Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[CH:9]=[CH:8][CH2:7][CH2:6]1>C(Cl)Cl>[C:1]([C:7]1[CH:8]=[CH:9][C:6]2[O:5][CH2:9][CH2:8][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: C1=COCC1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 186.7 %

Procedure:
To a 0° C. solution of acetyl chloride (1.64 mL, 23.0 mmol, 1.3 equivalents) in methylene chloride (30 mL) was added stannic chloride (2.49 mL, 21.3 mmol, 1.2 equivalents), maintaining the temperature below 5° C. The solution was stirred 15 minutes at 0° C., and then a solution of 2,3-dihydrofuran (2.00 mL, 17.7 mmol) in methylene chloride (5 mL) was added dropwise while maintaining the temperature below 8° C. The dark red solution was stirred 1 hour at 2° C. and then poured into 50 mL of ice water. The reaction was stirred an additional 30 minutes, and the layers were separated. The organic layer was washed with water and aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on 150 9 silica gel, eluting with 18% ethyl acetate in hexanes. The solvents were removed under reduced pressure to yield the title compound (2.68 g, 93%) as a yellow solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][OH:10]>CCCCCC>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][Br:7]
Reactant: C1=COCCC1
Reactant: OCCBr
Solvent: CCCCCC
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mechanically stirred solution of dihydropyran (1000 mL) and a strong acid resin (10.0 g) in hexane (2000 mL) was added 2-bromoethanol (985 g) dropwise over a period of 1.5 hours in a cold water bath to maintain an internal temperature of 35°-40° C. After being stirred overnight at room temperature, the reaction mixture was chromatographed, with hexane as the eluent. The hexane was evaporated to give an amber liquid which was distilled through a 2 inch (5 cm) diameter vigreux cole, collecting the material boiling between 75°-95° C. (3,300-4,700 Pa). This material was redistilled to give the ether as an oil (1195.5 g); bp 80°-90° C. (2666 Pa); NMR: 4.68 (m, 1), 4.01 (m, 1), 3.89 (m, 1), 3.77 (m, 1), 3.52 (m, 3), 1.75-1.50 (m, 6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Cl[C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: NC(=O)c1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1
Temperature: 120 °C
Yield: 87 %

Procedure:
A mixture of 3-flouro-benzyl alcohol (1.0 g, 7.92 mmol), 2-chloro-5-nitro-benzamide (1.59 g, 7.92 mmol) and K2CO3 (1.31 g, 9.51 mmol) in DMA (5 ml) was heated at 120° C. for 7 h. The mixture was cooled to rt, diluted with EtOAc(40 ml), filtered and concentrated in vacuo to give 14A (2.0 g, 87%).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH3:87][N:88]([CH3:94])[C:89](=[O:93])[C:90](O)=[O:91]>>[CH3:87][N:88]([CH3:94])[C:89](=[O:93])[C:90]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:91]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)C(=O)C(=O)O
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except N,N-dimethyloxamic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 627.6 (M−H)−, 1.91 min (method 5). 1H NMR (500 MHz, 2:1 MeOD:CDCl3) δ=7.93 (d, J=8.2 Hz, 2H), 7.55 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 5.30 (dd, J=1.7, 6.3 Hz, 1H), 4.77 (d, J=1.2 Hz, 1H), 4.65 (s, 1H), 3.22 (s, 3H), 3.01 (s, 3H), 2.71-2.59 (m, 2H), 2.46 (dd, J=8.2, 11.9 Hz, 1H), 2.14 (dd, J=6.3, 17.2 Hz, 1H), 2.02-1.93 (m, 1H), 1.89 (dt, J=3.4, 12.2 Hz, 1H), 1.79 (d, J=13.1 Hz, 1H), 1.75 (d, J=3.7 Hz, 1H), 1.71 (br. s., 1H), 1.66 (dt, J=3.5, 13.5 Hz, 1H), 1.61-1.54 (m, 2H), 1.54-1.48 (m, 4H), 1.46 (br. s., 1H), 1.45-1.40 (m, 3H), 1.40-1.34 (m, 1H), 1.28 (br. s., 2H), 1.20-1.14 (m, 2H), 1.13 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1CO>[CH2:1]([N:8]([S:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]2[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:10]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cnc3c2c(C)nn3C)cc1
Temperature: 70 °C

