Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=O)O1.[Br:11][C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1.Cl>C(O)(=O)C.O>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:4][CH2:5][C:6]([OH:7])=[O:8])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCc1ccc(Br)cc1
Yield: 52 %

Procedure:
2,2-dimethyl-[1,3]dioxane-4,6-dione (120 g, 0.84 mol) and 4-bromo-benzaldehyde (153.4 g, 0.84 mol) were dissolved in 300 mL of TEA and acetic acid. The reaction mixture was refluxed for overnight. At which point, the reaction mixture was diluted with water (4 L) and acidified with 6M HCl (1 L) until pH=2. The precipitated solid was filtered off and washed with diluted HCl, then dissolved in 5% NaHCO3 solution. The aqueous salt solution was washed with ether (4×500 mL), filtered and acidified with diluted HCl. Then filtered and dried under vacuum to provide 100 g (67%) of the desired product 3-(4-bromophenyl)propanoic acid (1A): 1H NMR (DMSO-d6, 400 MHz), 62.5 (m, 2H), 2.8 (m, 2H), 7.2 (m, 2H), 7.5 (m, 2H), 12.2 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>CS(C)=O>[O:1]=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCO
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC=O
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a mixed solution of tert-butyl (2-hydroxyethyl)carbamate (10.0 g) in dimethyl sulfoxide (50 mL) and triethylamine (12.3 g) was added sulfur trioxide pyridine complex (15.0 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was further stirred at room temperature for 3 hr, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=17:3→13:7) to give the title compound as a pale-yellow oil (yield 6.50 g, 66%). 1H-NMR (CDCl3) δ: 1.46 (9H, s), 4.08 (2H, d, J=4.5 Hz), 5.19 (1H, brs), 9.66 (1H, s).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: COC(=NC#N)c1ccoc1
Reactant: NCCc1ccccc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1ccoc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
Methyl N-cyano-3-furancarboximidate (0.30 g, 2.0 mmol) was dissolved in methanol (10 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.38 g, 1.59 mmol, yield: 79%) as colorless crystals.
Reaction SMILES: C(N[C:6](=[O:38])[C:7]([NH:34]C(=O)C)([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16]C(C)(C)C(C)(C)[O:13]1)(C)(C)C.[OH2:39]>Cl>[NH2:34][C:7]([CH:21]1[CH2:22][CH2:23][CH:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:25][CH2:26]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:13])[OH:16])[C:6]([OH:38])=[O:39]
Reactant: O
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1CCC(c2ccc(Cl)cc2)CC1
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)C1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 2-acetylamino-2-[4-(4-chlorophenyl)-cyclohexyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)hexanoic acid tert-butylamide (980 mg) in 6 N HCl (15 mL) was stirred at 90° C. for 1 day. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (10 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give 2-amino-6-borono-2-(4-(4-chlorophenyl)cyclohexyl)hexanoic acid (535 mg, 81%). 1H NMR (D4-MeOH, 300 MHz) δ 7.24 (d, J=8.5 Hz, 2H), 7.19 (dd, J=8.5 Hz, 2H), 2.50 (m, 1H), 1.78-2.06 (m, 7H), 1.38-1.56 (m, 7H), 1.21 (m, 1H) and 0.82 (t, J=6.5 Hz, 2H); MS (+CI): m/z for C18H27BClNO4: expected 367.2. found 368.2 (M+H)+, 350.2 (M+H−H2O)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](N)c1cccc(C(C)(C)C)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (S)-1-(3-(tert-butyl)phenyl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 559 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:6])=[CH2:5].[CH3:8][O:9][C:10](=[O:13])[CH2:11][SH:12].N1CCCCC1.C[O-].[Na+]>CO>[CH3:8][O:9][C:10]([CH:11]1[C:3](=[O:2])[CH:4]([CH3:6])[CH2:5][S:12]1)=[O:13]
Reactant: C=C(C)C(=O)OC
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C1SCC(C)C1=O

