Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21]S(C)(=O)=O)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21][C:33]3[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=3)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COS(C)(=O)=O)cs2)CC1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Temperature: 40 °C

Procedure:
A mixture of 4-(4-methanesulfonyloxymethyl-thiazol-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.5 mmol), 4-methanesulfonyl-phenol (86 mg, 0.5 mmol) and Cs2CO3 (170 mg, 0.52 mmol) in acetonitrile (4 mL) was heated at 40° C. overnight. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.83 (2H, m), 7.23 (1H, s), 7.09 (2H, m), 5.2 (2H, s), 3.64-3.54 (2H, m), 3.3˜3.24 (2H, m), 2.99 (3H, s), 2.2˜2.1 (2H, m), 1.72-1.64(2H, m), 1.41 (9H, s), 1.36 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4]([CH3:6])=O.[CH2:9]([NH2:12])[CH:10]=[CH2:11].[BH4-].[Na+]>C(O)C>[CH2:9]([NH:12][CH:4]([CH3:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1])[CH:10]=[CH2:11]
Reactant: C=CCN
Reactant: COC(OC)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCNC(C)C(OC)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
20 g of molecular sieve are added to 12 g (0.1 mol) of 1,1-dimethoxyacetone in 100 ml of ethanol and 7 g (0.12 mol) of allylamine are then added dropwise. The mixture is allowed to stand overnight at room temperature, decanted from the molecular sieve and cooled in an ice-bath to 0° C., and 4 g (0.1 mol) of sodium borohydride are added in small portions. The mixture is stirred overnight at room temperature and concentrated, the residue is taken up in 100 ml of water, and the mixture is saturated with potassium carbonate and extracted five times with 100 ml of chloroform each time. The extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([NH2:31])[CH:28]([CH3:30])[CH3:29].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:20](=[O:21])[C:19]1[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=1[C:17]([NH:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)CN
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)C1=C(C(=O)Nc2cc(OC3CCC(C)C3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.20 g, 3.18 mmol), isobutylamine (0. 360 g, 4.92 mmol), triethylamine (0.450 g, 4.44 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-isobutyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.700 g, 48.7% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3](=O)[CH2:4][C:5](=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1>C(O)C.O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:5]([CH:6]=[CH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][C:3]([C:2]([F:17])([F:16])[F:1])=[N:28]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(C=Cc1ccccc1)CC(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2nc(C(F)(F)F)cc2C=Cc2ccccc2)cc1
Yield: 17.8 %

Procedure:
1,1,1-Trifluoro-6-phenylhex-5-ene-2,4-dione (2.28 mmol) and 4-methoxyphenylhydrazine hydrochloride (435 mg, 2.5 mmol) were heated in ethanol (7 mL) at 70° C. overnight. The solution was diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with 1 N HCl, saturated sodium bicarbonate solution, and brine, then dried over MgSO4 and concentrated. SiO2 chromatography with 5-20% ethyl acetate/hexanes gave 0.14 g of the desired product, along with many mixed fractions. Only the clean fractions were carried on. LC-MS (C19H15F3N2O calculated 344) m/z 345 (M+H); 1H NMR (300 MHz, CDCl3) 7.43-7.30 (m, 7H), 7.12 (d, J=16.2 Hz, 1H), 7.05-7.00 (m, 2H), 6.88 (s, 1H), 6.78 (d, J=16.2 Hz, 1H), 3.89 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH:41]([OH:43])[CH3:42])/[CH:3]=[CH:4]/[CH2:5][CH:6]1[CH:11]([OH:12])[CH:10]([OH:13])[CH:9]([CH:14]([OH:40])/[C:15](/[CH3:39])=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]2[C:37](=[O:38])[NH:36][C:32]3=[CH:33]S[S:35][C:31]=23)=[O:28])=[O:18])[O:8][CH2:7]1.O[O:45][S:46]([O-:48])=O.[K+].C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH3:1][C@@H:2]([C@@H:41]([OH:43])[CH3:42])/[CH:3]=[CH:4]/[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([C@H:14]([OH:40])/[C:15](/[CH3:39])=[CH:16]/[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:29][C:30]2[C:37](=[O:38])[NH:36][C:32]3=[CH:33][S:46]([S:35][C:31]=23)(=[O:48])=[O:45])=[O:28])=[O:18])[O:8][CH2:7]1
Reactant: C/C(=C\C(=O)OCCCCCCCC(=O)Nc1c2sscc-2[nH]c1=O)C(O)C1OCC(C/C=C/C(C)C(C)O)C(O)C1O
Reactant: O=S([O-])OO
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C/C(=C\C(=O)OCCCCCCCC(=O)NC1=C2SS(=O)(=O)C=C2NC1=O)[C@@H](O)[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Yield: 75 %