Procedure:
A mixture of 0.48 g (0.97 mmol) of ethyl 4-[benzyl-(4-methoxybenzenesulfonyl) amino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate and 0.29 ml of 10N NaOH in 4 ml of tetrahydrofuran-methanol (1:1) was heated in an oil bath at 70° C. for 2 hours and the solvent removed under vacuum. The residue was dissolved in 20 ml of H2O and the solution extracted with 10 ml of diethyl ether. To the aqueous layer was added 2N citric acid (pH 4-5) and the precipitated solid filtered and washed with H2O to give a white solid which was dried under vacuum overnight to give crystals, mp 165-167° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A mixture of the 4-(pyridin-2-yloxymethyl)-benzaldehyde (26.8 g, 126 mmol) described in Manufacturing Example 2-2-2, nitromethane (34 mL, 630 mmol), ammonium acetate (19 g, 252 mmol) and acetic acid (90 mL) was stirred at 100° C. for 90 minutes. The reaction solution was partitioned into ethyl acetate and water. The organic layer was isolated, washed with water (5 times) and saturated aqueous sodium bicarbonate (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (31 g) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15](=[O:16])[NH:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15]([O:16][C:19](=[O:28])[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=c1[nH][nH]c(=O)c2c(O)c3ccc(Cl)cc3nc12
Solvent: O
Solvent: c1ccncc1
Product: O=C(CCc1ccccc1)Oc1n[nH]c(=O)c2nc3cc(Cl)ccc3c(O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-chloro-2,3-dihydro-10-hydroxypyridazino[4,5-b]quinoline-1,4-dione (0.60 g, 2.3 mM), as prepared in Example 2, and hydrocinnamoyl chloride (1.15 g, 6.84 mM) in pyridine (9 mL) was refluxed for 1 hr. Upon cooling to room temperature, the solution solidified. After 2 hr at room temperature, the mixture was diluted with water (60 mL) and the solids broken up with a glass rod to provide a free-flowing aqueous suspension which was stirred for 1 hr. The solids were collected, washed with water (10 mL), and resuspended in 50% aqueous methanol (60 mL). After stirring for 15 minutes, this suspension was filtered and the collected solids were washed with 50% aqueous methanol (10 mL) and then sucked dry under a stream of nitrogen to provide a tan solid. This material was dried for 2.5 days in vacuo (50 mTorr) at 100° C. and then was recrystallized from dimethylsulfoxide/methanol. The title compound was obtained (0.40 g, 44%), after drying 24 hr in vacuo (50 mTorr) at 100° C., as an off-white powder, mp >300° C.
Reaction SMILES: CC1C=C(C)C=C(C)C=1C=[N:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.[CH2:20]([Li])CCC.CI>O1CCCC1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([NH2:5])[CH3:20])=[CH:12][N:11]=1
Reactant: Cc1cc(C)c(C=NCc2ccc(Cl)nc2)c(C)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(N)c1ccc(Cl)nc1
Reaction time: 3 h

Procedure:
To a stirred solution of N-(2,4,6-trimethylbenzylidene)-2-chloro-5-pyridylmethylamine (10.9 g) in dried tetrahydrofuran (150 ml) cooled to -70° C. under N2 atmosphere was added butyl-lithium (10 w/v % in hexane, 26 ml), causing an immediate intense color to occur. After 30 minutes stirring at the temperature, methyl iodide (5.7 g) was added dropwise, and then the mixture was stirred for three hours without cooling. The solvent was removed under reduced pressure. To the residue, ethanol (50 ml) and 2N-hydrochloric acid (50 ml) were added and heated under reflux for one hour. The cooled solution was poured into water (100 ml) and extracted with methylene chloride (50 ml×2). The aqueous fraction was neutralized with 2N-sodium hydroxide and extracted with methylene chloride (50 ml×2). The extract was dried over sodium sulfate and evaporated to obtain 1-(2-chloro-5-pyridyl)ethylamine (4 g). nD20 1.5440
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>C(Cl)Cl>[CH3:16][NH:17][C:18]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1)=[O:19]
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Nc1ccc2c(c1)C(=O)NC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3 g. (14.7 mMole) 7-amino-4,4-dimethylisoquinoline-1,3-dione were dissolved in 100 ml. methylene chloride, mixed with 5 ml. methyl isocyanate, while cooling, and then further stirred for 2 hours at 25° C. Subsequently, the reaction mixture was evaporated, cooled, filtered off with suction and recrystallised from methanol. Yield: 3.7 g. (96.4% of theory); m.p. 257°-258° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:24][C:25](=[O:34])[C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[NH2:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:36]([C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH:48]=O)=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:36]([C:40]1[CH:54]=[CH:53][C:43]([O:44][C:45]2[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=2)[CH2:48][NH:33][C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[C:25]([NH:24][C@@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:16][CH:17]=3)=[CH:10][CH:11]=2)[C:3]([OH:2])=[O:35])=[O:34])=[CH:42][CH:41]=1)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C3CCCCC3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(Oc2cccc(CNc3ccc(Cl)cc3C(=O)N[C@@H](Cc3ccc(-c4ccc(C5CCCCC5)cc4)cc3)C(=O)O)c2)cc1
Reaction time: 7 h
Yield: 76 %

