Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:21]=[CH:22][CH:23]=1.N1C=CC=CC=1>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH:19]=1)=[O:6]
Reactant: CCCC(=O)Nc1cccc(N)c1
Reactant: O=C(O)c1ccccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(=O)Nc1cccc(NC(=O)c2ccccc2Br)c1
Reaction time: 18 h
Yield: 94.4 %

Procedure:
2-Bromobenzoic acid (259 mg, 1.29 mmol) was sealed in a flask with stir bar under nitrogen, then dissolved with dichloromethane (7.5 mL) and cooled on ice. Oxalyl chloride (113 μL, 1.29 mmol) and N,N-dimethylformamide (4 μL, 0.06 mmol) were added, then the reaction was removed from the ice bath and stirred for 3 h with a vent to an oil bubbler. N-(3-Aminophenyl)butyramide (200 mg, 1.12 mmol) was then added, followed by pyridine (209 μL, 2.58 mmol). After 18 h, LC-MS analysis showed complete consumption of the amine reactant. The reaction was diluted with ethyl acetate (40 mL) and 1 M aqueous HCl (40 mL), then the layers were separated and the organic phase was washed again with aqueous HCl, then twice with half-saturated aqueous NaHCO3, then brine. The organics were dried over Na2SO4, filtered, and concentrated to a colorless oil. The oil was redissolved with dichloromethane, then hexane was added to induce the precipitation of an amorphous solid. The suspension was concentrated and dried under hi-vacuum to yield the title compound (382 mg, 94%). LRMS (ESI+) (M+H): 361.12.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:11])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:11])[CH2:9][O:10][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: OCC(F)c1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(3-bromophenyl)-2-fluoroethanol (example 39, step b) (1.38 g) and imidazole (1.29 g) in DMF (14 mL) was cooled in ice-water, treated with tert-butyldimethylchlorosilane (1.049 g), then removed from the cooling bath and stirred at room temperature overnight. The solution was poured into water and extracted twice with diethyl ether. The combined organic extracts were washed twice with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 10% dichloromethane in isohexane to afford the subtitled compound as a colourless oil. Yield 1.94 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1([CH3:28])[CH2:17][CH:16]2[CH:18]([CH3:27])[C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:23])[C:21]([CH3:22])=[C:15]2[O:14]1.Cl>C(Cl)Cl.C(N(CC)CC)C>[CH3:28][C:13]1([CH:12]=[O:11])[CH2:17][CH:16]2[CH:18]([CH3:27])[C:19]([N+:24]([O-:26])=[O:25])=[C:20]([CH3:23])[C:21]([CH3:22])=[C:15]2[O:14]1
Reactant: CC1=C2OC(C)(CO)CC2C(C)C([N+](=O)[O-])=C1C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Under an argon atmosphere, 0.57 ml of oxalic acid dichloride was dissolved in 12 ml of methylene chloride, followed by cooling to −78° C. To this solution, a solution prepared by dissolving 1.1 ml of DMSO in 2 ml of methylene chloride was added dropwise at −65 C or lower, followed by stirring for 10 minutes. Furthermore, a solution prepared by dissolving 1.34 g of 2-hydroxymethyl-2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran in 4 ml of methylene chloride was added dropwise, followed by stirring at −78° C. for 3 hours. After the completion of the reaction, 4.2 ml of triethylamine was added dropwise and the reaction solution was heated to room temperature and then 1N-hydrochloric acid was added. The organic layer was extracted with chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate, and then solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to obtain 0.86 g of the objective product.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[C:30]([NH:38][NH2:39])(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:38][N:39]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccccc5)[nH]4)cc23)cc1
Yield: 47.7 %

