Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[OH:26]>CN(C=O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:26][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCN2CCCC2)c(Cl)c1
Temperature: 80 °C
Yield: 31.1 %

Procedure:
A suspension of Cs2CO3 (23.1 g, 71.0 mmol), 1-(2-chloroethyl)pyrrolidine, hydrochloride (9.0 g, 53.2 mmol) and 2-chloro-4-nitrophenol (3.0 g, 17.8 mmol) in DMF (50 mL) was heated at 80° C. for 4 days. After dilution with H2O (50 mL), the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O (30 mL), then with brine prior to drying over MgSO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 5%-10% gradient MeOH/CH2Cl2 to yield yellow brownish solid (1.5 g, 31%) MS (ESI) 271 (M+H)+.
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:33]([NH:32][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([Cl:31])[C:25]=2[Cl:24])=[O:34])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:18][CH2:19][S:20](=[O:23])[CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O)Nc1cccc(Cl)c1Cl
Yield: 44 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (117 mg, 0.35 mmol) and 2,3-dichlorophenylisocyanate (72 mg, 0.38 mmol) were coupled to form the desired urea (79 mg, 44%). 1H NMR (DMSO-d6): δ 9.34 (s, 1H), 9.27 (s, 1H), 8.28 (d, 1H), 8.05 (m, 1H), 7.32 (m, 2H), 7.21 (d, 1H), 3.75 (m, 2H), 3.65 (m, 2H), 2.89, (m, 4H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].[C:12]1([S:18]([N:21]2[C:29]3[CH:28]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:26]=[C:25]([NH2:34])[C:24]=3[CH:23]=[N:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][CH:2]([N:4]1[C:8]([C:9]([NH:34][C:25]2[CH:26]=[C:27]([Sn:30]([CH3:33])([CH3:32])[CH3:31])[CH:28]=[C:29]3[C:24]=2[CH:23]=[N:22][N:21]3[S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3]
Reactant: CC(C)n1nccc1C(=O)Cl
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)n1nccc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
1-(1-Methylethyl)-1H-pyrazole-5-carbonyl chloride (152 mg) in DCM (10 ml) was added dropwise to 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (350 mg) in DCM (15 ml) and pyridine (0.07 ml). The reaction was stirred at room temperature for 10 min before addition of further 1-(1-methylethyl)-1H-pyrazole-5-carbonyl chloride (10 mg). The reaction was stirred for 30 min, saturated sodium bicarbonate (aq) (25 ml) was added and stirred vigorously for 10 min before the DCM was separated through a hydrophobic frit and evaporated to dryness. The residue was dissolved in DCM and loaded onto a silica cartridge preconditioned with cyclohexane. The cartridge was eluted with 0-100% ether in cyclohexane. The compound containing fraction was evaporated to dryness to give title compound, 360 mg.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([O:10][CH3:11])[C@@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[C@@H:8]([O:10][CH3:11])[CH2:9]1)=[O:4]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Product: CO[C@H]1C[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-cyclopentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methoxy-cyclopentyl}-amide. Light yellow amorphous solid. MS: 490.1 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH3:32][O:33][CH2:34][CH2:35][NH2:36].Cl>CN1C(=O)CCC1.O>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:36][CH2:35][CH2:34][O:33][CH3:32])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: COCCN
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Temperature: 105 °C

