Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:12][N:10]1[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6][CH:5]([CH2:4][CH2:3][N:19]([CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: CNc1ccccc1
Agent: Cl
Product: CN1CC(CCN(C)c2ccccc2)Oc2ncccc2C1=O
Temperature: 95 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
2-(2-Chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one hydrochloride, 4.00 g (0.015 mole) was dissolved in N-methylaniline (30 ml) and heated to 95° C. with stirring for 2 days. Excess N-methylaniline was removed by rotary evaporation (95° C., vacuum pump). The residue was taken up in chloroform (80 ml) and washed with dilute aqueous sodium hydroxide (30 ml) The chloroform layer was decolorized with activated carbon and dried over sodium sulfate, filtered and concentrated by rotary evaporation. The remaining residue was dissolved in ethyl acetate (50 ml) and purified by high pressure liquid chromatography using a silica gel column and ethyl acetate as the eluent. After purification, crystals formed from ethyl acetate. These crystals were recrystallized from ethyl acetate, giving 1.40 g (31%) of pale brown crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[Br:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O.O>[Br:9][C:3]1[C:2]([F:1])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][C:4]=1[F:8]
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(F)c1Br
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(Br)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 2,6-difluorobromobenzene (125.5 g, 650 mmol) in 98% sulphuric acid (250 ml) was cooled in an ice-water bath and then treated with a 1:1 mixture of 98% sulphuric acid and fuming nitric acid (100 ml) added at such a rate that the internal temperature never exceeded 35° C. Once addition was complete the reaction was stirred at ambient temperature for 3 h then poured onto ice. This mixture was diluted with water (final volume 5 l), the resulting solid collected by filtration, washed with water, then dried under vacuum over phosphorus pentoxide, to afford 2-bromo-1,3-difluoro-4-nitrobenzene as a cream-coloured solid (145 g, 94%): 1H NMR (360 MHz, CDCl3) δ 7.10–7.15 (1H, m), 8.09–8.16 (1H, m).
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[C:6]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:5]=1
Reactant: CN(Cc1ccccc1)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(c2ccc(C(=O)N(C)Cc3ccccc3)cc2S(N)(=O)=O)CC1
Reaction time: 48 h

Procedure:
33.8 Grams of 4-chloro-3-sulfamoylbenzoic acid-N-methylbenzylamide (0.1 mole) were heated with 80 ml of N-methylpiperazine for 4 hours under reflux. Subsequently the solution was introduced into 0.4 l of water, the pH value of the mixture was adjusted to 9.0 by means of glacial acetic acid, and the mixture was then allowed to stand for 2 days at room temperature. The crystalline precipitate was separated and was recrystallized from a mixture of ethanol and water.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li]CCCC.[Li]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[N:32]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)CCCC(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-acetylbutyric acid 1-7 (25.0 g, 192 mmol), triethylamine (29.5 ml, 211 mmol) in tetrahydrofuran (500 mL) at −78° C. was added pivaloyl chloride (26.0 ml, 211 mmol). After 20 min, the mixture was warmed to 0° C. for 1.0 h and then recooled to −78° C. To a stirred solution of (S)-(−)-4-benzyl-2-oxazolidinone (37.4 g, 211 mmol) in tetrahydrofuran (500 ml) at −78° C. was added nBuLi (84.5 ml, 211 mmol, 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 10 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 1-8 as a solid which was triturated with ethyl ether and filtered to give a white solid.
Reaction SMILES: [H-].[K+].O1CCCC1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@:16]([OH:45])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:17]([S:19][C@@H:20]1[CH2:25][O:24][C@@H:23](/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])[O:22][CH2:21]1)[CH3:18].Cl[C:47]([O:49][CH2:50][CH2:51][Cl:52])=[O:48]>CCCCCC.C(OCC)(=O)C>[C:47](=[O:48])([O:45][C@:16]([C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[F:8])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:17]([S:19][C@@H:20]1[CH2:25][O:24][C@@H:23](/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])[O:22][CH2:21]1)[CH3:18])[O:49][CH2:50][CH2:51][Cl:52]
Reactant: O=C(Cl)OCCCl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@@](Cn1cncn1)(OC(=O)OCCCl)c1ccc(F)cc1F
Temperature: 0 °C
Yield: 88.8 %

Procedure:
A mixture of potassium hydride (30% dispersion in mineral oil; 739 mg, 5.53 mmol) and tetrahydrofuran (8 ml) was cooled to 0° C., and 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (1.00 g, 1.84 mmol) described in Reference example 1 was added thereto with stirring, then the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0° C., and then a mixture of 2-chloroethyl chloroformate (315 mg, 2.21 mmol) and tetrahydrofuran (1.5 ml) was added thereto with stirring. The resulting mixture was stirred at room temperature for 18 hours. After cooling, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to give an oily residue. The residue was subjected to column chromatography (eluent; ethyl acetate:hexane=1:1) to afford the title compound (1.06 g, 88% yield) as a colorless oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CC(O)CN
Product: CC(O)CNc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccccc1

