Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[C:11]1([CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CCc1ccccc1)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)CCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
To 1.68 mL of oxalyl chloride (19.2 mmol) in 35 mL of CH2Cl2 at −78° C. was added 2.73 mL (38.5 mmol) of dry DMSO in 5 mL of CH2Cl2. After the addition, 3.6 g (15.4 mmol) of 1-(3-phenylpropionyl)-4-hydroxypiperidine 134 in 5 mL of CH2Cl2 was added, and the mixture was stirred for 5 min in the cold. 10.73 mL (77 mmol) of triethylamine in 5 mL of CH2Cl2 was added, and the mixture was allowed to come to room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution. The organic phase was washed with water twice, with saturated brine, dried, and evaporated under vacuum to give 3.2 g (89) of 1-(3-phenylpropionyl)-4-ketopiperidine (135). GC/MS showed 100% purity with a molecular ion of 231.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][C:10]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:9]1.N([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]2[N:39]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[N:37][N:36]=2)=[CH:25][CH:24]=1)=[N+]=[N-].[H-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[N:39]([C:40]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:38]=[N:37][N:36]=3)=[CH:27][CH:28]=2)[C:10]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:9]1
Reactant: CC(C)CCc1nn(-c2ccccc2Cl)c(=O)[nH]1
Reactant: [N-]=[N+]=NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 39 %

Procedure:
The alkylation of 2-(2-chlorophenyl)-2,4-dihydro-5-(3-methylbutyl)-3H-1,2,4-triazol-3-one with 5-[4'-(bromomethyl)biphenyl-2-yl]-N-trityltetrazole (see Example 2, Step B) was carried out as described in Example 4, Step D, except that a 20% excess of sodium hydride and 50% excess of the alkylating agent were used. After work-up, the crude product mixture was flash chromatographed on silica gel (72 mL for 0.354 mmol, eluted with 0.3% MeOH/CH2Cl2) to give a 39% yield of the desired material, mass spectrum (FAB) m/e 742 (M+1)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH:15]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:16][N:17]1[C:22](=[O:23])[C:21]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]2[N:42]=[C:43]([CH3:45])[N:44]=[C:18]12>C(OCC)(=O)C>[CH3:13][O:14][CH:15]([C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:16][N:17]1[C:22](=[O:23])[C:21]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:20]([CH2:39][CH2:40][CH3:41])[N:19]2[N:42]=[C:43]([CH3:45])[N:44]=[C:18]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(OC)C(C)(C)C)c2nc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(OC)C(C)(C)C)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2-methoxy-3,3-dimethylbutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.22 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.087 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.058 g, 23%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Cl)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc(Cl)nc1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A mixture of methyl 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoate (Example 4(c), 67 mg, 0.22 mmol), lithium hydroxide monohydrate (55 mg, 1.3 mmol), water (2 mL), and dioxane (2 mL) was stirred at 110° C. for 1.5 hr and then concentrated. The residue was partitioned between water (4 mL) and diethyl ether (6 mL) were added. The ether layer was reextracted with water (1 mL). The combined aqueous solutions were neutralized with aqueous 10% citric acid solution to pH=5 and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate extracts were washed with brine (2 mL), dried (Na2SO4) and concentrated to give 3-(6-chloropyridin-3-yl)-2,2-dimethyl-3-phenylpropanoic acid (57 mg, 0.20 mmol, 89% yield). MS found: (M−H)−=288.19.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(Cl)CCl.C1C=[CH:25][C:26]2[N:31](O)[N:30]=[N:29]C=2C=1.C1C[O:36]CC1>>[N:31]([CH2:26][C:25]([N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:16][CH:15]=1)=[O:36])=[N+:30]=[N-:29]
Reactant: CCOC(=O)CNCc1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Product: CCOC(=O)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)CN=[N+]=[N-]
Reaction time: 12 h
Yield: 64 %