Procedure:
100.9 mg of thiomarinol (prepared as described in Example 6) were dissolved in a mixture of 5 ml of acetone and 5 ml of water, and then the resulting solution was ice-cooled. 112.2 mg of OXONE (a trade name for a product of Aldrich Chemical Co., Inc.) were added to the resulting solution, and then the mixture was stirred, whilst ice-cooling, for 40 minutes. At the end of this time, 1.2 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to this mixture, and the mixture was again stirred, whilst ice-cooling, for 30 minutes. 5 ml of water were then added to the reaction mixture, which was then extracted with a 10:1 by volume mixture of methylene chloride and tetrahydrofuran. The extract was dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was then isolated and purified by reverse phase, high performance liquid chromatography (using a Senshu Pak ODS-5251-N column, and 40% v/v aqueous acetonitrile as the eluent), to obtain 79.5 mg (yield 75%) of thiomarinol B having a light yellow color and having the physico-chemical properties listed above.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.C(N(CC)CC)C.[C:29]1([CH3:43])[CH:34]=[CH:33][C:32]([C:35]#[C:36][P:37](=[O:42])([OH:41])[O:38][CH2:39][CH3:40])=[CH:31][CH:30]=1.[Cl:44][CH2:45][CH2:46][CH2:47][C:48]#[CH:49]>[Au].ClC(Cl)C>[C:29]1([CH3:43])[CH:30]=[CH:31][C:32]([C:35]#[C:36][P:37](=[O:41])([O:42][C:48]([CH2:47][CH2:46][CH2:45][Cl:44])=[CH2:49])[O:38][CH2:39][CH3:40])=[CH:33][CH:34]=1
Reactant: C#CCCCCl
Reactant: CCOP(=O)(O)C#Cc1ccc(C)cc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(CCCCl)OP(=O)(C#Cc1ccc(C)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.9 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) and triethylamine (Et3N) (3.0 mg, 0.03 mmol) were put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen p-tolylethynylphosphonate (67.3 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain ethyl 5-chloropent-1-en-2-yl p-tolylethynylphosphonate (68.5 mg, 70%) which is a title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)C(C)C)c(O)c21
Reaction time: 3 h
Yield: 105.1 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), isobutyryl chloride (42.5 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 3 hr. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (118 mg, yield 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>[Ni].O.C(O)C>[NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: c1cnc2c(c1)NCC2
Yield: 11.8 %

