Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:10]([CH2:26][C:27](=[O:36])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].B(Br)(Br)Br.O.[OH-].[Na+]>ClCCl>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:27]([CH2:26][N:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=[C:11]2[C:14](=[O:25])[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]2)=[O:36])=[N:30][CH:31]=1
Reactant: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
30 mg (0.058 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 3 mL dichloromethane and cooled to 0° C. 234 μl of a 1 M BBr3-solution (4 equiv.) in dichloromethane were carefully added and the resulting mixture was stirred at room temperature for 16 h. Under cooling 3 mL water were added dropwise followed by the addition of 0.7 mL of a 1 M NaOH-solution. The mixture was concentrated under reduced pressure. Purification by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid. The corresponding dihydrochloride was obtained by treatment of the product with a 0.1 M HCl-solution and following lyophilization. Yield: 26 mg MS (ES+): m/e=499, chloro pattern.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N+:4]([C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br)([O-:6])=[O:5].Cl>CO>[CH3:1][O:2][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[N+:4]([O-:6])=[O:5]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
125 g of 30% strength sodium methylate solution (0.69 mol) in methanol are added dropwise to 130 g (0.6 mol) of o-nitrobenzyl bromide in 200 ml of methanol. During this procedure, the reaction mixture heats up to about 50° C. Stirring is continued for a further 3 hours, the reaction mixture being cooled to room temperature, after which ice water is added to the reaction vessel and the reaction mixture is neutralized by adding dilute hydrochloric acid. The aqueous phase is extracted with three times with ether, and the organic phase is dried over MgSO4 and evaporated down. 101 g (0.6 mol, quantitative yield) of the title compound are obtained as a residue in the form of a brownish oil. 1H-NMR (CDCl3 ; δ (ppm)): 8.1 (d, broad, 1H, aromatic); 7.8 (d, broad, 1H, aromatic); 7.5 (t, broad, 1H, aromatic); 7.45 (t, broad, 1H, aromatic); 4.85 (s, 2H, O--CH2); 3.5 (s, 3H, OCH3)
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:20]3[CH:34]=[CH:33][C:23]([C:24]([O:26]CC[Si](C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:33][CH:34]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)Oc3ccc(C(=O)OCC[Si](C)(C)C)cc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)Oc3ccc(C(=O)O)cc3)ccc21
Reaction time: 8 h

Procedure:
To a solution of 2-trimethylsilylethyl 4-[[(5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalen-2-yl)carbonyl]oxy]-benzoate (Compound E10, 100.0 mg, 0.198 mmol) in 2.0 mL THF at room temperature was added 155.3 mg of tetrabutylammonium fluoride (0.594 mmol 0.6 mL of a 1M solution in THF). After stirring overnight the reaction was diluted with EtOAc and washed with H2O and saturated aqueous NaCl before being dried over MgSO4. The solvents were removed under reduced pressure and the residue washed with hot acetonitrile leaving the product as a colorless solid.
Reaction SMILES: [C:1]([NH:10][OH:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)O.C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[O:11]1[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:9])=[N:10]1
Reactant: O=C(NO)c1ccccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Oc1noc2ccccc12
Yield: 53.7 %

Procedure:
To a solution of salicylhydroxamic acid (1.53 g, 10 mmol) in THF (40 ml) was added a solution of carbonyldiimidazole (1.62 g, 20 mmol) in tetrahydrofuran (20 ml). The mixture was stirred at reflux for 4 hrs. before evaporation to dryness. Water (20 ml) and conc. HCl (aq.) (5 ml) were added and the solution was refrigerated (5° C.) for 30 min. The resulting precipitate was collected by filtration and washed with 2M HCl. The solid material was dissolved in methanol and concentrated in vacuo yielding 725 mg (54%) of the title compound 71. TLC (10% methanol in DCM): Rf=0.2. HPLC-MS (Method A): M+=136.1 (UV/MS(%)=94/100). 1H-NMR (400 MHz, CDCl3, MeOD): δ=7.73 (1H, m); 7.56 (1H, m); 7.38 (1H, m); 7.28 (1H, m); 3.87 (1H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH3:11])=[N:9][N:10]=[C:4]2[CH:3]=1.C(Cl)Cl.[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.CC([O-])=O.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:11][C:8]1[N:5]2[CH:6]=[CH:7][C:2]([B:15]([OH:19])[OH:16])=[CH:3][C:4]2=[N:10][N:9]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1nnc2cc(Br)ccn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nnc2cc(B(O)O)ccn12
