Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>COCCOC.O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8]
Reactant: Clc1ccccc1Br
Reactant: COc1cccc(Cl)c1B(O)O
Solvent: COCCOC
Solvent: O
Product: COc1cccc(Cl)c1-c1ccccc1Cl
Yield: 73.7 %

Procedure:
Treatment of 2-bromochlorobenzene (15.5 g, 80.6 mmol) with 2-chloro-6-methoxybenzene boronic acid (5.0 g, 26.8 mmol) in DME-water (5:1, 250 mL) according to the procedure described for Example 69, Step 1 provided 5.0 g (74%) of 2.2′-dichloro-6-methoxybiphenyl as a colorless oil.
Reaction SMILES: C(O)C=C.CC(C)([O-])C.[K+].[C:11]([S:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])=[CH:18][CH:17]=1)(=O)[CH3:12].C([O:31][CH:32]1[NH:35]C(=O)C1)(=O)C>O1CCCC1>[CH2:23]([O:22][C:20]([C:19]1[CH:26]=[CH:27][C:16]([CH2:15][S:14][CH:11]2[NH:35][C:32](=[O:31])[CH2:12]2)=[CH:17][CH:18]=1)=[O:21])[CH:24]=[CH2:25]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: C=CCOC(=O)c1ccc(CSC(C)=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: C=CCO
Product: C=CCOC(=O)c1ccc(CSC2CC(=O)N2)cc1
Reaction time: 1 h
Yield: 82 %

Procedure:
Allyl alcohol (27 ml) in dry tetrahydrofuran (50 ml) was added dropwise to a solution of potassium tert-butoxide (4.93 g, 0.044 moles) in dry tetrahydrofuran (100 ml). After stirring for 5 minutes a solution of allyl 4-(acetylthiomethyl)benzoate (10.1 g, 0.04 moles) in dry tetrahydrofuran (100 ml) was added dropwise. After stirring for 15 minutes a solution of 4-acetoxyazetidin-2-one (5.16 g, 0.04 moles) was added dropwise. The mixture was stirred for 1 hour and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous was extracted with ethyl acetate. The combined extracts were washed with brine, dried and evaporated. Flash chromatography (silica gel, ethyl acetate-petrol) gave 4-(4-Allyloxycarbonylbenzylthio)azetidin-2-one as an oil (9.1 g, 82% yield. 1H NMR δ (CDCl3) 2.84 (1H, dd, H3a), 4.31 (1H, dd, H3b), 3.88 (2H, s, S--CH2), 4.68 (1H, dd, H4), 4.78 (2H, m, CH2O), 5.35 (2H, m, CH2CH--), 6.05 (1H, m, CHCH2), 6.07 (1H, br. singlet, N--H), 7.40 (2H, d, Ph-H), 8.03 (2H, d, Ph-H).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39](Cl)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26]
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(Cl)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 60 °C
Yield: 50.7 %

Procedure:
1.25 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.20 g of N-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycine ethyl ester were dissolved in 20 ml of N,N-dimethylformamide; 1.33 ml of N-ethyldiisopropylamine was added, followed by stirring under heating at an external temperature of 60° C. for 7.5 hours. After cooling, cold aqueous sodium bicarbonate was added; the reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the precipitated crystal was recrystallized from ethanol-ethyl acetate fir (1:3), collected by filtration, and dried, to yield 1.17 g of the title compound.
Reaction SMILES: [CH3:1][S:2]([Cl:5])(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:25](=[O:44])[NH:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH3:43])[CH2:32][CH2:31]2)[C:10]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]([CH3:22])[C:12](=[O:23])[C:11]=2[CH:24]=1.C(N(CC)CC)C.O>CN(C)C=O>[ClH:5].[CH3:43][O:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][NH:26][C:25]([C:9]2[C:10]3[O:15][C:14]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[C:13]([CH3:22])[C:12](=[O:23])[C:11]=3[CH:24]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=2)=[O:44])[CH2:31][CH2:32]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1N1CCN(CCCNC(=O)c2cc(N)cc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCCNC(=O)c2cc(NS(C)(=O)=O)cc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Product: Cl
Temperature: -20 °C
Reaction time: 3.5 h

