Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]([C:27]([O:29][CH3:30])=[O:28])[CH:20]=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[C:21]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[C:19]([CH:18]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Reaction time: 1 h

Procedure:
With cooling with ice, trifluoromethanesulfonic acid anhydride (4.04 mL, 24.0 mmol) was added to a mixture of dimethyl 5-hydroxyisophthalate (4.20 g, 20.0 mmol), triethylamine (6.69 mL, 48.0 mmol) and chloroform (40 mL), and stirred for 1 hour with cooling with ice. The reaction mixture was diluted with chloroform, shaken with aqueous saturated sodium hydrogencarbonate solution, then the organic layer was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:29])[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([O:25]C)=[O:24])[CH:20]=[C:19]([Cl:27])[C:18]=1[F:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:29])[NH:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[C:19]([Cl:27])[C:18]=1[F:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Cl)c(F)c(CNC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of (2S,4R)-2-(3-chloro-2-fluoro-5-methoxycarbonyl-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (140 mg, 0.3 mmol) in THF/MeOH/H2O 2:1:1 (4 mL) was added LiOH (7 mg, 0.3 mmol). The reaction mixture was stirred for 4 h at ambient temperature and the solvent was removed in vacuo to give the title compound which was used without further purification. MS (LC/MS): 319.0 [M−100]+. tR (HPLC conditions c): 4.40 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[N:38]=[C:37](Cl)[C:36]([Cl:40])=[CH:35][N:34]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([NH:22][C:35]3[C:36]([Cl:40])=[CH:37][N:38]=[C:33]([Cl:32])[N:34]=3)[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1CCc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(Cl)ncc2Cl)cc1CCc1cccc(NC(=O)OC(C)(C)C)c1
Yield: 95.8 %

Procedure:
tert-Butyl{3-[2-(5-amino-2-methoxyphenyl)ethyl]phenyl}carbamate (55 mg, 0.16 mmol), potassium carbonate (67 mg, 0.48 mmol), and 2,4,5-trichloropyrimidine (18 μL, 0.16 mmol) were stirred in N,N-dimethylformamide (1.5 mL) for 30 minutes. Purification by preparative LCMS (pH 2) gave the desired compound (75 mg, 95%). 1H NMR (300 MHz, DMSO-d6): δ 9.40 (s, 1H), 9.25 (s, 1H), 8.30 (s, 1H), 7.40 (m, 3H), 7.20 (m, 1H), 7.12 (m, 1H), 6.99 (d, 1H) 6.80 (d, 1H), 3.80 (s, 3H), 2.77 (m, 4H), 1.42 (s, 9H). LCMS for C24H27Cl2N4O3 (M+H)+: m/z=489.1.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].Cl.CO[C:10](OC)([CH3:12])[CH3:11].CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:11][C:10]1([CH3:12])[O:6][CH:3]([CH2:2][NH2:1])[CH2:4][O:5]1
Reactant: NCC(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Product: CC1(C)OCC(CN)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-aminopropane-1,2-diol (5 g, 54.88 mmol, 1.00 equiv) in water (15 mL). The pH value of the solution was adjusted to 1 with 37% hydrochloric acid. The resulting solution was stirred for 15 min at room temperature. Then the mixture was concentrated to dryness under vacuum. This was followed by the addition of 2,2-dimethoxypropane (32 mL), and 4-methylbenzene-1-sulfonic acid (423 mg, 2.46 mmol, 0.04 equiv). The resulting solution was stirred for 30 min at 85° C. The solid was collected by filtration, washed with acetone and then dissolved in dichloromethane. The PH value of the solution was adjusted to 9 with 2N sodium hydroxide solution. Two phases were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. Filtration and concentration under reducing pressure gave the title compound (light yellow oil). 1H-NMR (300 MHz, CDCl3): δ ppm 1.24(s, 3H), 1.33(s, 3H), 2.77 (s, 1H), 2.91(s, 1H), 3.67-3.72(m, 1H), 3.96-4.01(m, 1H), 4.20-4.28(m, 1H), 8.15(brs, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1COCC1.O>[CH3:19][S:20]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:22])=[O:21]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Reaction time: 18 h