Procedure:
To a 25 mL round bottom flask containing 137 (0.307 g, 1.18 mmol) and azido acid (0.89 g, 1.77 mmol) in THF mL) was treated with EDC (0.362 g, 1.89 mmol), HOBt (0.255 g, 1.89 mmol) and TEA (0.83 mL, 5.9 mmol) at room temperature and was stirred for 12 h. The reaction was concentrated on silica and was purified over silica gel using EtOAc:Hexanes (2:1) as an eluent to afford 138 (0.259 g, 64%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:45])([F:36])[C:41]([F:44])([F:43])[F:42])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: NCCC(F)(F)C(F)(F)F
Product: C[C@](F)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (R)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 3,3,4,4,4-pentafluoro-butylamine, the title compound was prepared in the same manner as described for example 1c. White solid (68%). MS: m/e=622(M+H+).
Reaction SMILES: [C:1](ON1C(=O)CCC1=O)(=[O:3])[CH3:2].[NH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[N:29]=[N:30][C:31]([N:34]([CH3:45])[CH:35]4[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]4)=[CH:32][CH:33]=3)[C:23]([OH:27])=[CH:24]2)=[CH:19][CH:18]=1.CCOCC>CS(C)=O>[OH:27][C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][NH:12][C:1](=[O:3])[CH3:2])=[CH:26]2)=[CH:21][C:22]=1[C:28]1[N:29]=[N:30][C:31]([N:34]([CH3:45])[CH:35]2[CH2:40][C:39]([CH3:41])([CH3:42])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]2)=[CH:32][CH:33]=1
Reactant: CN(c1ccc(-c2cc3ccc(OCCCN)cc3cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: CC(=O)ON1C(=O)CCC1=O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(=O)NCCCOc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
N-Acetoxysuccinimide (98 mg, 0.624 mmol) was added to a solution of Example 20-5 (50 mg, 0.108 mmol) and TEA (0.747 ml, 5.39 mmol) in DMSO (2 ml) at RT. The reaction mixture was stirred at RT for 30 min then concentrated in vacuo to remove excess Et3N. The resulting residue was purified by preparative HPLC (eluting with 5-80% MeCN/H2O with 0.1% TFA modifier). The appropriate fractions containing product were combined then adsorbed onto a MeOH conditioned SCX column (5 g, BSA Varian brand). The column was washed several times with MeOH then eluted with 3 N NH3 in MeOH. Evaporation of the solvent afforded a yellow oil. Et2O was added to the oil then concentrated to dryness affording the title compound as a yellowish orange solid (30 mg, 55% yield). LCMS Rt=0.52 min (LCMS method Q); MS (M+1)=506.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (br. s, 1H), 8.35 (s, 1H), 8.28 (d, J=10.10 Hz, 1H), 7.77 (d, J=9.09 Hz, 2H), 7.35 (d, J=9.60 Hz, 1H), 7.17 (s, 1H), 7.09 (d, J=2.02 Hz, 1H), 6.95 (dd, J=9.09, 2.53 Hz, 1H), 4.92-5.04 (m, 1H), 4.11 (t, J=6.32 Hz, 2H), 3.20-3.28 (m, 2H), 2.98 (s, 3H), 1.87-1.96 (m, 2H), 1.82 (s, 3H), 1.55-1.63 (m, 2H), 1.44-1.55 (m, 2H), 1.30 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1([CH:14]2C(=O)OC(C)(C)[O:16][C:15]2=[O:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].CN(C=O)C.O>CCOC(C)=O>[CH2:1]([C:3]1([CH2:14][C:15]([OH:23])=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(C2C(=O)OC(C)(C)OC2=O)CCc2ccc(OC)cc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1(CC(=O)O)CCc2ccc(OC)cc21
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.6 %

Procedure:
A 100 mL round bottom flask was charged with 42.1 (0.30 g, 0.94 mmol) and 10:1 DMF/water (5 mL). The solution was stirred overnight at 90° C., cooled to room temperature, and diluted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (0-30% EtOAc/hexanes) to afford 42.2 (0.204 g, 92% yield) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:23][N:24]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNCCc1ccccc1
Product: CN(CCc1ccccc1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with N-methyl-2-phenylethanamine (1.2 equiv) to give 170 (14.5 mg, M+1 431.1)
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:40])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([C:23]3[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)=[O:22])[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[BH4-].[Na+]>CO>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:40])[CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:23]3[N:27]([CH2:28][C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)[OH:22])[CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(C(O)CCCN2CCC(C(O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred, room temperature, solution of 1-[4-(1,1-dimethylethyl)phenyl]-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]carbonyl]-1-piperidinyl]-1-butanone (2.1 g, 3.9×10-3 mole) and methanol (80 ml) was added NaBH4 (0.42 g, 1.1×10-2 mole). After stirring overnight, the methanol was evaporated at reduced pressure. The concentrate was dissolved in a two phase mixture of EtOAc/H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc. The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a solid. Crystallization from cyclohexane/hexane afforded α-[1-[4-[4-(1,1-dimethylethyl)phenyl]-4-hydroxybutyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazole-2methanol as a colorless solid: 1.6 g (75%), m.p. 87°-90° C.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:35][C:36]([O:38]C)=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[CH:35][C:36]([OH:38])=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Oc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccccc1Oc1ccccc1
Yield: 54.5 %