Procedure:
A mixture of ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate(49.2 g, 115 mmol) and 2-methoxyethylamine (14.8 mL, 172 mmol) in NMP (400 mL) was heated at 95-115° C. for 1-2 h. The mixture was cooled to rt, diluted with water (600 mL) and acidified with 1N HCl (72 mL). The precipitate was collected by filtration, washed with water and dried overnight in a vacuum oven to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, br t, J=5 Hz), 8.51 (1H, s), 7.75 (1H, s), 7.32 (2H, dd, J=9, 6 Hz), 7.12 (2H, t, J=9 Hz), 5.12 (2H, s), 4.11 (2H, s), 3.54-3.44 (4H, m), 3.27 (3H, s), 3.12 (3H, s), 2.82 (3H, s); HRMS calcd for C23H25FN4O5+H+: 457.1887.Found: 457.1884.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1.[CH2:17]([O:24][C@@H:25]1[C@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:28]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:27][CH:26]1Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>CC#N.CCOC(C)=O>[Cl:1][C:2]1[N:3]([C@@H:26]2[O:27][C@H:28]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:25]2[O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:5]=2[N:6]=1
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=[N+]([O-])c1cc2nc(Cl)[nH]c2cc1[N+](=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2cc1[N+](=O)[O-]
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
To a mixture of 0.541 g (2.23 mmol) of 2-chloro-5,6-dinitrobenzimidazole in 12 mL of MeCN, was added 0.558 mL (2.23 mmol) of BSA. The reaction mixture was stirred at 75° C. for 15 min to give a clear solution. This solution was treated with the above MeCN solution of 2,3,5-tri-O-benzyl-D-ribofuranosyl chloride and 0.56 mL (2.90 mmol) of TMSOTf at 75° C. for 30 min. The reaction mixture was cooled and diluted with EtOAc (50 mL). The EtOAc solution was washed with sat. NaHCO3 solution (50 mL×2), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (2.2×18 cm, eluted with 20% EtOAc/hexane). Evaporation of fractions 10-14 (20 mL per fraction) gave 0.502 g (35%) of 60 as a syrup. MS: (FAB) m/e 645 (1%, MH+ =645). 1H NMR DMSO-d6): δ8.50, 8.49 (2×s, 2, 7-H and 4-H), 7.34, 690 (2×m, 15, 3×Ph), 6.09 (d, 1, 1'-H, J1'-2' =8.0 Hz), 4.73 ~4.27 (m, 9, 2'-H, 3'-H, 4'-H, and 3×PhCH2), 3.77 (dd, 1, 5'-H, J4'-5' =2.0 Hz, J5'-5" =11.0 Hz), 3.65 (dd, 1, 5"-H, J4'-5" =2.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([O:12]CC)=O.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:10](=[O:12])[CH2:9]1
Reactant: CCOC(=O)CSc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1CSc2ccccc2N1
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Ethyl (2-aminophenyl)mercaptoacetate (322 mg, 1.52 mmole), N-tert-butyloxycarbonylpiperidin-4-one (456 mg, 2.29 mmole), acetic acid (478 ml, 8.36 mmole), and sodium triacetoxyborohydride (966 mg, 4.56 mmole) were combined in 10 ml of dichloroethane at room temperature, protected from moisture and stirred overnight. Saturated sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The combined extracts were washed with sodium bicarbonate solution and brine, then dried and concentrated. The crude product was chromatographed on silica gel (ethyl acetate-hexane elution, 1:3 v/v) to give 210 mg of the title compound along with 99 mg of 2H-1,4-benzothiazin-3(4H)-one.
Reaction SMILES: [ClH:1].N[C:3]1[C:11]([S:12][CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].N([O-])=O.[Na+]>O.[Cu]Cl>[Cl:1][C:3]1[C:11]([S:12][CH3:13])=[CH:10][C:9]([CH3:14])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: CSc1cc(C)cc(C(=O)O)c1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cc(C)cc(C(=O)O)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
13 ml of concentrated hydrochloric acid were added to 6.00 g (30.4 mmol) of 2-amino-5-methyl-3-(methylthio)benzoic acid in 35 ml of water, and the mixture was heated at 60° C. for a few minutes. The solution was then cooled to a temperature of 0° C.-5° C., and a solution of 2.31 g (33.5 mmol) of sodium nitrite in 10 ml of water was slowly added dropwise at this temperature. The mixture was subsequently stirred at this temperature for another 1 h. This solution was added dropwise to a mixture, at RT, of 4.52 g (45.6 mmol) of copper(I) chloride, 35 ml of water and 27 ml of concentrated hydrochloric acid. The mixture was stirred at room temperature for 15 minutes and then slowly heated to reflux temperature. The contents were then heated under reflux for 15 minutes. For work-up, the reaction mixture was cooled and filtered, and the residue was washed with water. This gave 5.62 g of 2-chloro-5-methyl-3-(methylthio)benzoic acid as residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN1C(=O)CCC1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:3]=3)[S:9][C:10]=2[C:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(C2CCCCO2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-isonicotinamide with cesium carbonate and morpholine in NMP. ES-MS m/e (%): 455 (M+H+, 100).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:28][NH:29][CH3:30]>C(#N)C.O>[CH3:28][N:29]([CH3:30])[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18]
Reactant: CNC
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: CN(C)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (5.22 g, 19.43 mmol), potassium iodide (3.22 g, 19.43 mmol) and potassium carbonate (16.11 g, 117 mmol) in acetonitrile (100 ml) was added dimethylamine hydrochloride (6.34 g, 78 mmol). The resulting mixture was stirred overnight at 50° C. The mixture was then cooled to room temperature, diluted with water and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in dichloromethane as the eluent. 1H NMR (DMSO-d6) δ 8.14-8.10 (m, 2H), 7.37 (d, J=9.6 Hz, 1H), 3.94 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 1H), 2.27 (t, J=7 Hz, 2H), 2.13 (s, 6H), 1.66 (quint, J=7.5 Hz, 1H). ESI-MS (m/z, %) 278 (MH+, 100).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)([OH:3])=O.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:25])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([NH:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[O:3])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Reactant: Nc1cccnc1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)Nc3cccnc3)coc12
Yield: 19 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and 3-aminopyridine (0.088 g) to give Compound 156 (0.068 g, 19%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:39][C:40]([NH2:42])=[S:41].C([O-])(=O)C.[Na+].C(OCC)C>O.O1CCCC1>[NH2:42][C:40]1[S:41][CH:2]=[C:3]([C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:39]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Yield: 91 %