Procedure:
Reductive amination was carried out using (2S)-(2-amino-5-chloro-benzoylamino)-3-(4′-cyclohexyl-biphenyl-4-yl)propionic acid methyl ester (123 mg, 0.25 mmol), 3-(4-tert-butyl-phenoxy)-benzaldehyde (130 mg, 98%, 0.5 mmol), acetic acid (0.7 mmol), sodium triacetoxyborohydride (131 mg, 97%, 0.6 mmol) and DCE (2.5 mL). The mixture was stirred for 7 h. Purification by flash chromatography (ethyl acetate/hexanes 1:9) gave the title compound as colorless oil (139 mg, 0.19 mmol, 76% yield).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O.CC([O-])=O.[Na+]>>[CH3:15][C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][C@H:2]([CH2:3][CH2:4][CH2:20][C:19]([CH3:21])=[O:18])[CH3:1]
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Reactant: C=C(C)OC
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Product: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Yield: 87 %

Procedure:
44.9 g 3,7,11-trimethyl-1-dodecin-3-ol and 50.5 g isopropenyl methyl ether were initially introduced into a 300 ml V4A steel autoclave with a temperature probe, sampler and pressure indicator. 19 mg methanesulfonic acid were added, while stirring. The autoclave was forced up to 2 bar with nitrogen. The mixture was stirred at 90 to 95° C. for 8 hours. After cooling, the reaction mixture was neutralized with 1.7 ml methanolic NaOAc solution (10 g/1). After evaporation, the crude product was hydrogenated in 2-propanol with 10% Pd/A-charcoal. Phytone was obtained in a yield of 87%.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[CH3:33]B(O)O>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:18]=[C:19]([CH3:33])[CH:20]=[CH:21][CH:22]=3)(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:24]([N:26]2[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3cccc(Br)c3)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: CB(O)O
Product: Cc1cccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CCC(F)(F)C3)C2)c1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(3-Bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 188 step 4) and methylboronic acid. White solid (10%). MS (EI): 466.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].C(O)CC(C)C>C(O)CCC>[N+:11]([C:8]1[CH:9]=[CH:10][C:2]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN1CCN(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Solvent: CCCCO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCCN1CCN(c2ccccc2)CC1
Yield: 66.9 %

Procedure:
2-Chloro-5-nitrobenzoic acid (179 g), 182.5 g 1-(2-aminoethyl)-4-phenylpiperazine, 138 g K2CO3, 900 ml isoamyl alcohol and CuO catalyst were refluxed for 8 hours adding a pinch of CuO periodically. The mixture was cooled overnight, diluted with butanol and filtered. The solid was dissolved in water and neutralized to pH 4-4.5 with 3N HCl to give 247 g crude product. This was recrystallized from 3.5 liters dimethylformamide and 1 liter of water to give 220 g product, m.243-6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([NH:13][OH:14])=[O:12])=[CH:4][CH:3]=1.[OH:15]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][C:11]([NH:13][OH:14])=[O:12])=[O:15])=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C(CCSc1ccc(F)cc1)NO
Solvent: CC(=O)O
Product: O=C(CCS(=O)c1ccc(F)cc1)NO
Reaction time: 3 h