Procedure:
0.032 ml of methanesulfonyl chloride in 1 ml of dimethylformamide was added dropwise in 10 minutes to a solution of 0.21 g of compound of Example 94 and 0.062 ml of triethylamine in 4 ml of dimethylformamide, stirred at -20° C. Stirring was continued at the same temperature for 3.5 hours. After this period, the reaction mixture was poured into water and the suspension was filtered by suction, yielding 0.1 g of the title compound which was recrystallized from 80% ethanol (m.p. 272°-275° C.).
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[C:8]([N:11]2[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]2)[CH:7]([CH2:17][O:18][CH2:19][CH2:20][N:21]=[N+:22]=[N-:23])[C:6]2(C(OCCC#N)=O)[O:24][CH2:25][O:26][C:5]=12)(=[O:3])[CH3:2].[OH-:34].[Na+].[O:36]1[CH2:41]COCC1>>[C:1]([C:4]1[C:5]2[O:26][CH2:25][O:24][C:6]=2[C:7]([CH2:17][O:18][CH2:19][CH2:20][N:21]=[N+:22]=[N-:23])=[C:8]([N:11]2[CH:12]=[CH:13][CH2:14][C:15]([C:41]([OH:36])=[O:34])=[CH:16]2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C2OCOC2(C(=O)OCCC#N)C(COCCN=[N+]=[N-])C(N2C=CCC=C2)=C1C
Reactant: C1COCCO1
Reactant: [OH-]
Agent: [Na+]
Product: CC(=O)c1c(C)c(N2C=CCC(C(=O)O)=C2)c(COCCN=[N+]=[N-])c2c1OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
This product was obtained from deprotection of two batches of 5-acetyl-2-((2-azidoethyl)oxy)methyl-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-6-methyl-4-(3,4-methylenedioxy)phenylpyridine obtained from the previous experiment (340 mg and 200 mg) and were combined after completion of the reaction. A mixture of 5-acetyl-2-((2-azidoethyl)oxy)methyl-3-(2-cyanoethoxy)carbonyl-1,4-dihydro-6-methyl-4-(3,4-methylenedioxy)phenylpyridine (340 mg, 0.750 mmol; 200 mg (60%), 0.200 mmol), 1N NaOH (1.12 mL; 0.40 mL) in a mixture of dioxane (3 mL; 3 mL) were stirred at room temperature for 1.5 hours. The two batches were concentrated in vacuo, the combined batches were dissolved in 40 mL of water, washed with dichloromethane (30 mL) and EtOAc (20 mL), acidified with 1N HCl solution (pH=4-5), and extracted with dichloromethane (2×50 mL). The combined dichloromethane extracts were washed with brine (40 mL), dried (MgSO4), and the solvent was removed in vacuo to give 300 mg (25%) of the title compound as a yellow paste which solidified on standing: mp 120° C. (decomp.). The product was used in the next step after spectral characterization.
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][NH:5][C:6]([NH:35][C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:43])=[N:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH:22]3[CH2:27][O:26][CH2:25][CH2:24][N:23]3CC3C=CC=CC=3)=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1.FC(F)(F)C(O)=O.C(O)C.[H][H]>[Pd].C(Cl)Cl>[CH3:44][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([NH:35][C:36]1[C:37]([CH3:43])=[CH:38][CH:39]=[CH:40][C:41]=1[CH3:42])=[N:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH:22]3[CH2:27][O:26][CH2:25][CH2:24][NH:23]3)=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: [H][H]
Reactant: COc1cc2c(N=C(NCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc2c(N=C(NCCN(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1COCCN1
Yield: 81.3 %

Procedure:
A mixture of N-(2-dimethylaminoethyl)-N′-(2,6-dimethylphenyl)-N″-[7-(N-benzylmorpholin-3-ylmethoxy)-6-methoxyquinazolin-4-yl]guanidine (0.1 g), trifluoroacetic acid (0.091 ml), 10% palladium on carbon catalyst (0.03 g) and ethanol (12 ml) was stirred under an atmosphere pressure of hydrogen for 18 hours. The reaction was filtered and the filtrate was evaporated. The resulting gum was triturated under diethyl ether to give a solid which was dissolved in methylene chloride. The solution was washed with cooled 1N aqueous sodium hydroxide solution and with water. The organic solution was dried over magnesium sulphate and evaporated. There was thus obtained the title compound (0.069 g): NMR Spectrum: (CDCl3) 2.1 (s, 6H), 2.26 (s, 6H), 2.39 (m, 2H), 2.9 (m, 2H), 3.36 (m, 2H), 3.55 (m, 3H), 3.78 (d, 2H), 3.80–4.08 (m, 5H), 4.79 (s, 1H), 7.1 (s, 4H), 7.85 (s, 1H), 8.47 (s, 1H), 12.5 (s, 1H); Mass Spectrum: M+H+ 508.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[N:17][OH:18])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[N:17][O:18][CH2:25][CH3:26])[C:14]=2[C:15]=1[OH:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(c1O)C(=NO)CCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCON=C1CCCc2ncc(C(=O)OCC)c(O)c21
Temperature: 95 °C
Yield: 72.5 %