Procedure:
1.49 g of Raney nickel at 50% in water are added to a solution of 1.5 g of 4-azaindole in 45 ml of absolute ethanol, in an autoclave under argon. The mixture is hydrogenated under 100 bar of hydrogen at a temperature of 95° C. for 41 h. After a return to ambient temperature, the catalyst is filtered off through Clarcel and the filtrate is concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 70 g 15-40 μm silica cartridge, elution being carried out with pure dichloromethane and then with a 99/1 v/v mixture of dichloromethane/methanol with a flow rate of 80 ml/min, and then on a 30 g 15-40 μm silica cartridge, elution being carried out with pure dichloromethane with a flow rate of 30 ml/min. 0.18 g of 4-azaindoline is thus obtained in the form of a pale yellow solid which melts at 63° C. (Kofler bench).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Solvent: c1ccncc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline (2.2 mmol) in pyridine (4 mL) was treated with phenyl isocyanate (2.4 mmol) and stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and purification of the residue by flash chromatography (80-100% ethyl acetate/hexanes) provided the title product as a white powder (50%). ESMS [M+H]+: 423.2
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.CCCCCC>CN(C=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:2][C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(=O)CSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
1-Chloro-propan-2-one (1.0 g, 11.63 mmol) and potassium carbonate (2.9 g, 21.15 mmol) were added to a solution of 4-bromo-benzenethiol (2.0 g, 10.58 mmol) in DMF (5.0 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (100% hexane). The reaction mixture quenched with ice and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to yield the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 2.0 g of the product (80% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>ClCCl>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:27](=[O:28])[CH2:26][O:25][C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)COc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Solvent: ClCCl
Product: CN1CCN(C(=O)COc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetic acid (150 mg, 0.39 mmol) in dichloromethane (3 mL) is added oxalyl chloride (490 mg, 3.9 mmol) and 1 drop of N,N-dimethylformamide. The mixture is stirred at room temperature for 5 h, concentrated in vacuo, and residual solvents removed by co-evaporation three times with chloroform to yield [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride as a yellow solid. To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yloxy]-acetyl chloride (50 mg, 0.12 mmol) in dichloromethane at room temperature is added 1-methyl-piperazine (62 mg, 62 mmol) and the mixture stirred for 2.5 h. The mixture is partitioned between dichloromethane and water, the organic portion dried (sodium sulfate), filtered, and concentrated in vacuo. The crude residue is chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 28 mg (48%), as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[C:27]([Cl:34])[CH:26]=1.CCN(CC)CC>ClCCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:33])=[C:27]([Cl:34])[CH:26]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCC2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclobutyl-amine was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 days under reflux conditions to give the title compound as yellow oil. MS: m/e=509.4 [M+H+].
Reaction SMILES: CC[OH:3].[Br:4][C:5]1[CH:6]=[C:7]([N+:13]([O-])=O)[C:8]([C:11]#[N:12])=[N:9][CH:10]=1.C(OCC)(=O)C>[Ni].CCCCCC>[NH2:13][C:7]1[C:8]([C:11]([NH2:12])=[O:3])=[N:9][CH:10]=[C:5]([Br:4])[CH:6]=1
Reactant: CCO
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NC(=O)c1ncc(Br)cc1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 23 %

Procedure:
To a 100 mL round bottom flask, Raney Nickel (2.5 g) and EtOH (150 mL) were added. To the same flask was added 5-bromo-3-nitropyridine-2-carbonitrile (5 g, 0.0219 mol). The reaction mass was stirred under hydrogen for 14 h at ambient temperature. The catalyst was removed by filtration. The clear filtrate was evaporated to provide the crude product. The crude was subjected to column chromatography (60-120 silica gel, 30% ethyl acetate in hexane) to provide the title compound as a light yellow solid [1.1 g, 23%]. 1H NMR (300 MHz, DMSO-d6): δ 7.89 (brs, 1H), 7.79 (d, J=1.8 Hz, 1H), 7.40 (brs, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.04 (brs, 2H): LC-MS (ESI): Calculated mass: 215.0; Observed mass: 216.8 [M+H]+ (RT: 0.38 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1I.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(I)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)OC)c(Oc2ccccc2)c1
Yield: 103.7 %