Procedure:
1,4-dioxaspiro[4.5]decan-8-ol (1 g, 6.32 mmol) and triethylamine (1.3 mL, 9.48 mmol) taken in anhydrous THF and treated with methanesulfonyl chloride (0.73 mL, 9.48 mmol). Stirred for 18 h. Diluted with water and extracted with EtOAc. The ethyl acetate layer washed with sat NaCl, dried over Na2SO4 and evaporated to give the expected product. Used without further purification.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:12])[CH:3]=1.N([O-])=O.[Na+].[I-:17].[K+].N>Cl>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([I:17])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: Nc1ccc2c(O)cccc2c1
Agent: Cl
Agent: N
Agent: O=N[O-]
Product: Oc1cccc2cc(I)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
2-Amino-5-hydroxynaphthalene (4.80 g, TCI) was dissolved in 6 N hydrochloric acid (300 ml), added dropwise with an aqueous solution (22.5 ml) of sodium nitrite (2.25 g) over 30 minutes under ice cooling, and stirred for 30 minutes. The reaction mixture was added dropwise with an aqueous solution (75 ml) of potassium iodide (9.90 g, WAKO), stirred for 30 minutes, then warmed to room temperature, and further stirred for 3.5 hours. The reaction mixture was neutralized with aqueous ammonia, and then filtered through a Celite layer. The filtrate was added with ethyl acetate (90 ml×2) for extraction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain 1-hydroxy-6-iodonaphthalene (1.48 g). A solution of this substance (539 mg) in anhydrous THF (10 ml) was added with 60% sodium hydride (171 mg) under ice cooling, and stirred for 1 hour. The reaction mixture was cooled to −78° C. under argon gas atmosphere, added dropwise with a 1.6 M solution of n-butyllithium in hexane (3.75 ml) over 10 minutes, and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (1.16 ml) over 10 minutes, stirred for 30 minutes, then warmed to room temperature, and further stirred for 3 hours. The reaction mixture was added with water (3 ml) and 0.5 M aqueous sulfuric acid (7 ml), and extracted with diethyl ether (100 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 7-hydroxy-2-naphthaleneboronic acid. A solution of this substance in ethanol (1 ml), Compound No. A-1 (350 mg), 2 M aqueous sodium carbonate (2.4 ml) and (Ph3P)4Pd (116 mg) were reacted and treated according to the procedure described in the synthesis method of Compound No. V-3 with the modifications that the reaction was carried out for 14 hours, and the purification was performed by column chromatography (Quad, hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. V-5, 388 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]([CH3:24])([CH3:23])[CH2:11][C:12]([OH:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[CH:13]=O.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30](=[O:36])[NH:31]2>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:22][C:12]1([C:15]([F:20])([F:21])[C:16]([F:18])([F:19])[F:17])[CH2:11][C:10]([CH3:23])([CH3:24])[C:4]2[C:5](=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=2[O:2][CH3:1])[CH:13]1[NH:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][C:30](=[O:36])[NH:31]2
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1cc(C)ccc1C(C)(C)CC(O)(C=O)C(F)(F)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc2c1C(C)(C)CC(O)(C(F)(F)C(F)(F)F)C2Nc1cccc2[nH]c(=O)ccc12
Yield: 0.7 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 200 mg of 4-(2-methoxy-4-methylphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)pentanal and 93 mg of 5-aminoquinolin-2(1H)-one. 2 mg of the title compound is obtained by reaction of 80 mg of the imine with 1.6 ml of titanium tetrachloride solution (1 M in dichloromethane) in 5 ml of dichloromethane.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:22])[CH2:13][C:14]2[C:15]([Cl:21])=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:15]1[C:14]([C:13]2[C:12](=[O:22])[NH:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[C:3]=2[OH:4])=[CH:19][CH:18]=[C:17]([Cl:20])[N:16]=1
Reactant: COC(=O)c1nccnc1NC(=O)Cc1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)nc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-[2-(2,6-dichloro-pyrid-3-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (Example 1.5) (1.16 g) and potassium carbonate (0.943 g) in dry N,N-dimethylformamide (20 ml) was heated to 100° C. for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The mixture was filtered and the solid was washed with further ethyl acetate. The solid was then suspended in water and the pH of the suspension adjusted to pH 2 by addition of aqueous hydrochloric acid (2M). The aqueous phase was filtered to give Compound No. A13 of Table A as a beige solid which was washed with a small amount of water, followed by diethyl ether and allowed to dry (0.380 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH:28]=O.[BH4-].[Na+].O>C(O)C>[CH:15]1[C:27]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]=1[CH2:28][NH:14][CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:28][C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:26][C:27]=3[CH:15]=2)[CH2:10][CH2:9]1
Reactant: NCCCN1CCN(CCCN)CC1
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)Cc1cc(CNCCCN3CCN(CCCNCc4ccc5c(c4)Cc4ccccc4-5)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.513 mL, 2.49 mmol) and 2-fluorenecarboxaldehyde (1.018 g, 5.24 mmol) in absolute ethanol (20 mL) was added 3 Å molecular sieves (5 g). After stirring the mixture for 12 h at room temperature, sodium borohydride (1.9 g, 49.9 mmol) was added and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL) and the combined organic layers were extracted with HCl 1N (2 25×50 mL). The combined aqueous layers were neutralized with NaOH 1N (50 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the oily residue purified by flash chromatography (neutral aluminium oxide, CH2Cl2/MeOH: 90/10).
Reaction SMILES: CC[O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5].Cl.Cl.[C@H]1(CN2CCC(NC(C3NC4C(C=3)=C(OCC3C5C=CC=CC=5OC=3)C=CC=4)=O)CC2)[C@@H]2N(CCCC2)CCC1>>[CH3:27][O:26][C:22]1[C:21]2[C:17]([CH2:16][O:15][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:13]=3[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]4)=[CH:18][O:19][C:20]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc2c(OCc3coc4cccc(OC)c34)cccc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c12