Procedure:
A mixture of 2-phenoxybenzaldehyde (2.12 g; 10.70 mmol) and methyl (triphenylphos-phoranylidene)acetate (4.01 g; 11.76 mmol) in 60 mL of THF was refluxed overnight. The reaction was cooled, diluted with ethyl acetate (50 mL) and washed with water (3X). The crude residue Was purified on a silica gel column eluting with hexane to obtain 1.4 g (52%) of 2-phenoxycinnamic acid, 1H NMR (CDCl3): δ 3.78 (s, 3H); 6.56 (d, 1H, J=16.1); 6.87 (d, 1H, J=8.5); 7.00 (d, 2H, J=7.5); 7.10-7.15 (m,2H); 7.28-7.33 (m, 3H); 7.36 (d, 1H, J=8.5); 8.02 (d, 2H, J=16.2).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4([CH3:22])[NH:20][C:19](=S)[CH2:18][O:17][CH2:16]4)[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.[NH3:25]>CO>[ClH:1].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4([CH3:22])[CH2:16][O:17][CH2:18][C:19]([NH2:25])=[N:20]4)[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: N
Reactant: CC1(c2cccc(-c3nc4ccc(Cl)cc4o3)c2)COCC(=S)N1
Solvent: CO
Product: CC1(c2cccc(-c3nc4ccc(Cl)cc4o3)c2)COCC(N)=N1
Product: Cl
Temperature: 100 °C
Yield: 9 %

Procedure:
In a tube the (RS)-5-[3-(6-chloro-benzooxazol-2-yl)-phenyl]-5-methyl-morpholin-3-thione (260 mg, 0.7 mmol) was treated with a solution of ammonia in methanol (7M). The sealed tube was heated at 100° C. for 3 hours. For the workup, the reaction mixture was cooled to room temperature and evaporated. For purification the crude product was passed on a SCX column, and then further purified by preparative HPLC. Finally, the treatment with hydrochloric acid followed by evaporation yielded the title compound (23 mg, 9% of theory) MS (ISP): m/z=342 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12](OC)=[O:13].CCOC(C)=O.O>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[CH2:12][OH:13]
Reactant: COC(=O)c1cnc2cc(C)nn2c1N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ncc(CO)c(N)n2n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a 1 L three-necked round bottom flask was added Methyl 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (20.6 g, 100 mmol, 1.0 eq.) and THF (400 mL). The mixture was cooled to 0° C. and LiBHEt3 (315 mL of a 1.0 M solution in THF, 315 mmol, 3.0 eq.) was added slowly through an addition funnel under nitrogen. After addition, the mixture was stirred at room temperature for 4 h. Additional LiBHEt3 (30 mL of a 1.0 M solution in THF, 30 mmol, 0.3 eq.) was added and the mixture was stirred for an additional 1 h. The mixture was slowly treated with EtOAc (600 mL) and then water (300 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×300 mL). The combined organic phases were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by a short silica gel column (2.5 inch in height and 4 inch in diameter) using MeOH in CH2Cl2 as the eluent. Concentration by rotary evaporation provided (7-amino-2-methylpyrazolo[1,5-a]pyrimidin-6-yl)methanol (1-1) as a light yellowish solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(N1[C:18](=[O:19])[CH:17]=[CH:16][C:15]1=[O:20])(OC)=O.S(=O)(=O)(O)O>C(=O)(O)[O-].[Na+].O>[CH:16]1[C:15](=[O:20])[N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:18](=[O:19])[CH:17]=1
Reactant: COC(=O)N1C(=O)C=CC1=O
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCN1C(=O)C=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A solution of 4.2 g (32.3 mmol) of 6-aminocaproic acid in 163 ml of saturated sodium bicarbonate solution is treated at 0° C., with vigorous stirring, with 5 g (32.3 mmol) of N-carbomethoxymaleimide. After 1 hour, the solution is diluted with 256 ml of water and stirred at room temperature for 1 hour. The pH of the solution (8.2) is then brought to 6.4 by adding concentrated sulfuric acid. The solution is then concentrated to 100 ml and acidified to pH 2 by adding 1 M sulfuric acid, and is extracted three times with ethyl acetate. The organic phases are combined, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue is purified by chromatography on a silica column (elution: chloroform/acetic acid, 95:5). In this manner, 4.7 g of N-maleoyl-6-aminocaproic acid are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:7][C:6](=[O:8])[CH:5]([C:9](=O)[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:4](=[O:31])[O:3]1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[O:3][C:4](=[O:31])[CH:5]([CH2:9][C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[C:6](=[O:8])[O:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CC1C(=O)OC(C)(C)OC1=O
Reaction time: 0.67 h

