Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH:11]1([S:16]([CH2:19][C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=3)[N:21]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH:11]1([S:16]([CH2:19][C:20]2[CH:25]=[C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[CH3:32])[N:23]=[C:22]([C:33]3[CH:39]=[CH:38][C:36]([NH:37][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:35][CH:34]=3)[N:21]=2)(=[O:17])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCC2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)C2CCCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
Phenyl chloroformate (0.759 mL, 6.05 mmol) was added to 4-[4-(cyclopentylsulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.68 g, 4.03 mmol) and sodium hydrogen carbonate (0.508 g, 6.05 mmol) in dioxane (20 mL) at 5° C. under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and washed with water (125 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product which was triturated with a mixture of diethyl ether and isohexane to give the desired material as a white solid (2.10 g).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:1]([O:4][C@H:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([F:24])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](Cc1ccccc1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H](Cc1ccccc1)C(=O)F
Reaction time: 1 h
Yield: 88.1 %

Procedure:
(R)-2-acetoxy-3-phenylpropanoic acid 11.1.C (1170 mg, 5619 μmol) was azeotroped and dissolved in DCM under nitrogen. Pyridine (454 μl, 5619 μmol) was added followed by cyanuric fluoride (1423 μl, 16858 μmol) at −20° C. After 1 h, reaction was worked up with ice and DCM to afford 1.04 g (88%) crude (R)-1-fluoro-1-oxo-3-phenylpropan-2-yl acetate 11.1.D. The crude was directly used for next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)C(=C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1)c1cc(F)cc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C#N)c2)C1
Temperature: -2.5 °C

Procedure:
To a solution of 27.15 g (51.64 mmol) of methyl (3-bromo-5-fluorophenyl){1-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-ylidene}acetate in 120 mL of THF and 220 mL of MeOH, were added small portions of sodium borohydride (total: 740 mg, 31.05 mmol) at −5-0° C. The mixture stirred at −5-0° C. and the reaction was followed by HPLC. Then the reaction was quenched with 2N HCl at 0° C. (to pH=7-7.5) and concentrated to remove the organic solvents. The residue was dissolved in 300 mL of CH2Cl2 and 300 mL water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL×2). The combined organic layer was dried over Na2SO4 and concentrated. The residue was separated by silica gel chromatography with cyclohexane/ethyl acetate to afford the methyl (2S)-(3-bromo-5-fluorophenyl){1-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl}acetate; 1H-NMR(CDCl3) δ 2.66(t, 1H, J=6.2 Hz), 2.92(dd, 1H, J1=7.5 Hz, J2=5.7 Hz), 3.08-3.16(m, 2H), 3.41(t, 1H, J=7.2 Hz), 3.69(s, 3H), 3.83(d, 1H, J=10.7 Hz), 4.34(s, 1H), 6.96 (d, 1H, J=8.9 Hz), 7.17(d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=12 Hz), 7.27-7.32 (m, 5H), 7.39 (t, 1H, J=7.6 Hz), 7.50 (d, 1H, J=7.5 Hz), 7.60 (d, 1H, J=7.5 Hz), 7.70 (s, 1H); Mass Spectrum: m/e=527(M+1, 35Cl79Br), 529 (M+1, 37Cl79Br/35Cl81Br), 531 (M+1, 37Cl81Br).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].O=S(Cl)[Cl:26]>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([Cl:26])=[O:23])=[CH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1cc(Oc2ccc3c(C(=O)O)cccc3c2)ccn1
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(Oc2ccc3c(C(=O)Cl)cccc3c2)ccn1
Temperature: 110 °C

Procedure:
A mixture of 6-(2-carbamoylpyridin-4-yloxy)-1-napthoic acid (Step a, 1.0 g, 3.2 mmol) and SOCl2 (600 μL, 8.1 mmol) in toluene (25 mL, Aldrich) was heated at 110° C. for 7 h. The solution was concentrated under reduced pressure and azeotroped from toluene (3×10 mL) to provide the title compounds as a yellow solid. MS (ESI, pos. ion) m/z: 327.5 (M+1). Mass Calc'd for C17H11ClN2O3: 326.73.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][N:48]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:49]3=[O:58])[C:38]2=[O:59])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][N:48]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:49]3=[O:58])[C:38]2=[O:59])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: O=C1c2ccccc2C(=O)N1CCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, making variation to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 2-{2-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione, the title compound was obtained (56%): 1H NMR (300 MHz, CD3OD) δ 9.97 (s, 1H), 8.72-8.62 (m, 4H), 8.07-7.67 (m, 5H), 7.01 (s, 1H), 6.71 (s, 1H), 6.70 (s, 1H), 5.79 (t, 1H), 4.88-4.50 (m, 6H); MS (ES+) m/z 455 (M−17), 473 (M+1), 495 (M+23).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]([OH:12])[CH2:10][CH2:9][C:4]2(OCC[O:5]2)[CH2:3]1.Cl.C(OCC)(=O)C>CO>[OH:12][CH:11]1[CH2:10][CH2:9][C:4](=[O:5])[CH2:3][C:2]1([CH3:13])[CH3:1]
Reactant: CC1(C)CC2(CCC1O)OCCO2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(=O)CCC1O
Yield: 88 %