Procedure:
The title compound is prepared from ester 125 by cleavage with KOH/EtOH/THF (as described in example 50 for 105).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:13][CH:14]=3)[C:9]([C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)C(C)(C)Cc1c(C(=O)c2ccccc2)c2cc(OC(=O)c3ccccc3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy indol-2-yl]-2,2-dimethylpropanoate (609 mg) from Example 8 (Step A) was dissolved in 10 mL of 1,2-dichloroethane and the solution charged with 0.5 mL of benzoyl chloride and 680 mg of AlCl3. The reaction was heated to 80° C. under argon for 1.5 h, then quenched with 20 mL of 0.5N Na, K tartrate solution, extracted with 3×20 mL of ether, washed with 10 mL of H2O and dried (MgSO4). Removal of solvent provided an oily residue which was chromatographed on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([S:11][C:12]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1)=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[N+]([O-])([O-])=O>>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH:4]([S:11][C:12]([C:14]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1)=[O:13])[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: O=C(Cc1ccccc1)SC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: O=[N+]([O-])[O-]
Product: O=C(SC(Cn1ccnc1)c1ccc(Cl)cc1Cl)c1ccccc1

Procedure:
1-[2,4-dichloro-β-(benzylcarbonylthio)phenethyl]imidazole as nitrate, mp 115°-116° C. (decomp-foaming).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: NC(=O)c1c(N)ncn1Cc1ccc(F)cc1
Product: CN(CC(=O)Nc1ncn(Cc2ccc(F)cc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.12 g (9.01 mmol) of 4-amino-1-(4-fluorobenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 58 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 2.63 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(4-fluorobenzyl)-5-imidazolecarboxamide (yield 72%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[SiH](CC)(CC)CC>C(Cl)Cl>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:9]2[C:8]3[C:12](=[CH:13][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[NH:11][C:10]=2[CH3:14])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Cc1cc2ccc(S(C)(=O)=O)cc2[nH]1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
A solution of 6-methanesulfonyl-2-methyl-1H-indole (112 mg), prepared as described in Example 1 Step 3, in 9 ml CH2Cl2 was treated with p-bromo-benzaldehyde (100 mg) and 0.2 ml TMS-OTf. After cooling to 0° C., 0.26 ml of Et3SiH was added. The solution was stirred for 30 minutes followed by partitioning between EtOAc and water. Purification by TLC (2:1 hexane/EtOAc) gave 130 mg of 3-(4-bromo-benzyl)-6-methanesulfonyl-2-methyl-1H-indole 201, MS: 379 ([M+H]+).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][NH:28][CH2:29][CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=1)(=[O:22])=[O:21].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C1COCC1.C(N(CC)CC)C.C(#N)C>[C:1]([C:9]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:10]=1[C:11]([N:28]([CH2:29][CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:36][CH:35]=1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Reactant: CCCC(O)CNCc1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCC(O)CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)c1ccc(Br)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
[Step 1] To a solution (20 ml) of 2-benzoyl-4-bromobenzoic acid (2.0 g) in THF were added 1-(4-methanesulfonylbenzylamino)pentan-2-ol (1.8 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.9 g), 1-hydroxy-1H-benzotriazole monohydrate (1.0 g), acetonitrile (20 ml) and triethylamine (5 ml) at room temperature. The reaction mixture was stirred at room temperature for 12 hrs. and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with diisopropyl ether to give 2-benzoyl-4-bromo-N-(2-hydroxypentyl)-N-(4-methanesulfonylbenzyl)benzamide (3.0 g).
Reaction SMILES: C([C:8]1[CH2:9][S:10][C@@H:11]2[CH:22](NC(=O)CC3SC=CC=3)[C:21](=[O:32])[N:12]2[C:13]=1[C:14]([O:16]C(C)(C)C)=[O:15])C1C=CC=CC=1>FC(F)(F)C(O)=O>[S:10]1[C@@H:11]2[CH2:22][C:21](=[O:32])[N:12]2[C:13]([C:14]([OH:16])=[O:15])=[CH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)C1=C(Cc2ccccc2)CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=CCS[C@@H]2CC(=O)N12
Reaction time: 1 h