Procedure:
The procedure described in example 119 using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylamine (0.25 mL, 1.86 mmol) and benzoic hydrazide (170 mg, 1.25 mmol) was followed to yield the title compound (105 mg, 48% yield). 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.74 (s, 1H), 8.0–8.2 (m, 5H), 7.75 (d, 1H), 7.35–7.6 (m, 5H), ES-MS (m/z) 356 [M+1]+.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, 92 mg of isoamyl nitrite was added dropwise to a mixture of 0.26 g of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridylthio]acetate, 0.10 g of copper (I) chloride, 0.21 g of copper (II) chloride, and 2.5 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.10 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridylthio]acetate (compound a-8).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Methyl 2-fluoro-4-hydroxybenzoate (1.4685 g; manufactured by Changzou Fine Chemical Co., Ltd.) and potassium carbonate (3.6-917 g; manufactured by Sigma-Aldrich Co.) were suspended in dehydrated DMF (21 mL; manufactured by Kanto Chemical Co., Inc.), and benzyl bromide (1.22 mL; manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was stirred overnight at 50° C. The reaction solution was cooled to room temperature, and then was poured into water. The mixture was extracted two times with ethyl acetate. The organic layer was washed twice with water and once with brine, and was dried over anhydrous sodium sulfate. Subsequently, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=97:3→77:23). Thus, the title compound (2.2207 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[H][H]>CO.[Pd].C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N2CCNCC2)cc1

Procedure:
4-(4-Benzyl-piperazin-1-yl)-benzoic acid methyl ester (19.4 mmol) is dissolved in methanol (150 ml) and Pd/charcoal is added (0.6 g). The mixture is stirred in a hydrogen atmosphere until consumption has ceased. The catalyst is filtered off and the filtrate evaporated. The residue is suspended in diethylether/pentane and the solid filtered of and dried (vacuum). A powder with mp. 95-97° C. is obtained.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:4].[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([CH2:14][N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])=[O:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccccc1NC(=O)CCl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccccc1NC(=O)CN(Cc1ccccc1)Cc1ccccc1
Yield: 82.6 %

Procedure:
To a stirred solution of 28.1 g of 2-chloro-N-(2-methoxyphenyl)acetamide (C.A. 50, 8730i) in 200 ml toluene was added 58.3 g of dibenzylamine and refluxed for 48 hours. After separation of dibenzylamine hydrochloride, the solvent was removed from the reaction mixture. Crystallization of the residue from isopropylether gave 41.9 g colorless crystals of 2-[bis(phenylmethyl)amino]-N-(2-methoxyphenyl)acetamide, mp 92°-94°.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([OH:22])=O)=[CH:11]2)[C:4]=1[CH3:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[F:49][CH:50]([F:53])[CH2:51][NH2:52]>C(Cl)Cl>[F:49][CH:50]([F:53])[CH2:51][NH:52][C:20]([C:12]1[C:13]2=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:23])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:22]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Reactant: NCC(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NCC(F)F)c3ncc(C)cc32)c1C
Temperature: 25 °C
Yield: 16.7 %

Procedure:
See FIG. 24(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.32 mmol) was taken in a thermal reactor. DCM (3 mL) was added to get a suspension. Triethyl amine (0.089 mL, 0.64 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (0.381 mL, 0.64 mmol). 2,2-difluoroethanamine (26.0 mg, 0.32 mmol) was added and stirred at RT for ON. After the completion of the reaction, reaction mixture was concentrated and dissolved in DCM:MeOH. This crude compound was subjected for reverse phase purification to obtain N-(2,2-difluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (20.00 mg, 16.64%) as a off white solid. ES+MS m/z: 376 (M−1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 4 H ) 2.40 (s, 3 H ) 3.77-3.89 (m, 2 H ) 3.93 (s, 4 H) 5.65 (s, 2 H ) 7.77 (s, 1 H ) 8.20 (s, 1 H ) 8.40 (s, 1 H ) 8.36 (s, 1 H ) 8.91 (br. s., 1 H ).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[Br:21]Br>C(Cl)Cl>[Br:21][C:6]1[S:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[C:3]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:2]=1[CH3:1]
Reactant: COC(=O)c1scc(C)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a stirred suspension of methyl 4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 7b, 8.80 g, 27.0 mmol) in DCM (150 ml), bromine (5.19 g, 1.67 ml, 32.0 mmol) was added at 0° C. in a drop wise manner. The reaction mixture was stirred at 25° C. for 2 hr and the progress of the reaction was monitored by TLC. The reaction mixture was then concentrated completely and again dissolved in DCM (250 ml). The organic layer so obtained was washed with water (2×50 ml), brine (1×50 ml) and dried over sodium sulfate and concentrated under reduced pressure to obtain crude product as semi-solid (10.2 g), which was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (9.0 g, 82.34%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])=[N:5]/[O:6][CH3:7].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][Br:16])=[N:5]/[O:6][CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO/N=C(/C(=O)OC)c1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CO/N=C(/C(=O)OC)c1ccccc1CBr
Temperature: 25 °C
Yield: 106.7 %