Procedure:
A solution of 7,7-dimethyl-1,4-dioxaspiro[4.5]decan-8-ol (1.0 equiv.) in 2.0 N hydrochloric acid aqueous solution (3.7 equiv.) and MeOH (0.9 M) was stirred at room temperature overnight. TLC (petroleum ether:ethyl acetate=3:1) showed that the reaction was completed. The solvent was removed under reduced pressure, the resulting residue was basified with saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give 4-hydroxy-3,3-dimethylcyclohexanone (88% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm) 3.69-3.71 (m, 1H), 2.42-2.45 (m, 2H), 2.09-2.25 (m, 1H), 2.04-2.08 (m, 4H), 1.91-1.95 (m, 1H), 0.98 (s, 6H)
Reaction SMILES: Br.[CH3:2][S:3]([C:6]1[CH:7]=[C:8]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][N:34]=[C:35]=[O:36])[CH3:29]>C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:37])[CH2:32][CH2:33][NH:34][C:35]([NH:17][C:15]1[S:16][C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH:7]=2)=[C:13]([CH3:18])[N:14]=1)=[O:36])[CH3:29]
Reactant: CCOC(=O)CCN=C=O
Reactant: Cc1nc(N)sc1-c1cccc(S(C)(=O)=O)c1
Agent: Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2cccc(S(C)(=O)=O)c2)s1
Temperature: 60 °C

Procedure:
A stirred suspension of 5-(3-methanesulphonyl-phenyl)-4-methyl-thiazol-2-ylamine hydrobromide (176d) (0.172 g, 0.64 mmol) in DCM (15 ml) is treated with Hunigs base (0.45 ml, 2.36 mmol) followed by ethyl-3-isocyanatopropionate (0.092 g, 0.64 mmol). The reaction mixture is stirred and heated to 60° C. for 10 hours and then the solvent in removed in vacuo. The product is purified by chromatography on silica to give the titled compound
Reaction SMILES: [CH3:1][O:2][C:3](=[O:52])[C@H:4]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH:5][C:6](=[O:47])[C@@H:7]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[NH:8][C:9](=[O:36])[C@H:10]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:27])[C@H:13]([CH2:25][OH:26])[NH:14]C(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:52])[C@H:4]([CH2:48][CH:49]([CH3:50])[CH3:51])[NH:5][C:6](=[O:47])[C@@H:7]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[NH:8][C:9](=[O:36])[C@H:10]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:27])[C@H:13]([CH2:25][OH:26])[NH2:14]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
Nα -Benzyloxycarbonyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucine methyl ester, 9.0 g., is dissolved in 850 ml. of boiling methanol. The solution is shaken with hydrogen and 1200 mg. of 20% palladium-on-carbon at room temperature and atmospheric pressure. The reaction is complete in thirty to forty minutes as shown by thin layer chromatography. The reaction mixture is filtered, the solvent evaporated from the filtrate and the residue dried under reduced pressure, 7.1 g., and is used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[C:11](N1C=CN=C1)(N1C=CN=C1)=[O:12]>C1COCC1>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[O:10][C:11](=[O:12])[NH:1][C:2]=2[CH:7]=1
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(C)c2oc(=O)[nH]c2c1