Procedure:
4-Hydroxy-5-hydroxyimino-5,6,7,8-tetrahydroquinoline-3-carboxylic acid ethyl ester (3.75 g) was suspended in 100 ml of dimethylformamide and then dissolved therein by stirring the suspension on an oil bath at 95° C. Thereafter, 1.04 g of potassium carbonate and then 2.32 g of ethyl iodide were added thereto. The resulting reaction mixture was stirred for 4 hours. After the dimethylformamide was distilled off under reduced pressure, water and ethyl acetate were added to the residue. The organic layer was separated and then stripped of solvent to obtain a yield of 3.0 g of the desired compound. This compound melted at 89°-91° C. (uncorrected values). Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3440, 3000, 2960, 1740, 1640, 1465, 1220, 1190, 1110, 1060, and 990 cm-1, and its n.m.r. spectrum (CDCl3, 60Mc, TMS) had signals at δ values of 1.38 (3H, t, J=6.75 Hz), 1.42 (3H, t, J=7.5 HZ), 1.7-2.2 (2H, m), 2.7-3.15 (4H , m), 4.25 (2H, q. J=6.75 Hz), 4.40 (2H, q, J=7.5 Hz), and 8.77 (1H, s).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.C([O:23][C:24](=[O:42])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34]CC2C=CC=CC=2)=[CH:30][CH:29]=1)[NH2:26])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH:1]1([C:7]([NH:26][C@H:25]([C:24]([OH:42])=[O:23])[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Cyclohexanoyl chloride (7 mL, 47 mmole) was added dropwise to a stirred solution of dry pyridine (400 mL) and O-benzyltyrosine benzyl ester (25 g, 46.8 mmole). The reaction temperature was maintained at 0° C. throughout the addition. The reaction mixture was stirred for an additional 2 hours after the addition was complete. The reaction mixture was concentrated to dryness in vacuo to provide a solid material. The solid was washed with aqueous hydrochloric acid (1N, 4×400 mL). The residue was dissolved in ethyl acetate (300 mL), washed with aqueous hydrochloric acid (1N, 2×500 mL), aqueous sodium bicarbonate (2×300 mL), and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, provided an oil which was dissolved in methanol/tetrahydrofuran (400 mL/70 mL) and was hydrogenated at atmospheric pressure and room temperature over 10% palladium on carbon (600 mg). The reaction mixture was filtered through Celite and concentrated in vacuo to provide a solid which was recrystallized from ethyl acetate/hexane. The crystals were collected to-provide the N-cyclohexanoyl-(L)-tyrosine (8.7 g, 64%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[O:8]C.[NH:14]1[CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C.C(Cl)CCl>CN(C=O)C>[N:14]1([C:11](=[O:13])[CH2:10][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([F:1])[CH:3]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: C1CNC1
Reactant: COc1ccc(CC(=O)O)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cc1ccc(O)c(F)c1)N1CCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3-fluoro-4-methoxyphenyl)acetic acid (0.94 g, 5.52 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.379 g, 6.63 mmol) and N,N-diisopropylethylamine (2.89 ml, 16.6 mmol), and EDC (1.59 g, 8.29 mmol) was added into the solution and stirred at RT for 4 hrs. The residue was purified by reverse-phase HPLC (SunFire Prep C18 OBD 5 um 19×100 mm column; 10-100% acetonitrile in 0.1% formic acid in water gradient), to give the title compound. LC/MS (m/z) 210.2 (M+15)+.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=C(CC(N)=O)C=CC=1OC.[C:24]1([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([CH2:34][CH:35]=O)[CH2:31][CH:32]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)(CC=O)CC=O>>[C:1]([N:9]1[CH:32]=[CH:31][C:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:35]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCC(CC=O)(c1ccccc1)c1ccccc1
Reactant: NC(=O)c1ccccc1
Agent: CC(C)(CC=O)CC=O
Agent: COc1ccc(CC(N)=O)cc1OC
Product: O=C(c1ccccc1)N1C=CC(c2ccccc2)(c2ccccc2)C=C1