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added 7-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine (318 mg, 1.5 mmol), PdCl2(dppf).DCM (245 mg, 0.3 mmol), bis(pinacolato)diboron (508 mg, 2 mmol), and KOAc (442 mg, 4.5 mmol). Anhydrous dioxane (8 mL) was added, and the mixture was heated to 100° C. for 3 hours. After cooling to room temperature, the mixture was filtered over a plug of Celite, and concentrated to provide the crude product, which was used directly without further purification. LCMS-ESI+: calc'd for C7H9BN3O2: 178.1 (M+H+); Found: 178.1 (M+H+).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:23])(=[NH:22])[CH3:21]>>[CH3:21][C:20]1[N:22]=[CH:4][C:5]2[CH2:6][C:7](=[O:18])[NH:8][C:9]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=3[C:11]=2[N:23]=1
Reactant: CC(=N)N
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC(=O)N2
Agent: Cl
Product: Cc1ccc2c(c1)-c1nc(C)ncc1CC(=O)N2
Yield: 98 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and acetamidine hydrochloride. Yield: 98%.
Reaction SMILES: [BH4-].[Na+].[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:5][C:6](OC)=[O:7]>CO>[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(N)CCO)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a stirred solid of sodium borohydride (94.18 grams, 2.49 mol) at 0° C., was added methanol (50 mL). To this mixture at 0° C. was added a solution of methyl 3-amino-3-(3',4'-dimethoxyphenyl)propionate (59.5 grams, 249 mmol) in methanol (950 mL) over 1 hour. The mixture was stirred in that ice-water bath until the temperature of the reaction mixture stayed at 35° C. or lower for 30 minutes. (Caution: If the ice-water bath was removed too early, a highly exothermic reaction may occur.) The water bath was then removed and the solution was refluxed for 16 hours. The solution was allowed to cool to room temperature. To the solution was added water (300 mL), followed by methylene chloride (250 mL) at 0° C. The resulting suspension was filtered. Half of the filtrate was removed in vacuo. The resulting solution was dissolved in methylene chloride (500 mL) and water (300 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (3×500 mL). The combined organic layers were washed with brine (100 mL), and dried over magnesium sulfate. Removal of solvent gave an oil. The resulting oil was dried in vacuo to afford 3-amino-3-(3',4'-dimethoxyphenyl)-1-propanol as a white solid (42.15 grams, 80% yield): mp 63.5°-65.5° C.; 1H NMR (CDCl3)δ6.91-6.78(m, 3H), 4.15-4.04(m, 1H), 3.89(s, 3H), 3.88(s, 3H), 3.84-3.71(s, 2H), 2.91-2.45(m, 1H), 1.95-1.78(m, 2H); Anal Calcd for C11H17NO3 :C, 62.54; H, 8.11; N, 6.63. Found: C, 62.01; H, 7.80; N, 6.49.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 95.5 %

Procedure:
To 2.0 g (14.5 mmol) of 3-nitroaniline and 4.5 ml (32 mmol) of triethylamine in 60 ml of methylene chloride stirred at room temperature was added 5.4 ml (16 mmol) of octadecanoyl chloride in 10 ml of methylene chloride. The reaction mixture was kept at room temperature for 18 hours and then was washed with 1N HCl, dried and concentrated at reduced pressure to a solid. Recrystallization from methanol gave 5.6 g (95% yield, mp 75°-76°) of N-(3-nitrophenyl)octadecanamide.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[N-]1C=CN=C1.[NH2:42][O:43][CH2:44][CH2:45][OH:46]>C1COCC1>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][CH2:21][O:22][CH3:23])=[CH:15][C:14]=2[F:24])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:42][O:43][CH2:44][CH2:45][OH:46])=[O:7]
Reactant: COCC#Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1
Reactant: NOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Product: COCC#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