Procedure:
2-Iodo-terephthalic acid dimethyl ester (10 g, 31 mmol), phenol (3.23 g, 34 mmol), tetrakis-acetonitrilecopper hexafluorophosphate (2.9 g, 7.8 mmol), and cesium carbonate (10.2 g, 31 mmol) were added to a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, a reflux condenser and containing toluene (350 mL). The reaction was refluxed 5 h under nitrogen with stirring. After cooling, EtOAc (200 mL) was added and the mixture was filtered. The filtrate was concentrated to afford the crude title compound (9.2 g) that was used without purification.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[CH:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[C:16]([CH3:20])([CH2:18]Br)[S:17][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:29](=[O:30])[N:14]2[C:15]([C:21]([O:23][CH2:24][C:25]([Cl:27])([Cl:26])[Cl:28])=[O:22])=[C:16]([CH3:18])[CH2:20][S:17][C@H:13]12)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenoxyacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (500 mg.), chloroform (10 cc) and pyridine (170 mg.) was heated under reflux for 10 hours. After cooling, the reaction mixture was washed with water, dilute phosphoric acid and water in order, dried and then concentrated. The residue was subjected to chromatography on silica gel and eluated to yield an oil. The oil was crystallized from a mixture of acetone and petroleum ether to yield 2,2,2-trichloroethyl 7-(2-phenoxyacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 111°-113° C.
Reaction SMILES: CN(C)C1C=CC=CC=1.[Br:10][CH2:11][C:12](Br)=[O:13].[CH2:15]([O:22][C:23]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[C:26]([NH2:27])=[C:25]([C:34]([F:37])([F:36])[F:35])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([C:34]([F:36])([F:37])[F:35])[C:26]([NH:27][C:12](=[O:13])[CH2:11][Br:10])=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Br)CBr
Reactant: Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(CBr)Nc1c(C(F)(F)F)cc(OCc2ccccc2)cc1C(F)(F)F
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Under an argon atmosphere, N,N-dimethylaniline (2.78 mL, 21.9 mmol) and bromoacetyl bromide (1.91 mL, 21.9 mmol) were added dropwise to a solution of 4-benzyloxy-2,6-bis(trifluoromethyl)aniline (4.90 g, 14.6 mmol) in anhydrous toluene (150 mL) under ice cooling. Immediately after the dropwise addition, the mixture was heated under reflux and then stirred for 1 hour. After cooling, the reaction mixture was filtered through Celite and the insoluble matter was washed with toluene. The residue obtained by distilling the filtrate under reduced pressure was purified by chromatography on a silica gel column (developing solvent; hexane:acetone=10:1→6:1→5:1). The crude product thus obtained was recrystallized from hexane-acetone, whereby 4.31 g (yield: 64.7%) of N-[4-benzyloxy-2,6-bis(trifluoromethyl)phenyl]-2-bromoacetamide was obtained as colorless needle-like crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[OH:20]O>[Cl-].[Na+].O.C[Re](=O)(=O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][N+:14]([O-:20])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: CC(C)(C)c1ccc(-c2ccncc2)cc1
Agent: C[Re](=O)(=O)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(-c2cc[n+]([O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the mixture of 4-[4-(tert-butyl)phenyl]pyridine (8.7 g, 41 mmol) and methyltrioxorhenium (VII) (Aldrich) (170 mg, 0.7 mmol) in a 100-mL round-bottomed flask was added CH2Cl2 (18 mL). The mixture was then treated with 12 mL of hydrogen peroxide (Aldrich) dropwise. The reaction was stirred at room temperature under nitrogen overnight. Methylene chloride and brine were then added, and the aqueous layer was extracted with CH2Cl2 (40 mL). The organic layer was dried over Na2SO4, concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 228 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1ccc2ncccc2c1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2ccc3ncccc3c2)n1
Yield: 75 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 6-hydroxyquinoline (270 mg, 1.49 mmol), and purification by column chromatography (AcOEt cyclohexane, 1:1), the title compound was obtained (324 mg). Yield: 75%. 1H NMR (250 MHz, DMSO-d6) δ 7.56-7.59 (m, 1H, Harom 3), 7.70 (dd, 1H, Harom 7, Jm=2.6 Hz, Jo=9.1 Hz), 7.87 (d, 1H, Harom 5, J=2.4 Hz), 8.12 (d, 1H, Harom 8, J=9.0 Hz), 8.37 (d, 1H, Harom 4, J=8.1 Hz), 8.56 (s, 1H, HPz 5) 8.65 (s, 1H, HPz 3), 8.93 (dd, 1H, Harom 2, J=1.0 Hz, J=4.9 Hz). m/z: 258.0 [(M+H)+, calcd for C13H8ClN3O 257.0].
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].C(O)C>[NH2:15][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9]
Reactant: Cc1cccc(S(=O)(=O)NC(C)C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1N
Yield: 100 %

Procedure:
To a mixture of 4.13 g of the material from Step A and 0.25 g of 10% palladium on carbon was added 150 mL of ethanol. The reaction mixture was stirred under a balloon of hydrogen for three days. The mixture was filtered through celite and the solvent was removed with a rotary evaporator to afford 3.65 g of the title compound as a brown oil. 1H NMR (CDCl3) δ 1.03 (d, 6H), 2.21 (s, 1H), 3.60 (m, 1H), 4.57 (br d, 1H), 4.86 (br s, 2H), 6.73 (dd, 1H), 7.24 (d, 1H), 7.64 (d, 1H).