Procedure:
(S)-tert-Butyl 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (22.0 g, 48 mmol) in 200 mL DCM was cooled to −5° C. Acetic acid (32 g, 527 mmol) was added in one portion and sodium tetrahydroborate (4.5 g, 120 mmol) as a solid was added portion wise over about 40 minutes. The reaction mixture was stirred for another 40 minutes and the reaction mixture was stored in the freezer overnight and was then washed with brine (3×150 mL) and water (2×100 mL). The organic layer was dried over MgSO4. The desired product was obtained as a white amorphous solid (21.0 g, 98%). No further purification was performed and the reaction was carried on to the next step.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@@:5]([N:13]1[CH2:17][CH2:16][N:15]([N:18]=[CH:19]C3C=CC=CC=3)[C:14]1=[O:26])([C:10]([OH:12])=[O:11])[CH2:6]2.Cl.[N+](C1C=C([N+]([O-])=O)C=CC=1NN)([O-])=O.[OH2:42].O.[NH3:44]>CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]2[C@@H:3]1[S:4][C@:5]([C:10]([OH:12])=[O:11])([N:13]1[CH2:17][CH2:16][N:15]([NH:18][C:19]([NH2:44])=[O:42])[C:14]1=[O:26])[CH2:6]2
Reactant: O
Reactant: N[C@@H]1C(=O)N2C[C@@](C(=O)O)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Reactant: N
Agent: Cl
Agent: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Product: NC(=O)NN1CCN([C@]2(C(=O)O)CN3C(=O)[C@@H](N)[C@H]3S2)C1=O
Reaction time: 3 h
Yield: 66 %

Procedure:
In 150 ml of methanol was suspended 10.0 g of (3R,5R,6R)-6-amino-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane. Thereto was added 9.2 g of 2,4-dinitrophenylhydrazine hydrochloride at 20°-25° C. The mixture was stirred at the same temperature for 3 hours. 100 ml of water was added to the reaction mixture. The mixture was adjusted to pH 8.0 with concentrated ammonia water. The resulting crystals were removed by filtration. To the filtrate was slowly added concentrated hydrochloric acid to adjust the filtrate to pH 1.5. To the filtrate was added 2.5 g of active carbon, and the mixture was stirred at room temperature for 5 minutes. The active carbon was removed by filtration and washed with water. The filtrate and washings were combined and to the resulting mixture was added 3.9 g of sodium cyanate at room temperature in 60 minutes while maintaining the reaction mixture at pH 1.6 to 2.1 with concentrated hydrochloric acid. After the addition, the mixture was stirred at room temperature for 60 minutes. The resulting crystals were collected by filtration and suspended in 50 ml of water. To the suspension was added concentrated ammonia water to adjust the suspension to pH 9.0. Then, 0.4 g of active carbon was added, and the mixture was stirred at room temperature for 5 minutes. The active carbon was removed by filtration and washed with water. Concentrated hydrochloric acid was added to a mixture of the washings and the previously obtained filtrate to adjust the pH to 4.5. The mixture was stirred at room temperature for 30 minutes. The resulting crystals were collected by filtration, washed with water and acetone in this order, and dried under reduced pressure to obtain 5.81 g (yield: 66.0%) of (3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:27][CH:28]([CH3:30])[CH3:29])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[C:10]2[N:9]([S:32]([CH3:31])(=[O:34])=[O:33])[C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:27][CH:28]([CH3:30])[CH3:29])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2[nH]c3c(F)cccc3c2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(c3cccc(F)c3n2S(C)(=O)=O)C1
Reaction time: 8 h

Procedure:
A suspension of 200 mg (6-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 17) in 5 ml dichloromethane was treated with 106 mg methane sulfonyl chloride, followed by 118 mg triethylamine. The reaction mixture was stirred overnight. Concentration and chromatography (silica gel; ethyl acetate) yielded the title compound as a slightly yellowish solid (17 mg; 7%). MS (m/e): 509.0 (M+CH3COO).