The title compound was prepared from reaction of the product of Example 5, Step B, 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]-amino]benzoic acid. This product (200 mg, 0.60 mmol) was dissolved in dry THF (5 mL) and CDI (193 mg, 1.19 mmol) added. After 0.5 hours at room temperature, TLC showed complete conversion to the desired imidazolide. A solution of 2-(aminooxy)ethanol (184 mg, 2.39 mmol) in dry THF (2 mL) was added and the reaction mixture stirred overnight at room temperature. The reaction solvent was then removed under reduced pressure and the resulting residue partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (50 mL). The EtOAc layer was then dried (Na2SO4), the solvent removed under reduced pressure, and the resulting oil purified by column chromatography on silica gel (50% EtOAc/hexanes) to give 3,4-difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]-N-(2-hydroxyethoxy)benzamide as a white solid (165 mg, 71%); mp (EtOAc/Et2O) 121-123° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.84 (br s, 1 H), 8.85 (br s, 1 H), 7.46-7.38 (m, 1 H), 7.32 (dd, J=12.1, 1.7 Hz, 1 H), 7.29-7.21 (m, 1 H), 7.14 (dd, J=8.4, 1.6 Hz, 1 H), 6.79 (td, J=8.8, 4.7 Hz, 1 H), 4.74 (br s, 1 H), 4.30 (s, 2 H), 3.84 (t, J=4.8 Hz, 2 H), 3.56 (t, J=4.9 Hz, 2 H), 3.32 (s, 3 H). Anal. Calcd for C19H17F3N2O4: C, 57.9; H, 4.4; N, 7.1. Found C, 57.9; H, 4.3; N, 7.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[I-].[Na+].Cl[C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O.[Cu]I.[Cu].CO>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([CH:24]=1)[O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [Cu]
Agent: [Cu]I
Agent: [H-]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)cc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 15 g of methyl 2-hydroxy-4-methoxy-benzoate in 185 ml of dimethylformamide under argon was added 3.63 g of a 60% dispersion of sodium hydride in oil. To this slurry was added 12.35 g of sodium iodide, 15.69 g of copper(I)-iodide, and 0.525 g of copper powder. The mixture was heated for 15 minutes at 85° C. and 17.4 g of 2,4-dichloronitrobenzene was added. After 48 hours at 85° C., the reaction was cooled to 25° C. and methanol was added. The reaction was filtered and the filtrate was concentrated in vacuo to about 50 ml then diluted with 150 ml of ethylacetate. The solution was washed with a 20% aqueous solution of sodium thiosulfate and the organic portion was separated and dried over sodium sulfate. The solvent was evaporated to leave a tan solid. Recrystallization from ethyl acetate gave the title compound, mp 121°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)[CH3:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]=[C:24]([C:9]2[CH:10]=[CH:11][C:6]([CH:4]([C:3]([O:2][CH3:1])=[O:13])[CH3:5])=[CH:7][CH:8]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)C(C)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C)c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Under inert gas atmosphere 3.43 g (2.97 mmol) Pd(PPh3)4 are added to 17.2 g (59.4 mmol) 2-(4-iodo-phenyl)-propionic acid methyl ester (Bioorg. Med. Chem. Lett. 2010, 20, 896), 20.2 g (65.3 mmol) 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 18.9 g (178 mmol) sodium carbonate in 200 mL 1,2-dimethoxyethane and 30 mL water. The mixture is stirred for 2 h at 100° C. and for additional 12 h at 80° C. After that time, water is added and the mixture is extracted with EtOAc (3×). The combined organic layers are washed with water (2×) and brine and dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; heptane:EtOAc gradient 100:0->60:40).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([O:20]CC)=[O:19])=[CH:8][C:9]=1[NH:10]2.O.[OH-].[Li+]>C1COCC1.C(O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH:5]=[CH:6][C:7]([C:18]([OH:20])=[O:19])=[CH:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(=O)O)ccc12
Temperature: 25 °C

Procedure:
A suspension of ethyl 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylate (Intermediate 48-1, 1.81 g, 5.01 mmol) and lithium hydroxide monohydrate (0.601 g, 15.03 mmol) in THF-ethanol-water (3:1:1, 50 mL) was heated at reflux for 2 h. The mixture was cooled to rt and concentrated. The residue was stirred in water and treated with 1 M hydrochloric acid to pH 1-2. The precipitate was collected by filtration, washed with water, and dried to afford 5-bromo-8-carbamoyl-9H-carbazole-2-carboxylic acid as a light brown solid (1.84 g, ca. 90% purity, 99%). 1H NMR (400 MHz, DMSO-d6) δ 12.95 (br. s., 1H) 12.02 (s, 1H) 8.69 (d, J=8.53 Hz, 1H) 8.47 (s, 1H) 8.28 (br. s., 1H) 7.94 (d, J=8.28 Hz, 2H) 7.87 (d, J=8.28 Hz, 1H) 7.65 (br. s., 1H) 7.51 (d, J=8.03 Hz, 1H). Mass spectrum m/z 331, 333 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1.C(O)(=O)C>C(O)C.CN(C=O)C>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=Cc1ccc(O)cc1O