Procedure:
9.85 g (0.046 mol) of 3-(p-fluorophenylthio)-propiohydroxamic acid dissolved in 46 ml of acetic acid are oxidised by adding 4.6 ml of hydrogen peroxide of 110 volumes strength. The reactants are left in contact for 3 hours, the mixture is evaporated to dryness in vacuo, the residue is taken up in ethyl acetate and the product is filtered off and recrystallised from ethanol.
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:33])[CH:21]([NH:22][C:23](=[O:32])[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccc(Cl)c3)[C@H]2S1
Yield: 73.1 %

Procedure:
Acetic acid (4.1 ml) and zinc powder (3.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylate (2.6 g) in anhydrous dimethylformamide (30 ml), and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (150 ml) and ethyl acetate (75 ml), and then extracted. The extract was washed with water and dried. After the solvent was distilled off, the residue was crystallized by adding acetonitrile. The crystals were collected by filtration, washed with ether and dried to give colorless crystals of 2-methyl-7-[2-(3-chlorophenyl)acetamido]-3-cephem-4-carboxylic acid (1.4 g), mp 173° to 174° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23]>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(C)=CCCl
Reactant: CC(=O)c1c(O)cc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1c(O)cc(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
In 250 ml of anhydrous tetrahydrofuran was dissolved 50.0 g of 2',4',6'-trihydroxyacetophenone, and 123.1 g of anhydrous potassium carbonate was added to the solution and the mixture was stirred at room temperature for 30 minutes. Then, 37.2 g of 1-chloro3-methyl-2-butene was added dropwise to the mixture over a period of 20 minutes and reaction was carried out at room temperature for 24 hours. After the reaction, the reaction mixture was extracted with 2 l of ethyl acetate and the solvent was removed from the ethyl acetate layer by distillation, and the residue was recrystallized from a benzene/petroleum ether mixed solvent to obtain 38.6 g (yield=55.0%) of 2',4',6'-trihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a yellow prism.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])C1C=CC=CC=1>C1COCC1.CO.[Pd].[C]>[CH3:20][C:14]1([CH3:19])[CH2:13][CH:12]([N:21]([CH2:26][CH3:27])[S:22]([CH3:25])(=[O:24])=[O:23])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[O:15]1
Reactant: CCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O

Procedure:
12 g of N-[6-benzyloxy-2,2-dimethylchroman-4-yl]-N-ethylmethanesulfonamide were dissolved in 250 ml of THF/methanol (1:1) and hydrogenated in a shaking duck using Pd/carbon. After absorption of hydrogen was complete, the catalyst was filtered off with suction, the filtrate was concentrated and the residue was crystallized using diisopropyl ether, 7.7 g, m.p. 169-170° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH:26](/B(O)O)=[CH:27]\[CH3:28].C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:26]=[CH:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccccc2C1
Reactant: C/C=C/B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 61.6 %

Procedure:
To a solution of 2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (600 mg, 1.34 mmol) and trans-1-propen-1-ylboronic acid (460 mg, 5.36 mmol) in EtOH (10 mL) and dioxane (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0), (4.84% Pd, 285 mg, 0.13 mmol) and 2M aqueous solution of K2SO4 (2.68 mL, 5.36 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified by HPLC and gave the pure product (142) as white solid (300 mg, 63%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[C:23]#[N:24])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25](I)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.O>[C:9]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]#[N:24])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ICCc1ccccc1
Reactant: N#CC1CCCCN1C(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CCc2ccccc2)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 200 ml of a solution of lithium diisopropylamide (140 mmol) in tetrahydrofuran was added 15 g of solid 1-benzoyl-2-piperidinecarbonitrile at -78° C. and the mixture was stirred for 30 minutes. Then, 100 ml of a solution of 33.2 g of phenethyl iodide in tetrahydrofuran was added dropwise at -78° C. After completion of dropwise addition, the temperature of the reaction mixture was gradually increased to 0° C. The reaction mixture was diluted with water and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The pooled organic layer was dried over magnesium sulfate and filtered and the solvent was distilled off. The group was purified by silica gel column chromatography using ethyl acetate-hexane (1:2) as the eluent. The active fraction was concentrated under reduced pressure and the solid group was recrystallized from ethyl acetate-hexane to provide 17.3 g of colorless crystals.