Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].F[P-](F)(F)(F)(F)F.[N:23]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:23])=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)c1ccc(O)c(OC(F)(F)F)c1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(O)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-3-(trifluoromethoxy)benzoic acid (841 mg, 3.79 mmol) in dimethylformamide (10 ml) were added (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (1.84 g, 4.17 mmol), hydroxybenzotriazole hydrate (563 mg, 4.17 mmol), diisopropylethylamine (1.99 ml, 11.4 mmol), and ammonium chloride (405 mg, 7.58 mmol). The resulting solution was stirred at room temperature for 2 h, and then diluted with ethyl acetate and washed with 0.5 M HCl and brine (2×). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography using a Horizon Biotage, 65i Si column, eluting with 1 column volume of dichloromethane, followed by a linear gradient of ethyl acetate in dichloromethane from 0% to 100% over 10 column volumes to afford the title compound. Mass spectrum (ESI) 222.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(CC(C)C)c2ccc(Br)cc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-1-(6-methoxy-pyridin-3-yl)-5-methyl-hexan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a colorless oil, MS (ESI+): m/z=362.1 [M+H]+.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20](O)=[O:21])[CH:13]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:20](=[O:21])/[CH:19]=[CH:18]/[C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Cl
Product: O=C(/C=C/c1cccnc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-pyridyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 258 (MH+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:9]([C:10](OC)=[O:11])[CH2:8][N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:14]([N:7]1[CH2:8][CH:9]([CH2:10][OH:11])[CH:5]([CH2:3][OH:2])[CH2:6]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CN(Cc2ccccc2)CC1CO
Temperature: 25 °C
Yield: 114.3 %

Procedure:
To a cooled (0° C.) solution of 1-benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (8.66 g, 31.2 mmol) in THF (40 mL) was added LAH (2 M in THF, 62 mL, 62 mmol) over a ten minute period. The reaction mixture was stirred while warming (rt, 17 h). The reaction mixture was then cooled (0° C.), and stirred (15 min), and slowly treated sequentially with an addition of H2O (2.8 mL), 2 M NaOH (4.3 mL), and H2O (8.5 mL). The reaction mixture was then heated to reflux (64° C., 1 h). The reaction mixture was cooled and filtered through Celite® and the solid was washed with EtOAc. The filtrate was concentrated in vacuo to afford the title compound as a yellow oil (7.89 g, 100%). 1H NMR (500 MHz, CDCl3): 7.38-7.21 (m, 5H), 3.84-3.70 (m, 4H), 3.65-3.59 (m, 2H), 2.70-2.58 (m, 4H), 2.58-2.47 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[F:11][C:4]1[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Fc1cc(Br)cn2ccnc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Fc1cc(-c2ccc(C(F)(F)F)cc2)cn2ccnc12
Yield: 99.4 %

Procedure:
Prepared from 6-bromo-8-fluoro-imidazo[1,2-a]pyridine (example C.29 step 4) (1.5 g, 7 mmol) and commercially available 4-trifluoromethylphenylboronic acid (1.46 g, 7.7 mmol) as described in example C.20 step 2. Obtained the title compound as a light brown solid (1.95 g, 100%). MS (ISP) 281.1 [(M+H)+].
Reaction SMILES: [CH:1]1([CH2:8][O:9][C:10]2[N:15]=[C:14]([C:16]([O:18]C)=O)[CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]#[N:22]>>[CH:1]1([CH2:8][O:9][C:10]2[N:15]=[C:14]([C:16](=[O:18])[CH2:20][C:21]#[N:22])[CH:13]=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(OCC2CCCCCC2)n1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OCC2CCCCCC2)n1

Procedure:
CH3CN addition to methyl 6-(cycloheptylmethoxy)picolinate following the method used in Example 6 gave 3-(6-(cycloheptylmethoxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (2.12 g, quant.).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:26])([F:25])[O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:17]3([OH:24])[C:16]4[C:20](=[CH:21][CH:22]=[C:14]([O:13][C:12]([F:11])([F:26])[F:25])[CH:15]=4)[NH:19][C:18]3=[O:23])[C:10]=2[O:9][CH2:8]1
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Reactant: Brc1cccc2c1OCO2
Product: O=C1Nc2ccc(OC(F)(F)F)cc2C1(O)c1cccc2c1OCO2
Yield: 46.9 %