Procedure:
The title compound was prepared using the method of Example 2b after substituting equivalent quantities of benzamide for (3,4-dimethoxyphenyl)acetamide and 3,3-diphenylglutaraldehyde (the compound of Example 4a) for 3,3-dimethylglutaraldehyde as starting materials. The crude product was purified by silica gel flash chromatography eluting with a 7% ethyl acetate/hexane solution. The eluate was evaporated in vacuo to yield a clear oil which, after triturating with methanol, gave the title compound as a white solid, mp 91°-93° C.
Reaction SMILES: P(Cl)(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:27][C@@H:28]([C@H:30]1[C:51](=[O:52])[N:32]2[CH:33]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[C:34](=O)[C@H:35]([CH3:36])[C@H:31]12)[CH3:29].FC(F)(F)S(O)(=O)=O.[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:72][CH2:71][N:70]([C:73]([C@@H:75]2[CH2:79][C@H:78]([SH:80])[CH2:77][N:76]2[C:81]([O:83][CH2:84][C:85]2[CH:90]=[CH:89][C:88]([N+:91]([O-:93])=[O:92])=[CH:87][CH:86]=2)=[O:82])=[O:74])[CH2:69][CH2:68]1)(=[O:63])[NH2:62]>C(#N)C>[C:61]([O:64][CH2:65][CH2:66][N:67]1[CH2:68][CH2:69][N:70]([C:73]([C@@H:75]2[CH2:79][C@H:78]([S:80][C:34]3[C@H:35]([CH3:36])[C@@H:31]4[C@@H:30]([C@H:28]([OH:27])[CH3:29])[C:51](=[O:52])[N:32]4[C:33]=3[C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[CH2:77][N:76]2[C:81]([O:83][CH2:84][C:85]2[CH:86]=[CH:87][C:88]([N+:91]([O-:93])=[O:92])=[CH:89][CH:90]=2)=[O:82])=[O:74])[CH2:71][CH2:72]1)(=[O:63])[NH2:62]
Reactant: NC(=O)OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCOC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 28.6 %

Procedure:
91 μl of diphenyl phosphorochloridate and 77 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 152 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 2.0 ml of anhydrous acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, 176 μl of diisopropylethylamine and a solution of 318 mg of (2S,4S)-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethanesulfonate [prepared as described in step (1) above] in 2.0 ml of anhydrous acetonitrile were then added dropwise to the mixture, whilst ice-cooling, and the mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was allowed to stand overnight in a refrigerator, after which it was freed from the solvent by distillation under reduced pressure. The resulting residue was mixed with an aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by chromatography through a Lobar column (a product of Merk & Co., Inc., LiChroprep Si60, size B). Those fractions eluted with a 5:1 by volume mixture of ethyl acetate and methanol were collected and concentrated by evaporation under reduced pressure, to give 99 mg of the title compound as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[NH2:16])[CH3:2].CC[N:19]([CH:23]([CH3:25])[CH3:24])C(C)C.[Br:26][CH2:27]/[CH:28]=[CH:29]/[C:30](Cl)=[O:31].[Cl-].[Na+]>C1COCC1>[Br:26][C:27]1[CH:25]=[C:23]([NH:19][C:8]2[C:7]3[C:12](=[CH:13][C:4]([O:3][CH2:1][CH3:2])=[C:5]([NH:16][C:30](=[O:31])[CH:29]=[CH:28][CH2:27][Br:26])[CH:6]=3)[N:11]=[CH:10][C:9]=2[C:14]#[N:15])[CH:24]=[CH:29][CH:28]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1cc2ncc(C#N)cc2cc1N
Reactant: O=C(Cl)/C=C/CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCBr

Procedure:
To a mixture of 1.34 g (3.5 mmol) of 4-[3-bromo-phenyl)amino]-7-ethoxy-6-amino-3-quinolinecarbonitrile and 3.66 ml (21 mmol) of Hunig's base in 80 ml of dry THF at 0° C., with stirring, was added a THF solution containing 3.85 g (21 mmol) of 4-bromo crotonyl chloride dropwise. The mixture was stirred for additional 30 minutes at 0° C. 50 ml of saturated sodium chloride solution was added to the reaction mixture, then it was extracted with ethyl acetate. The ethyl acetate solution was dried over sodium sulfate and then the drying agent was filtered off. This solution was used without further characterization.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C>[CH3:13][C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:7][N:6]2[C:8]([CH:11]=[O:12])=[CH:9][N:10]=[C:5]2[CH:4]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc2ncc(C=O)n2cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2ncc(C=O)n2cc1-c1cccnc1
Yield: 62 %