Procedure:
100 g (1 mole) of methacrylic acid methyl ester are added dropwise to 106 g of thioglycolic acid methyl ester and 1 ml of piperidine. The reaction mixture is added dropwise to a solution of 40 g of sodium methylate in 200 ml of methanol. The mixture is stirred for a further half an hour, poured onto water, acidified and extracted with methylene chloride and the organic phase is washed with water and dried with sodium sulfate. After distillation, 4-methyl-3-oxotetrahydro-2-thiophencarboxylic acid methyl ester is obtained (bp. 110° to 115°/14 Pascal).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:10])=[O:5])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:1]([O:3][C:4]([C@@H:6]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:15])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)O
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)N1CCOCC1

Procedure:
Similarly to the procedure described in example 6, condensation of N-[4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid with morpholine in the presence of dicyclohexylcarbodiimide yields N-[N'-(4-ethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl)-3-aminopropionyl]-morpholine as an oil; NMR (CDCl3) δ7.28 and 7.22 (s, 10H), 5.74 (t, 1H, J=7 Hz), 4.03 (q, 2H, J=8 Hz), 1.08 (t, 3H, J=8 Hz).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CN(C)C=O.[CH2:15]([Sn](CCCC)(CCCC)CCCC)[CH:16]=[CH2:17]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH:16]=[CH2:15]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(F)ccc1N
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A round-bottom flask was fitted with a condenser, stirbar and septa and flushed with nitrogen. 2-bromo-4-fluoro aniline (9.70 g, 40.9 mmol), N,N-dimethylformamide (100 mL), allyltributyltin (15.0 mL, 48.9 mmol) and Pd(PPh3)4 (1.50 g, 1.30 mmol) were added, giving a mixture that was warmed to 80° C. After 17 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (300 mL) and washed with 1:1 H2O:saturated aqueous NaCl solution (2×150 mL). The aqueous washes were combined and extracted with ethyl acetate (50 mL). The organic extracts were then combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil that was purified via flash chromatography on silica gel (0% to 35% ethyl acetate/hexanes linear gradient) to give the desired product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N>>[CH2:3]1[CH2:4][CH2:5][CH2:6][CH:1]([CH2:7][CH2:8][CH2:9][NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[CH2:2]1
Reactant: NCCCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: N
Product: O=S(=O)(NCCCC1CCCCC1)c1ccccc1

Procedure:
The title compound was prepared according to example 1063A (replacing phenethylamine with 3-phenylpropylarnine, and example 1063B, replacing p-toluenesulfonyl chloride with benzenesulfonyl chloride to afford a colorless oil. MS (DCI/NH3) m/e 299 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.C(Cl)Cl.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23]([N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[O:25])=[CH:21][C:20]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2ccc(N(C)C(=O)c3cc4c(s3)-c3ccc(Br)cc3OCC4)c(Cl)c2)CC1
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.180 g, 0.355 mmol) in tetrahydrofuran (6.00 mL, 74.0 mmol) and water (6.00 mL, 333 mmol) was added lithium hydroxide, monohydrate (0.0596 g, 1.42 mmol). The reaction mixture was stirred at room temp. overnight. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid. To a solution of 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (175 mg, 0.355 mmol;) in methylene chloride (5.1 mL, 79 mmol) was added 1-methyl-piperazine, (0.047 mL, 0.43 mmol), N,N-diisopropylethylamine (0.618 mL, 3.55 mmol) then O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.269 g, 0.710 mmol). The mixture was stirred at room temp. for 2 hr. LCMS indicated the reaction was complete. The reaction was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (5% MeOH/DCM) to give 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (yield 82%). MS: (ESI+) 576.4
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6]>O1CCCC1.O>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][C@H:16]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[C:17]([OH:19])=[O:18])=[O:13])=[CH:31][CH:32]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CCOc1ccc(C(=O)NC[C@@H](C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
2.1 ml (2.1 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N are added to a solution of 610 mg (1.4 mmol) of methyl (S)-3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoate in 12 ml of tetrahydrofuran and 2 ml of water. The reaction medium is stirred at ambient temperature for 18 h then the solvents are concentrated under vacuum. The mixture is brought to pH=6 by addition of 2.5 ml of an aqueous solution of hydrochloric acid having a concentration of 1N. The solid which precipitates is filtered, rinsed with water then with diethyl ether, and dried under vacuum. 420 mg (72%) of (S)-3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15].O.NN>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOc1cc([N+](=O)[O-])ccc1Br
Agent: NN
Solvent: O
Solvent: CO
Product: COCCOc1cc(N)ccc1Br
Temperature: 80 °C