Procedure:
Methyl-(E)-2-(2-tolyl)-2-methoxyiminoacetate (4.74 g) was dissolved in carbon tetrachloride (100 ml), and N-bromosuccinimide (4.89 g) and benzoylperoxide (554 mg) were added thereto. The resultant mixture was heated under reflux for 1 hour and cooled to room temperature. insoluble materials were removed by filtration. On concentration of the solvent, the residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate to give methyl-(E)-2-(2-bromomethylphenyl)-2-methoxyiminoacetate (6.98 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[S:18]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:20]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1cc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c(C)c1
Yield: 64 %

Procedure:
2,4,6-Trimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,4,6-trimethylbenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a pink solid, m.p. 92-95° C., yield 64%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([C:36]#[C:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:30]=[CH:29]2.[BH4-].[Na+]>ClCCl.O.CO>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][N:46]([CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][CH2:38]/[CH:37]=[CH:36]\[C:31]1[CH:30]=[CH:29][C:28]2[C:33](=[CH:34][CH:35]=[C:26]([O:25][CH3:24])[CH:27]=2)[CH:32]=1)[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: COc1ccc2cc(C#CCOCCCCCCNCc3ccccc3)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc2cc(/C=C\COCCCCCCN(Cc3ccccc3)CC(O)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of N-[5-(bromoacetyl)-2-(phenylmethoxy)phenyl]methanesulphonamide (0.96 g), N-[6-[3-(6-methoxy-2-naphthalenyl)-2-propynyloxy]hexyl]benzenemethanamine (1.38 g) and DEA (0.47 g) in dichloromethane (22 ml) was stirred at room temperature under nitrogen for 22 h, diluted with water (100 ml) and extracted with dichloromethane (2×100 ml). The combined organic extracts were dried and evaporated in vacuo to give an oil. The oil was dissolved in methanol (20 ml) and dichloromethane (20 ml) and sodium borohydride (0.25 g) were added portionwise to the solution at 0° C. under nitrogen. The solution was stirred at room temperature for 1 h, cooled to 0° C. and a further portion of sodium borohydride (0.1 g) added. The solution was stirred at room temperature for 30 min and then carefully diluted with water (10 ml) and evaporated in vacuo. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous phase was re-extracted with dichloromethane (100 ml) and the combined organic fractions dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System C (100:2:1) gave the title compound as a colourless oil (0.77 g), t.l.c. (System C 98:2:1) Rf 0.23.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH:6]2[C:21](=[O:22])[N:8]3[C:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]23)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.[O:29]1CCCC1>O>[C:4]([C:3]1[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=1[C:1]([NH:5][CH:6]1[C:21](=[O:22])[N:8]2[C:9]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:28])([OH:29])=[O:23]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC1
Reactant: C1CCOC1
Solvent: O
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3C(=O)O)[C@H]2SC1