Procedure:
t-Butyl 3-benzyl-7-[2-(thienyl)acetamido]-3-cephem-4-carboxylate (IV) (44 mg) was dissolved in anhydrous trifluoroacetic acid (0.5 ml). After 1 hour at room temperature, the solvent was removed under reduced pressure, toluene was added and the mixture repeated. This was repeated twice more to give (VI) as a pale yellow foam.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[C:24](\[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)/[CH2:25][O:26][CH3:27])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:47]>CO>[CH3:27][O:26][CH2:25]/[C:24](/[C:28]1[CH:29]=[C:30]([C:34]([NH2:35])=[NH:47])[CH:31]=[CH:32][CH:33]=1)=[CH:23]/[C:22](=[O:36])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methoxybut-2-enamide (150 mg, 0.298 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added, and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10 ml) for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-(methoxymethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (34 mg, (25%) as a fluffy off-white powder after lyophilization. ES-MS (M+H+): 465.15
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([NH:13][C:14](=[O:39])[CH:15]([NH:20][C:21](=[O:38])[CH:22]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]([C:40]([O:42]C(C)(C)C)=[O:41])[CH2:9]1)=O)(C)(C)C.[S:47](Cl)(Cl)(=[O:49])=[O:48]>ClCCl>[C:10]([O:42][C:40]([CH:10]1[CH:11]([NH:13][C:14](=[O:39])[CH:15]([NH:20][C:21](=[O:38])[CH:22]([CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[NH:23][C:24]([C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:25])[C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:12][N:8]([S:47]([C:35]2[CH:36]=[CH:37][C:32]([CH3:22])=[CH:33][CH:34]=2)(=[O:49])=[O:48])[CH2:9]1)=[O:41])([CH3:40])([CH3:9])[CH3:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CC1NC(=O)C(NC(=O)C(NC(=O)c1cnccn1)C1CCCCC1)C(C)(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC(NC(=O)C(NC(=O)C(NC(=O)c3cnccn3)C3CCCCC3)C(C)(C)C)C(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 8 h
Yield: 93 %

Procedure:
The product from Example 23, Part B (100 mg, 0.17 mmol) was dissolved in dichloromethane (1.7 ml). TEA (84 ul, 0.6 mmol) was added followed by the sulfonyl chloride (65.6 mg, 0.34 mmol). The reaction was stirred overnight then loaded onto a silica plug and eluted with ethyl acetate to give the title compound as a white solid (112 mg, 93% yield). MS (APCI) m/z 699 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([CH3:18])([CH3:17])[C:13](OC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:21][NH2:22]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:18])([CH3:17])[C:13](=[O:14])[NH:21][N:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)C2(C)C)cc1OC
Temperature: 25 °C

Procedure:
192 g of methyl 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-3-oxopropanoate (compound D1) is dissolved in 600 ml of ethanol, 145 ml hydrazine hydrate is added and the mixture is heated under reflux for 17 h. The mixture is concentrated in vacuo, resuspended in 400 ml of ethanol and concentrated again. The solids are refluxed for 60 min in 400 ml of ethanol, cooled to RT and filtered. The product is washed with 50 ml of ethanol followed by 100 ml of diethyl ether and dried in vacuo at 50° C.