Procedure:
6-bromo-7-methylimidazo[1,2-a]pyridine-3-carbaldehyde (Compound of step 1, 2000 mg, 7.90 mmol), Pyridine-3-boronic acid (1170 mg, 9.49 mmol), dichlorobis (triphenylphosphine) palladium (II) (200 mg, 10% mmol) and 2M aqueous Na2CO3 (7 mL) were added to DMF (25 mL) and refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with H2O and brine. The solvent was evaporated to obtain crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 62%; 1H NMR (DMSO-d6; 300 MHz): δ 9.92 (s, 1H), 9.20 (s, 1H), 8.69-8.70 (m, 2H), 8.54 (s, 1H), 7.95-7.99 (m, 1H), 7.90 (s, 1H), 7.53-7.58 (m, 1H), 2.34 (s, 3H); MS: m/z 238 (M+1)+
Reaction SMILES: C[C:2]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[Cl:17])[C:5]([O:7][CH3:8])=[O:6])=O.C1(C)C=CC(S([CH2:27][N+:28]#[C-])(=O)=O)=CC=1.C[O-].[Na+].O>CO>[CH3:8][O:7][C:5]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[CH:27][NH:28][CH:2]=1)=[O:6]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 58 %

Procedure:
With stirring, 20 g of methyl α-methylcarbonyl-2,3-dichlorocinnamate are added at 0° C. to a 22 % by weight solution of (p-tolylsulfonyl)methyl isocyanide prepared according to Example P1 (a). Then 26.3 g of a 30% solution of sodium methylate in methanol are added dropwise over 2 hours. The mixture is stirred for 2 hours and then 35 ml of water are added dropwise. The reaction mixture is concentrated at +50° C. under vacuum. After addition of 70 ml of water, the reaction mixture is concentrated once more under vacuum and then filtered. The filter residue is washed with toluene and recrystallised from ethanol, affording 10.8 g (58% of theory) of 4-methoxycarbonyl-3-(2,3-dichlorophenyl)-pyrrole which melts at 200°-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@@H:27](O)[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F-].[F:39]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C1COCC1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([F:39])[CH2:26][CH2:25]1)[CH2:10][N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C[C@H](C[C@H]1CC[C@@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
A mixture of benzyl (S)-2-(t-butoxycarbonylamino)-3-(cis-4-hydroxycyclohexyl)-propyl(methyl)carbamate (1 g, 2.38 mmol), base Et3N (5 mL, 28 mmol), a fluoride source NEt3(HF)3 (1.9 mL, 9.52 mmol) and perfluorobutanesulfonyl fluoride (2.1 mL, 9.52 mmol) were stirred in THF (24 mL, 1 mmol/10 mL) in a capped vial or flask at 50° C. until LC revealed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL), dried over MgSO4, and evaporated. The residue was then purified by preparative HPLC to give benzyl (S)-2-(t-butoxycarbonylamino)-3-(trans-4-fluorocyclohexyl)propyl-(methyl)carbamate (200 mg, 20%) as a white solid.
Reaction SMILES: [CH2:1]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH2:14][Br:15])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>>[BrH:15].[N:4]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]=[C:17]4[N:21]([CH:14]=3)[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18]4)=[CH:8][CH:7]=2)[CH2:5][CH2:1][CH2:2][CH2:3]1
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(CBr)c1ccc(N2CCCC2)cc1
Product: Br
Product: c1ccc2c(c1)sc1nc(-c3ccc(N4CCCC4)cc3)cn12
Yield: 16 %

Procedure:
The title compound is prepared from α-bromo-4-(1-pyrrolidino)acetophenone (Lancaster) and 2-aminobenzothiazole using method B and 10 hours of reflux in 16% yield: mp 283-287° C.; 1H-NMR (DMSO-d6) 1.98 (m, 4H), 3.31 (m, 4H), 6.68 (m, 2H), 7.51 (d, 1H), 7.66 (d, 3H), 8.11 (m, 2H), 8.71 (s, 1H); Anal. (C19H18BrN3S) C, H, N.