Procedure:
With 7.80 g of 4-bromo-1,3-benzodioxol and 2.30 g of 5-trifluoromethoxyisatin as starting materials, 1.65 g of the title compound was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([CH2:25][CH3:26])[C:36]([O:38][CH3:39])=[O:37])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.091 g, 0.24 mmol) and triethylamine (0.05 mL, 0.36 mmol) in CH2Cl2 (1 mL) was added methyl chloroformate (0.03 mL, 0.36 mmol), and the mixture was stirred at room temperature for 20 minutes. Once no starting material was seen by analytical LCMS, the reaction was quenched with H2O and diluted with CH2Cl2 and saturated aqueous NaHCO3. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:15][CH2:14][N:13]([CH3:17])[CH3:12])[CH:3]=1
Reactant: CN(C)CCO
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCn1cc(Br)c2c(Cl)ncnc21
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.860 mmol), 2-(dimethylamino)ethanol (230 mg, 2.58 mmol) and triphenylphosphine (451 mg, 1.721 mmol) in Tetrahydrofuran (THF) (10 mL) was added dropwise DEAD (0.272 mL, 1.721 mmol). The solution was allowed to stir at room temperature. After 2 hr the reaction was concentrated then loaded on to a 25 g Biotage SNAP column and eluted with 0 to 8% MeOH in DCM gradient over 30 minutes to give [2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]dimethylamine (175 mg, 67.0% yield) as a white solid. LC/MS (ES) m/z=303.1, 305.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.04 (s, 1H), 4.36 (t, J=6.19 Hz, 2H), 2.67 (t, J=6.19 Hz, 2H), 2.16 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:12]([NH:28][C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CCCCCCCCCCCCCCCCN
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cn1

Procedure:
A mixture of 5.13 g. of methyl 6-chloronicotinate, 7.23 g. of hexadecylamine and 150 ml. of hexamethylphosphoramide is stirred at 130° for 6 hours. Cooling and dilution with water affords a precipitate which is collected by filtration and recrystallized from ethyl acetate and then from acetone to yield methyl 6-hexadecylamino-3-pyridinecarboxylate as a tan solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH:9]=2)[CH:4]=[CH:3]1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30](Br)[C:31]([OH:33])=[O:32])=[CH:29][C:24]=2[O:23][CH2:22]1>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH:30]([C:4]3[C:5]4[C:10](=[CH:9][C:8]([C:11]([O:13][CH2:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[O:12])=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)[C:31]([OH:33])=[O:32])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Cn1ccc2ccc(C(=O)OCc3ccccc3)cc21
Reactant: O=C(O)C(Br)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Product: Cn1cc(C(C(=O)O)c2ccc3c(c2)OCO3)c2ccc(C(=O)OCc3ccccc3)cc21
Temperature: 90 °C
Yield: 60.9 %

Procedure:
Benzyl 1-methyl-1H-indole-6-carboxylate (from (b), 9.8 g) and 2-(1,3-benzodioxol-5-yl)-2-bromoacetic acid (from Preparation 1, 10.5 g) were stirred together in dimethylformamide (100 ml) and a steady stream of nitrogen was passed through the solution which was warmed to 90° C. After 4 h the reaction mixture was cooled to room temperature and the dimethylformamide removed in vacuo. The oily residue was partitioned between ethyl acetate (300 ml) and 2M hydrochloric acid and the organic phase was washed with more 2M hydrochloric acid (3×50 ml) and brine (50 ml). The organic phase was dried (MgSO4) and decolourising charcoal was added. The slurry was filtered and concentrated to give an orange oil. Flash column chromatography (gradient elution from 100% CH2Cl2 to 95% CH2Cl2/5% MeOH) gave 9.97 g of the subtitle compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[IH:10]>CCCCCC>[I:10][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: CSc1nccc(Cl)n1
Reactant: I
Solvent: CCCCCC
Product: CSc1nccc(I)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
4-Chloro-2-methylthiopyrimidine (40 g, 249 mmol) is added to Hydroiodic acid (57% in water, 200 mL). The suspension is vigorously stirred in the absence of light for 72 h at rt. A bright yellow solid formed which is collected by filtration. The solid is added to saturated aqueous NaHCO3 (500 mL) and stirred for 2 min. CHCl3 (600 mL) is added and the solid dissolved. The aqueous layer is extracted 2 times with CHCl3 (350, then 300 mL) and the organic extracts combined, washed with water (100 mL), dried over MgSO4 and filtered. The organic solvent is removed in vacuo to give colorless oil. Addition of n-hexane and removal of solvent again produced the title compound as a white solid (57.9 g, 230 mmol, 92%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=2)[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[OH:39][C:40]1[C:45]([Cl:46])=[CH:44][C:43]([Cl:47])=[CH:42][C:41]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[Cl:46][C:45]1[C:40]([OH:39])=[C:41]([S:48]([N:11]([CH2:10][C:9]2[CH:27]=[CH:28][CH:29]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:31][CH:30]=3)[CH:8]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=2)(=[O:50])=[O:49])[CH:42]=[C:43]([Cl:47])[CH:44]=1
Reactant: CCCCCCCCc1ccc(CNCc2cccc(Oc3ccc(F)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc(CN(Cc2cccc(Oc3ccc(F)cc3)c2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
To a mixture of N-(3-(4-fluorophenoxy)benzyl)-1-(4-octylphenyl)methanamine (100 mg, 0.238 mmol, 1.0 eq) in DCM (10 mL) was added triethylamine (72 mg, 0.72 mmol, 3.0 eq) followed by 2-hydroxy-3,5-dichlorobenzenesulfonyl chloride (62 mg, 0.238 mmol, 1.0 eq). After stirring at ambient temperature for 4 h, the reaction mixture was diluted with 100 mL DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude residue was purified by preparative HPLC to afford the title compound (25 mg, 16%). 1H NMR (400 MHz, CD3OD) δ 7.64-7.63 (d, 1H), 7.55-7.54 (d, 1H), 7.21 (m, 1H), 7.19-7.11 (m, 2H), 7.09-7.02 (m, 4H), 6.95-6.91 (m, 2H), 6.88-6.86 (d, 1H), 6.80-6.78 (d, 1H), 6.68 (s, 1H), 4.43-4.40 (d, 4H), 3.35-3.30 (m, 6H), 2.55-2.51 (t, 2H), 1.57-1.56 (t, 3H), 1.3 (s, 10H), 0.87-0.91 (t, 3H). MS (ESI): 644.0 (M−H)−.
Reaction SMILES: O=C1N(CC(OC(C)(C)C)=O)C2C=CC=CC=2N1.[O:19]=[C:20]1[N:24]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]1[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1>>[O:19]=[C:20]1[N:24]([CH2:25][C:26]([OH:28])=[O:27])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]1[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccncn2)c2ccccc21
Agent: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: O=C(O)Cn1c(=O)n(-c2ccncn2)c2ccccc21