Procedure:
An open 250 mL round bottom flask was charged with 1-bromo-2-(2-methoxyethoxy)-4-nitrobenzene (Method 10) (5 g, 18.11 mmol), 5 wt % FeCl3 on SiO2 (17.6 g, 5.43 mmol), activated carbon (10 g), and 100 mL MeOH. This resulting mixture was heated with stirring to 80° C. Hydrazine monohydrate (10.6 mL, 217 mmol) was then carefully added to the reaction mixture. After complete addition of the hydrazine monohydrate, the reaction mixture was stirred at 80° C. for an additional 40 min. The reaction was then allowed to cool to rt and filtered through a bed of Celite. The filter cake was washed with MeOH (˜150 mL) and EtOAc (˜150 mL). The resulting filtrate was conc in vacuo to give the title compound which was used without further purification (3.16 g, 71%) m/z: 247.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[CH:10]=[C:6]2[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH:3]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CN1C(=O)CCC1>CN(C=O)C>[CH:11]1([C:9]2[CH:10]=[C:6]3[N:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=4)[CH:3]=[C:2]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: OC1CCNCC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C4CC4)cc3n2)cc1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC(O)CC3)n3nc(C4CC4)cc3n2)cc1
Temperature: 25 °C

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2J, 100 mg, 0.27 mmol) and 4-hydroxypiperidine (55.0 mg, 0.54 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 15 minutes. After cooling to room temperature, DMF (1 ml) was added. The crude product mixture was filtered by syringe filter and purified by preparatory HPLC (20-40% ACN/water, TFA mode). Lyophilization of the collected fractions gave the titled compound product (30 mg, 26% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.78 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.34 (s, 1H), 6.02 (s, 1H), 5.18 (s, 1H), 4.84 (d, J=4.3 Hz, 1H), 4.12 (d, J=12.6 Hz, 2H), 3.79 (dd, J=4.2, 8.5 Hz, 1H), 3.41-3.36 (m, 1H), 2.11-2.00 (m, 1H), 1.91 (br. s., 2H), 1.65-1.51 (m, 2H), 1.45 (s, 6H), 1.04-0.94 (m, 2H), 0.88-0.75 (m, 2H); ESI-MS: m/z 436.3 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([C:20]#[N:21])=[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:12]=2)[CH:7]=[CH:6]1.[BH4-].[Na+]>C1COCC1>[CH3:4][N:5]1[C:13]2[C:8](=[N:9][C:10]([CH:20]([NH2:21])[CH3:1])=[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[CH:12]=2)[CH:7]=[CH:6]1
Reactant: C[Mg]Br
Reactant: Cn1ccc2nc(C#N)c(N3CCOCC3)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Methylmagnesium bromide (3.0 M in THF, 0.60 mL, 1.8 mmol) was added to a stirred solution of 1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridine-5-carbonitrile (145 mg, 0.60 mmol) in dry THF (6 mL) at RT. The reaction mixture was stirred for 1 h, then cooled to 0° C. and quenched with MeOH (5 mL). Sodium borohydride (45 mg, 1.2 mmol) was added. The reaction mixture was stirred for 20 minutes, quenched with 1N HCl (1.5 mL), and stirred for an additional 20 minutes. Next, the solution was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (6×). The organic layers were combined, dried over MgSO4, and concentrated to give the title compound as a yellow oil (83%). 1H NMR (500 MHz, CD3OD) δ ppm 7.83 (s, 1H), 7.46 (d, 1H, J=3.5 Hz), 6.56 (d, 1H, J=3.5 Hz), 4.97 (q, 1H, J=7.0 Hz), 3.83-3.90 (m, 4H), 3.84 (s, 3H), 3.01-3.07 (m, 2H), 2.88-2.94 (m, 2H), 1.54 (d, 3H, J=7.0 Hz); ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261; found 261.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10]1>CS(C)=O>[O:9]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]4=[O:33])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:4]1
Reactant: CC(=O)NC[C@@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CCO4)CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A mixture of 60% sodium hydride (6.0 mmol), trimethyloxo sulfonium iodide (6.1 mmol) was stirred for 30 minutes and (R)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (4.80 mmol) in DMSO (20 ml) was stirred for 75 hour at the room temperature. The reaction mixture was poured on ice water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuum to provide crude compound. The crude compound was purified over silica gel column to provide title compound in 20% yield.
Reaction SMILES: [C:1]([O:4][CH:5]1[C@@H:9]2[CH:10]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:12])[N:8]2[CH:7]([C:24]([O:26]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:25])[CH:6]1[CH3:40])(=[O:3])[CH3:2].C(Cl)(Cl)Cl>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C@@H:9]2[CH:10]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:12])[N:8]2[CH:7]([C:24]([OH:26])=[O:25])[CH:6]1[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1C(C)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1C(C)C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@@H]12
Reaction time: 1 h