Procedure:
A mixture of 2-amino-4,6-dimethylphenol (412 mg, 3.00 mmol) and 1,1′-carbonyldiimidazole (730 mg, 4.50 mmol) in THF (15 mL) was heated at reflux for 3 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with 1.0 N aqueous HCl (2×), then brine, then the EtOAc was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=164 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10].[CH3:17]I>CN(C)C=O>[CH3:3][C:4]1[N:5]=[CH:6][S:7][C:8]=1[CH:9]([O:10][CH3:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ncsc1C(O)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(c1ccccc1)c1scnc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (80% dispersion in mineral oil, 80 mg) was added to a stirred solution of 1-(4-methyl-5-thiazolyl)-1-phenyl-methanol (500 mg) in dry N,N-dimethylformamide (10 ml) at 0° C. After 10 minutes, methyl iodide (0.15 ml) was added. The mixture was allowed to warm to room temperature and after a further 30 minutes the mixture was evaporated to dryness. The residue was purified by flash chromatography to give the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=O)=[CH:2]1.[N:21]1(OC(N(C)C)=[N+](C)C)[C:25]2C=C[CH:28]=[CH:29][C:24]=2N=N1.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(N)CCC>>[CH2:25]([NH:21][C:12](=[O:14])[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)[CH2:24][CH2:29][CH3:28]
Reactant: O=C(O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: On1nnc2ccccc21
Solvent: CCCCN
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNC(=O)C(=Cc1c[nH]c2ncccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenyl-2-propenoic acid (100 mg, 0.3784 mmol.) in 2 ml of DMFd were added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoborate (121.5 mg, 0.3784 mmol.), N-hydroxybenzotriazole (51.1 mg, 0.3784 mmol) and N,N-diisopropylethylamine (129.2 μl, 0.7568 mmol). After stirring at room temperature for 30 min., 34.5 μl (0.3784 mmol.) of n-butylamine were added and the obtained solution was stirred at room temperature, for 24 hours. The resulting mixture was concentrated by evaporation of the solvent in vacuo, the residue was diluted with dichloromethane washed with 1 N NaOH, 1 N HCl, brine, dried over sodium sulphate and evaporated. The residual solid was triturated with Et2O to afford 49 mg of the title compound as a white solid (yield 41%) m.p. 177-179° C. (dec.)
Reaction SMILES: [H-].[Na+].[NH:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>C1COCC1>[CH3:16][C:15]([O:14][C:12]([N:3]([CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)[NH:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
NaH (362 mg, 9.04 mmol) was added to a stirred solution of Di-Tert-Butyl Hydrazodicarboxylate (2 g, 8.61 mmol) in anhydrous THF (50 ml). The reaction was stiffed at ambient temperature for 10 minutes then treated with a solution of Methy 4-(Bromomethyl)Benzoate (1.98 g, 8.61 mmol) in anhydrous THF (20 ml). The reaction was stirred at ambient temperature for 4 hours. The reaction was partitioned between ether (˜100 ml) and water (˜100 ml). The layers were separated and the aqueous layer was re-extracted with ether (˜50 ml). The ether layers were combined, washed with brine (˜50 ml), dried (MgSO4), filtered and evaporated to yield the title compound (3.3 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:20]=[C:21]([CH:26]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:28]=3)[C:22](OC)=[O:23])=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:18][C:19]3[CH:28]=[C:27]([C:29]([NH:31][CH3:32])=[O:30])[CH:26]=[C:21]([CH2:22][OH:23])[CH:20]=3)=[O:17])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc(CO)cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3-[({1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}carbonyl)amino]-5-[(methylamino)carbonyl]benzoate (intermediate 31) (0.206 g, 0.43 mmol) in THF (5 mL), was added a 1M solution of LiAlH4 in THF (0.65 mL, 1.5 eq.). The reaction was stirred at RT for one night. Water was added and the compound was extracted with AcOEt, dried over sodium sulfate and concentrated in vacuo. After trituration from hot methanol, filtration and dry, the title compound was obtained as a white solid (0.03 g, 15.8%). HRMS calculated for C20H19Cl2N5O3 (M+H)+448.0943, found: 448.0910, Rt: 2.66 min. MP: 223-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH2:15][C:16]#[N:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([N+:18]([O-])=O)[CH:3]=1>C(O)(=O)C.[Fe]>[NH2:17][C:16]1[CH2:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N:18]=1
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1[N+](=O)[O-])CC#N
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Temperature: 90 °C
Yield: 58 %

Procedure:
To a solution of (E)-ethyl 3-(4-bromo-2-nitrophenyl)-2-(cyanomethyl)acrylate (1.00 g, 2.9 mmol) in acetic acid (25 mL) was added iron powder (1.10 g, 19.0 mmol). The mixture was heated to 90° C. for 5 hours. Upon cooling the acetic acid was removed under vacuum and the resulting semisolid was dissolved in 50% K2CO3 (100 mL) and EtOAc (100 mL). The mixture was filtered to remove insoluble material and the phases were separated. The aqueous phase was extracted with EtOAc (2×100 mL). The combined organics were dried and concentrated. The concentrate was purified via flash chromatography (Biotage 40m, 5% MeOH/CH2Cl2) to yield (1E,4E)-ethyl 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate (0.52 g, 57%).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29]C(C)=CC=O.Cl.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[CH3:28][C:23]([CH3:24])=[CH:22][CH2:21][N:7]([C@H:1]1[CH2:2][CH2:3][C@H:4]([CH3:29])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1
Reactant: CC(C)=CC=O
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)=CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 4-trans-methyl-cyclohexylamine hydrochloride, 3-methyl-but-2-enal and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]1[C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][N:13]=[CH:12]1)([CH3:3])=[CH2:2].Cl>[OH-].[Na+]>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[CH:12]1)([CH3:3])=[CH2:2]
Reactant: C=C(C)c1cccc(C)c1-n1cncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)c1cccc(C)c1-n1cncc1C(=O)O
Yield: 71.5 %