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(N=Cc3ccc(O)cc3O)cc2)=NN1

Procedure:
A solution containing 0.42 g (0.003 mol) of 2,4-dihydroxybenzaldehyde, 0.57 g (0.003 mol) of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.05 ml of acetic acid in a mixture of 40 ml of ethanol and 20 ml of DMF was refluxed for 4 h. After cooling the product was filtered and washed with ethanol. Yield 0.80 g (85%), m.p. 350° C. (decomp).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(-c2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, phenylboronic acid, tetrakis(triphenylphosphine)palladium(O) and sodium carbonate in dioxane/water. EI-MS m/e (%): 272 (M+, 58), 271 ([M—H]+, 100).
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:21])[C:9]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17](OC)=[O:18])[C:10]=3[CH:11]=[CH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1>[OH:18][CH2:17][C:13]1[C:10]2[CH:11]=[CH:12][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([I:1])[C:7]=3[CH:8]([OH:21])[C:9]=2[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc2c(=O)c3c(I)cccc3ccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCc1cccc2c1C=Cc1cccc(I)c1C2O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg of the mixture of methyl 6-iodo-5-oxo-5H-dibenzo[a,d]cycloheptene-1-carboxylate and its 4-iodo form prepared in Example 6-d was dissolved in 5 ml of dry tetrahydrofuran, and 0.75 ml of a 1M solution of diisobutyl aluminium hydride in toluene was added at room temperature. To the reaction mixture was added with small amounts of water and ethyl acetate, followed by stirring at room temperature for 30 minutes. Then, the reaction mixture was filtered through Celite, washed with ethyl acetate, and the solvent was removed, to give 40 mg of a mixture of the title compound with its 4-iodo form as a colorless powder.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@H:45]([CH:61]2[N:64]([CH3:65])[C:63](=[O:66])[CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[C@H:45]([CH:61]4[N:64]([CH3:65])[C:63](=[O:66])[CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: CN1C(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 95.2 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (235 mg, 0.40 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (149 mg, 0.41 mol, compound of Reference Example 7) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (265 mg, yield: 94.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:34][C:35]3[CH:36]=[N:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccc(C(F)(F)F)nc3)c3cc(Cl)ccc23)c1
Temperature: 0 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.050 g, 0.15 mmol) was dissolved in DMF:THF (1:1, 4 mL) and cooled to 0° C. Lithium bis(trimethylsilyl)amide solution (0.375 mL, 0.375 mmol, 1.0M in hexanes) was added. 3-(Chloromethyl)-6-(trifluoromethyl)pyridine (0.044 g, 0.225 mmol) was added and the reaction was allowed to warm to room temperature. After 20 minutes the reaction was heated to 50° C. for 1 hour and then submitted to aqueous workup to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH3:2].[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:20])(=[O:29])=[O:28])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)CCCNc1ccccc1C(=O)OC
Solvent: c1ccncc1
Product: CCOC(=O)CCCN(c1ccccc1C(=O)OC)S(=O)(=O)c1ccccc1C
Yield: 90.7 %

Procedure:
A mixture of 2.65 g of methyl 2-[(4-ethoxy-4-oxobutyl)amino]benzoate, 2.0 g of 2-methylphenylsulfonyl chloride and pyridine is heated on a steam bath for 16 hours. The mixture is concentrated under a vacuum (remove pyridine) and 1N HCl added. The mixture is extracted with dichloromethane and the extract washed with 1NHCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrons magnesium silicate and the filtrate evaporated to give 3.8 g of solid which is crystallized from ethanol to give crystals, m.p. 100°-102° C.