 100%). LCMS m/z 331.0, 333.0 (M-(CH3)2NH+H2O)+, ret. time=2.13 min.