Procedure:
A solution of benzhydryl 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (syn isomer)(1.2 g), thiourea (0.5 g) and sodium acetate (trihydrate)(0.7 g) in water (20 ml) and tetrahydrofuran (20 ml) was stirred at 30° C. for 3.5 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diethyl ether to obtain benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.05 g).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:8][C@@H:9]([C:11]([O:13]C(C)(C)C)=[O:12])[NH2:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:18]([OH:20])=[O:19])[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(O)cc1)C[C@H](N)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N[C@@H](C[C@@H](Cc1ccc(O)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Di-tert-butyl 4-(4-hydroxybenzyl)-L-glutamate (27 mg, 58 μmol) was dissolved in trifluoroacetic acid (1 ml) and stirred at room temperature for 2 h. The mixture was then taken up in toluene and concentrated under reduced pressure. The residue was purified by preparative HPLC (RP-18; solvents: acetonitrile (+0.1% trifluoroacetic acid), water (+0.1% trifluoroacetic acid); gradient: 30%->40% acetonitrile (20 min)).
Reaction SMILES: [H-].[Na+].[C:3]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:22][CH2:23][C@@H:24]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[CH2:14]([O:13][C:3]([CH:4]([CH2:22][CH2:23][C@@H:24]([NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCBr)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 46.3 %

Procedure:
To a suspension of 66 mg sodium hydride (60% in oil, 1.66 mmol) in N,N-dimethyl-formamide (10 mL) was added a solution of 456 mg benzyl tert-butyl malonate (commercial, 1.82 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The mixture was stirred for one hour at room temperature before a solution of 560 mg tert-butyl (2R)-4-bromo-2-[(tert-butoxycarbonyl)amino]butanoate (1.66 mmol) in N,N-dimethylformamide (5 mL) was added. The mixture was stirred for 60 hours at room temperature and was then evaporated in vacuo. The residue was purified by column chromatography on silica gel (1.5→20% ethyl acetate in hexane) to give the title compound (390 mg, 46% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[NH:25][CH:26]=[N:27]4)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[CH:21]=1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COCC(Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 32.4 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (110 mg, 0.39 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (93 mg, 0.39 mmol) and DIPEA (340 mL, 1.9 mmol) in n-butanol (2.5 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 171 as a white solid (51 mg, 32%). LCMS (Method B): RT 3.52 min [M+H]+ 404.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.25-8.01 (2H, m), 7.87 (1H, s), 7.77-7.47 (6H, m), 7.15-7.05 (1H, m), 6.87 (1H, dd, J=8.93, 2.37 Hz), 5.64 (1H, s), 3.84 (2H, d, J=6.60 Hz), 3.14 (3H, s). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[N:17]2[C:13]([S:14][CH:15]=[CH:16]2)=[CH:12][N:11]=1)C(=O)C(F)(F)F.[OH-].[Na+]>CO>[CH3:1][NH:2][CH2:9][C:10]1[N:17]2[C:13]([S:14][CH:15]=[CH:16]2)=[CH:12][N:11]=1
Reactant: CN(Cc1ncc2sccn12)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNCc1ncc2sccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.2 %