Procedure:
A solution of 800 mg. (2 mmol.) of t-butyl 7-phthalimido-3-methyl-3-cephem-4-carboxylate in 25 ml. of tetrahydrofuran and 8 ml. of water was cooled in an ice bath. To the solution 660 mg. of Na2S.9H2O were added, and the mixture was stirred and cooled for 10 min. At the end of this period 10 ml. of water were added, and the mixture was extracted with 40 ml. of ethyl acetate. The extract was discarded. The aqueous portion was acidified to pH 4.3 with 1N H2SO4 and then extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated, giving 700 mg. of the title compound. The product was recrystallized from chloroform/cyclohexane; m.p. 178°-179°; ir (nujol) 1770, 1735, and 1680 cm-1 ; nmr (CDCl3 + DMSOd6) δ 1.5 (s, 9, t-Bu), 2.1 (s, 3, CH3), 3.2 and 3.5 (ABq, 2, J = 18 Hz), 5.02 (d, 1, J = 4.5 Hz), 5.82 (dd, 1, J = 4.5 and 9Hz), and 7.4-8 (m, H, ArH).
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH2:12][C@@H:11]([NH:14][CH3:15])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([N:22]([CH2:29][C:30](O)=[O:31])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:9]1[CH2:13][CH2:12][C@@H:11]([N:14]([CH3:15])[C:30](=[O:31])[CH2:29][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN[C@@H]1CCN(C(=O)c2ccccc2)C1
Reactant: O=C(O)CN(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C(=O)CN(c1ccccc1)c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of (R)-(1-benzoyl-pyrrolidin-3-yl)-methyl-amine(0.32 g, 1.68 mmol) in dry CH2Cl2 (20 ml) was added diphenylaminoacetic acid (0.38 g, 1.68 mmol) under nitrogen. To the reaction was added EDC (0.65 g, 3.36 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give 0.68 g of desired product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([N:20]([CH3:22])[CH3:21])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:21][N:20]([CH3:22])[C:18]1[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=[CH:16][N:17]=1
Reactant: CN(C)c1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ncnc(N2CCNCC2)n1
Temperature: 40 °C

Procedure:
A solution of 1 mmol of 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dichloromethane was chilled and treated with 14 mmol of trifluoroacetic acid. The reaction mixture was heated to 40° C. for 30 min. After cooling, 50 ml of 2M aqueous sodium hydroxide is added. The organic layer was separated, dried and concentrated to yield the title compound as a yellowish oil. MS (m/e): 267.0 (M+CH3COO+, 100%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=O)[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.B(F)(F)F.CCOCC.C1(C)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2c(cc1OC)CCN(CCCCl)CC2
Temperature: 100 °C

Procedure:
Here, 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane (1.5 g, 0.005 mol) is dissolved in tetrahydrofuran (20 ml) and, after the addition of boron trifluoride etherate (0.55 ml, 0.0044 mol) and a 2 molar solution of boranedimethylsulfide in toluene (3 ml, 0.006 mol), the mixture is refluxed for 2 hours. Then, further boranedimethylsulfide solution (3 ml) is added and again the mixture is refluxed for 2 hours. After decomposition with methanol the solvents are distilled off and the residue is heated to 100° C. for 10 minutes with semi-concentrated hydrochloric acid (6 ml). The reaction product is extracted with ethyl acetate, the acidic aqueous phase is made alkaline and again extracted with ethyl acetate. The extract is dried, concentrated by evaporation and purified over an aluminium oxide column (activity stage II-III) with methylene chloride.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([OH:7])=[CH:5][CH3:6].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>CN(C)C=O>[CH2:24]([O:8][CH2:3][CH:4]([OH:7])[CH:5]=[CH2:6])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC=C(O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(O)COCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 18.5 q of washed sodium hydride in 500 ml of dry dimethylformamide in a water bath is added dropwise, 67.4 q of 2-butene-1,2-diol. A solution of 235 g of hexadecylbromide in 100 ml of dimethylformamide is added dropwise. This mixture is stirred at room temperature for 2 days then poured into water and extracted with ether. The ether extract is separated, dried, evaporated and purified by chromatography, to give 30 g of the desired compound.