Procedure:
Essentially following the procedures described for Intermediate 4, but using tert-butyl (2-oxo-3-pyrimidin-4-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=271 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:24])=[C:6]([CH:23]=1)[NH:7][C:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:9]=1.Cl[CH:26]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:27][C:28](Cl)=[O:29].[OH-].[Na+]>C(#N)C.C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:24][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH:31]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:26][CH2:27][C:28]2=[O:29])=[CH:23][C:6]=1[NH:7][C:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=2[Cl:22])[N:9]=1
Reactant: CCCCCCCC(Cl)CC(=O)Cl
Reactant: Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC1CCC(=O)N1c1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
26 g of 3-(5-amino-2-chloroanilino)-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one was suspended in 200 ml of acetonitrile and to the suspension 15.5 g of γ-chlorodecanoyl chloride described above was added dropwise under refluxing. After refluxing for 1 hour, the reaction mixture was cooled and water was added to the mixture followed by extracting with ethyl acetate. By distilling off the solvent under reduced pressure, the crystalline residue was obtained. The residue was dissolved in 300 ml of toluene; to the solution 3 g of tetrabutylammonium chloride was added, and then a solution containing 30 g of sodium hydroxide dissolved in 30 ml of water was added. After stirring vigorously at 60° C. for 4 hours, the reaction mixture was cooled and separated. The organic solvent layer was washed with water and the solvent was distilled off under reduced pressure. The residual crystals were recrystallized from acetonitrile to obtain 29 g of the desired compound. The melting point was 224° to 227° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.N[CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH2:24][S:25][C:26]3[N:30]([CH3:31])[N:29]=[N:28][N:27]=3)[CH2:22][S:23][C@H:18]12.O>C1COCC1.CC#N.CN(C=O)C>[CH3:31][N:30]1[C:26]([S:25][CH2:24][C:21]2[CH2:22][S:23][C@@H:18]3[CH2:17][C:35](=[O:36])[N:19]3[C:20]=2[C:32]([OH:34])=[O:33])=[N:27][N:28]=[N:29]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Temperature: -5 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-[2-(N-chloroacetyl)-imino-3-methoxy-4-thiazolinyl]-2-methoxyimino-acetic acid (3.07 g) in anhydrous THF (120 ml) cooled at -5° C., N,N'-dicyclohexylcarbodiimide (2.06 g) was added. After stirring for 10 minutes at -5° C. and 50 minutes at room temperature, the precipitate dicyclohexylurea was filtered off, and the solution was added into a cooled (-10° C.) solution obtained by stirring 7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (3.3 g) and N,O-bis-(trimethyl-silyl)-acetamide (8.1 g) in anhydrous THF (200 ml), CH3CN (80 ml) and DMF (4 ml) for 1 hour at 50° C. The mixture was stirred 20 minutes at -10° C. and 90 minutes at room temperature. H2O (10 ml) was added in order to hydrolize the silylated product, and the major part of the solvents were evaporated under reduced pressure. The residue was partitioned between H2O (50 ml) and ethyl acetate (100 ml); the organic layer was separated and the aqueous one was extracted again with ethyl acetate. The combined extracts were dried (Na2SO4), concentrated to a small volume and diluted with ethyl ether. The precipitated solid was collected and washed with ethyl ether, thus giving 5.1 g of 7β[2-(2-N-chloroacetyl)-imino-3-methoxy-4-thiazolinyl]-2-methoxyimino-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid. This compound was dissolved in MeCN (200 ml) and heated with diphenyldiazomethane (1.9 g). After stirring 1 hour at room temperature, the solvent was evaporated, the residue was taken up with ethyl acetate, washed with dilute NaHCO3 solution, then with water, dried (Na2SO4), and again evaporated to dryness. The residue was triturated with ethyl ether and filtered, thus affording 6.3 g of benzhydryl ester.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N=C=NC(C)C)(C)C.[CH2:21]([O:24][C:25](=[O:53])[C:26]1[CH:31]=[CH:30][C:29]([N:32]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)=[C:28]([NH2:52])[CH:27]=1)[CH:22]=[CH2:23]>C(Cl)Cl>[CH2:21]([O:24][C:25](=[O:53])[C:26]1[CH:31]=[CH:30][C:29]([N:32]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:36][CH:35]=2)=[C:28]([NH:52][C:9](=[O:11])[CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:27]=1)[CH:22]=[CH2:23]
Reactant: O=C(O)COc1ccccc1
Reactant: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: C=CCOC(=O)c1ccc(N(Cc2ccc(OC(F)(F)F)cc2)C(=O)OC(C)(C)C)c(NC(=O)COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
318 mg of phenoxyacetic acid were dissolved in methylenchloride and 0.36 ml of diisopropylcarbodiimide added. 950 mg of 3-amino-4-[tert-butoxycarbonyl-(4-trifluoromethoxy-benzyl)-amino]-benzoic acid allylester were added and the reaction mixture stirred at room temperature for 16 h. The product was extracted from methylenchloride/water without further characterization.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[Br:12][CH2:13][CH2:14][CH2:15]Br>CN(C=O)C>[Br:12][CH2:13][CH2:14][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: BrCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: BrCCCn1ccc2ccccc21
Reaction time: 72 h
Yield: 30.9 %