Procedure:
To a solution of 394 mg (1.49 mmol) of the above-obtained 5-(N-methyl-N-trifluoroacetylamino)methylimidazo[5,1-b]thiazole in 3 ml of methanol was added 3 ml of a 10% aqueous solution of sodium hydroxide, and the mixture was stirred at room temperature for 1 hour. The methanol was distilled off under reduced pressure. The resultant was extracted three times with chloroform. The organic layer was dried over anhydrous potassium carbonate, and concentrated under reduced pressure to give 272 mg of the title compound as an oil.
Reaction SMILES: [CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:12][CH2:13]C(F)(F)F)[C:6]([O:18][CH3:19])=[N:5]1)([CH3:3])[CH3:2].BrCC[O:23][CH2:24][C:25]([F:28])([F:27])[F:26]>>[CH:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][CH:7]([CH2:12][CH2:13][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:6]([O:18][CH3:19])=[N:5]1)([CH3:2])[CH3:3]
Reactant: FC(F)(F)COCCBr
Reactant: COC1=NC(C(C)C)C(OC)=NC1CCC(F)(F)F
Product: COC1=NC(C(C)C)C(OC)=NC1CCOCC(F)(F)F
Yield: 65 %

Procedure:
This compound was made in 65% yield by the same procedure as 2-Isopropyl-3,6-dimethoxy-5-(3,3,3-trifluoro-propyl)-2,5-dihydro-pyrazine, substituting 1-Iodo-3 ,3 ,3-trifluoropropane with 2-(2-Bromoethoxy)-1,1,1-trifluoroethane. 1H-NMR: 400 MHz, (CDCl3) δ: 4.11-4.05 (m, 1H), 3.95 (t, J=3.5 Hz, 1H), 3.86-3.75 (m, 3H), 3.74-3.66 (m, 7H), 2.30-2.18 (m, 2H), 1.92-1.82 (m, 1H), 1.03 (d, J=6.9 Hz, 3H), 0.70 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([NH2:32])[C:26]=1[Cl:33])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[C:17]([O:21][C:22](=[O:34])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N:32]=[C:1]=[S:2])[C:26]=1[Cl:33])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N)c1Cl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (0.42 g, 1.8 mmol) is added to a mixture of (3-amino-2,4-dichloro-benzyl)-carbamic acid tert-butyl ester (0.50 g, 1.7 mmol) and dioxane (25 mL) and stirred at rt for 2 h and at reflux for 2 d. The mixture is concentrated, diluted with DCM and filtered over silica gel. The filtrate is concentrated to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[N:10]([N:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH:11]=1)=[O:5])C.ClC1C=C(C2C=NN3C=CC(C(O)=O)=NC=23)C=CC=1>>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]2[CH:13]=[N:12][N:10]3[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8][C:9]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnc2c(-c3cccc(Cl)c3)cnn2c1
Agent: O=C(O)c1ccn2ncc(-c3cccc(Cl)c3)c2n1
Product: O=C(O)c1cnc2c(-c3cccc(Cl)c3)cnn2c1

Procedure:
This compound was synthesized from 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-6-carboxylic acid ethyl ester, according to the process for synthesizing the foregoing 3-(3-chlorophenyl)-pyrazolo-[1,5-a]-pyrimidine-5-carboxylic acid. mp: 272-275° C. (decomposed).