Procedure:
Benzhydryl 1-acetoxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylate (18 mg.) was dissolved in 3 ml. of ethyl acetate. Hydrogenation catalyst (18 mg. of 10% palladium on carbon) was added and the mixture hydrogenated at atmospheric pressure and room temperature for 1 hour. When tlc (4:1 chloroform:ethyl acetate) indicated no change, a second aliquot of catalyst (18 mg.) was added. According to tlc assay, some conversion occurred during the next hour, at which time a third aliquot of catalyst (18 mg.) was added. At the end of another hour of hydrogenation, tlc assay indicated reduction to be complete. Catalyst was recovered by filtration with ethyl acetate wash. The combined filtrate and washes were evaporated to dryness in vacuo to yield 1-acetoxy-2-methyl-6-(2-phenoxyacetamido)carbapenam-3-carboxylic acid [Rf 0.77 (18:1 acetone:water); ir (CH2Cl2) 1775, 1725, 1675 cm-1 ].
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19](F)[CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[C:21]([CH:22]=1)[O:1][CH:2]([CH2:14][CH3:15])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluoronitrobenzene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1.C(N(C(C)C)[CH:28]([CH3:30])[CH3:29])C.C(Br)C=C>CN(C)C=O>[CH2:30]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[O:5][N:4]=1)[CH:28]=[CH2:29]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1Cc2c(-c3nc(CN)no3)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCNCc1noc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 6 %

Procedure:
5.17 g (15 mmol) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 45 ml of N,N-dimethylformamide, 6.5 ml (37.5 mmol) of N-ethyldiisopropylamine and 3.63 g (30 mmol) of allyl bromide were stirred at room temperature for 1 hour. The reaction solution was evaporated and the residue was chromatographed on 250 g of silica gel while eluting with ethyl acetate. The uniform fractions having the smaller Rf value were evaporated. There was obtained 0.344 g (6%) of 3-(3-allylaminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a]-[1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 171°-174°.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[NH:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([NH2:29])=[O:28]>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:25]5[CH2:32][CH2:31][CH2:30][C@H:26]5[C:27]([NH2:29])=[O:28])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:2])[CH3:3]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4CCC[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 67 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and L-prolinamide, were reacted and the crude product recrystallised from IMS to give 369 as a white solid (130 mg, 67%). LCMS: RT=2.48 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d6) δ: 9.06 (1H, s), 7.80 (1H, s), 7.35 (1H, br), 6.94 (1H, br), 5.96 (1H, s), 5.90-5.88 (1H, m), 4.50 (4H, d, J=17.28 Hz), 4.32 (1H, m), 3.61 (1H, m), 3.45 (1H, m)), 2.26 (2H, s), 2.24-2.15 (1H, m), 1.98-1.97 (3H, m), 1.47 (6H, dd, J=6.59, 3.27 Hz)