Procedure:
8.0 g (0.03 mol) of ethyl 1-(2-isopropenyl-6-methylphenyl)imidazole-5-carboxylate (see Example 128) are heated for 2 hours at 80° C. with 100 ml of 2N sodium hydroxide solution. The mixture is cooled and acidified to pH 3 with concentrated hydrochloric acid, and the precipitate is filtered off under suction. 5.2 g (72% of theory) of 1(2-isopropenyl-6-methylphenyl)imidazole-5-carboxylic acid, a colorless solid of melting point 204° C. (decomposition), are obtained.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21](O)=[O:22])=[N:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29])[CH3:25]>>[Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][CH2:20][C:21]([NH:29][C@@H:28]([CH3:30])[C:27]([O:26][CH2:24][CH3:25])=[O:31])=[O:22])=[N:4][CH:3]=1
Reactant: N#Cc1ccc(-n2c(Br)cnc2SCC(=O)O)c2ccccc12
Reactant: CCOC(=O)[C@H](C)N
Product: CCOC(=O)[C@H](C)NC(=O)CSc1ncc(Br)n1-c1ccc(C#N)c2ccccc12

Procedure:
(2S)-ethyl 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetamido)propanoate was prepared by coupling 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-acetic acid with alanine ethyl ester according to the procedure described in example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C@:20]2([CH2:31][F:32])[CH2:25][C@@H:24]([C:26]([F:29])([F:28])[F:27])[O:23][C:22]([NH2:30])=[N:21]2)[C:16]([F:19])=[N:17][CH:18]=1>>[NH2:30][C:22]1[O:23][C@H:24]([C:26]([F:27])([F:29])[F:28])[CH2:25][C@:20]([C:15]2[CH:14]=[C:13]([NH:12][C:9](=[O:11])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)[CH:18]=[N:17][C:16]=2[F:19])([CH2:31][F:32])[N:21]=1
Reactant: COc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Product: COc1ccc(C(=O)Nc2cnc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc1

Procedure:
The title compound was synthesized using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-methoxy-picolinic acid and (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (as described in Example 138, method S). MS m/z=446.0 [M+H]+. Calculated for C18H16F5N5O3: 445.3
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60]([N:62]2[CH2:67][CH2:66][CH:65]([N:68](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C:69]([NH2:71])=[NH:70])[CH2:64][CH2:63]2)=[O:61])[CH2:43]1>>[NH:68]([CH:65]1[CH2:66][CH2:67][N:62]([C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:61])[CH2:63][CH2:64]1)[C:69]([NH2:71])=[NH:70]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: N=C(N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCC(NC(=N)N)CC4)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl -1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonylguanidino)piperidin-1-ylcarbonyl]pyrrolidine (prepared as described in Preparation 5) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][CH2:14][OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][CH:14]([Cl:18])[OH:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: OCCC1CCCN1CC1=CCCCC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: OC(Cl)CC1CCCN1CC1=CCCCC1

Procedure:
17.8 g of 2-[1-(1-cyclohexenylmethyl) 2-pyrrolidinyl]ethanol (0.085 mole) and 50 ml of chloroform are introduced into a 250 ml balloon flask provided with a stirrer, a thermometer, a condenser and a dropping funnel, then 15.3 ml of thionyl chloride is dropped in, the temperature being kept at about 25°-25° C. by cooling.
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[C:16]([CH:20]1[CH2:24][CH:23](OC)O[CH:21]1OC)(=[O:19])[CH2:17][CH3:18]>>[C:16]([C:20]1[CH:24]=[CH:23][N:2]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:12]=2[Cl:13])[NH:9][C:8](=[O:14])[C:7](=[O:15])[NH:6]3)[CH:21]=1)(=[O:19])[CH2:17][CH3:18]
Reactant: [NH3+]c1cc2[nH]c(=O)c(=O)[nH]c2cc1Cl
Reactant: CCC(=O)C1CC(OC)OC1OC
Agent: [Cl-]
Product: CCC(=O)c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2Cl)c1

Procedure:
14.2 mmol of 6-ammonio-7-chloro-2,3(1H,4H)-quinoxalinedione chloride were reacted with 14.2 mmol of 3-propionyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.