Procedure:
To a solution of 23.4 g of indole in 200 ml of DMF, cooled to 10° C., were added 22.4 g of potassium hydroxide and 101 g of 1,3-dibromopropane. The mixture was stirred under nitrogen for 3 days. The solid formed was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel with 5% diethyl ether in petroleum ether to give 14.7 g of 1-(3-bromopropyl)indole.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:17][CH2:18][CH3:19])=[C:13]([CH:16]=1)[C:14]#[N:15])C1C=CC=CC=1>CO.[Pd]>[CH2:18]([O:17][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:16][C:13]=1[C:14]#[N:15])[CH3:19]
Reactant: CCOc1ccc(OCc2ccccc2)cc1C#N
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(O)cc1C#N
Reaction time: 4 h

Procedure:
40.02 g of 5-benzyloxy-2-ethoxybenzonitrile (158 mmol) (example 32A) and 5% Pd/C (4.0 g) are initially charged in 1 l of methanol. The mixture is then hydrogenated under an atmosphere of hydrogen (1 atm) for about 4 h. The mixture is filtered through kieselguhr and evaporated and the crystalline residue is dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:19][C@@H:18]([C:20]2[CH:31]=[CH:30][C:23]3[O:24][C:25]([CH3:29])([CH3:28])[O:26][CH2:27][C:22]=3[CH:21]=2)[O:17][C:16]1=[O:32].[CH3:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[CH3:28][C:25]1([CH3:29])[O:24][C:23]2[CH:30]=[CH:31][C:20]([C@H:18]3[O:17][C:16](=[O:32])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:3]=[C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH:35]=[CH:34][CH:33]=4)[CH2:19]3)=[CH:21][C:22]=2[CH2:27][O:26]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCOCCOCc4cccc(NS(C)(=O)=O)c4)C(=O)O3)ccc2O1
Yield: 64.6 %

Procedure:
A solution of (5R)-3-(5-{2-[(3-aminobenzyl)oxy]ethoxy}pentyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (52 mg) in pyridine (4 ml) was treated with methanesulfonyl chloride (13 mg) at 20° C. for 3 h. The mixture was quenched with sat. aqueous sodium bicarbonate (20 ml) and partitioned with DCM. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified using SPE eluting with DCM then EtOAc-PE (3:1). The selected fractions were evaporated in vacuo to yield the title compound (39 mg).