Procedure:
5-(2-Hydroxy-propylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 1-amino-2-propanol. Mass spectrum (ES) MH+=395.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][O:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:39][CH2:40][CH2:41][CH2:42][CH2:43]Br>CN(C=O)C.CCOC(C)=O>[Br:39][CH2:40][CH2:41][CH2:42][CH2:43][N:12]([O:13][C:14]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10](=[O:11])[CH2:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: BrCCCCBr
Reactant: O=C(CSc1ccc(F)cc1)NOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CSc1ccc(F)cc1)N(CCCCBr)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-fluoro-phenylsulfanyl)-N-trityloxy-acetamide (132.1 mg, 0.228 mmol) from step C and Cs2CO3 (125.6 mg, 0.385 mmol) in anhydrous DMF (3 mL) was added 1,4-dibromo-butane (0.2 ml, 364.8 mg) in one portion and the resulting solution was warmed to 60° C. After TLC indicated the completion of the reaction (<30 min), the reaction mixture was diluted with EtOAc and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material, which was then used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)=[N:6][CH:7]=1.N12CCCN=C1CCCCC2.[CH:28]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29]1.C1C[O:40][CH2:39]C1>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[Cl:15])[O:8][C:5]1[N:6]=[CH:7][C:2]([C:39]([N:34]2[CH2:33][CH2:32][N:31]([CH:28]([CH3:29])[CH3:30])[CH2:36][CH2:35]2)=[O:40])=[CH:3][CH:4]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: C1CCOC1
Reactant: Clc1ccc(Oc2ccc(Br)cn2)cc1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)N1CCN(C(=O)c2ccc(Oc3ccc(Cl)c(Cl)c3)nc2)CC1
Temperature: 125 °C
Yield: 76 %

Procedure:
To a solution of 5-bromo-2-(3,4-dichloro-phenoxy)-pyridine (0.303 g, 0.949 mmol) in THF (4 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.30 mL, 2.0 mmol), cyclopropyl piperazine (0.30 mL, 2.4 mmol), trans-di-m-acetatobis[2-(di-o-tolylphosphino)benzyl]di-palladium (II) (Hermann's catalyst; 36.7 mg, 0.039 mmol), t-BuPHBF4+ (17.4 mg, 0.060 mmol), and Mo(CO)6 (301 mg, 1.14 mmol). The reaction mixture was heated in the microwave for 6 min at 125° C., cooled to rt, then concentrated. Purification by FCC gave the desired product (284 mg, 76%). MS (ESI): mass calcd. for C19H21Cl2N3O2, 393.10; m/z found, 394.7 [M+H]+. 1H NMR (CDCl3): 8.24 (dd, J=2.5, 0.8 Hz, 1H), 7.83 (dd, J=8.3, 2.5 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.30 (d, J=2.8 Hz, 1H), 7.03 (dd, J=8.8, 2.5 Hz, 1H), 7.00 (dd, J=8.3, 0.8 Hz, 1H), 3.90-3.40 (br m, 4H), 2.74 (h, J=6.8 Hz, 1H), 2.64-2.43 (br m, 4H), 1.04 (d, J=7.1 Hz, 6H).
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14]C=2)[C:6]1=[O:18].[NH2:20][O:21][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[CH2:10]([N:7]1[CH2:8][CH2:9][CH:5]([CH2:4][C:3]([NH:20][OH:21])=[O:19])[C:6]1=[O:18])[C:11]1[CH:12]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CC1CCN(CCc2ccccc2)C1=O
Reactant: NO[K]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CC1CCN(Cc2ccccc2)C1=O)NO
Temperature: 0 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
12 mg of (2-oxo-1-phenethyl-pyrrolidin-3-yl)-acetic acid methyl ester (25r) prepared by the above Step 1 was dissolved in methanol solution (0.04 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.07 ml, 0.12 mM) was added thereto at 0° C. and the resulting mixture was stirred for 4 hrs at room temperature. The resulting mixture was neutralized with 0.02 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 1.6 mg of 2-(1-benzyl-2-oxo-pyrrolidin-3-yl)-N-hydroxy-acetamide (25s) (yield: 8%).
Reaction SMILES: [P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])(N)(=[O:3])[OH:2].[P:25](=[O:29])([OH:28])([OH:27])[OH:26]>N1C=CC=CC=1>[P:1]([O:5][C@@H:6]1[C@@H:10]([CH2:11][OH:12])[O:9][C@@H:8]([N:13]2[C:23]3[N:22]=[C:20]([NH2:21])[NH:19][C:17](=[O:18])[C:16]=3[N:15]=[CH:14]2)[C@@H:7]1[OH:24])([O:27][P:25]([OH:29])([OH:28])=[O:26])(=[O:3])[OH:2]
Reactant: O=P(O)(O)O
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(N)(=O)O)[C@H]2O)c(=O)[nH]1
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](OP(=O)(O)OP(=O)(O)O)[C@H]2O)c(=O)[nH]1
Reaction time: 96 h

Procedure:
A mixture of 0.35 millimoles of the guanosine-3'-monophosphoramidate and 1.5 millimoles of inorganic phosphoric acid was dissolved in 2.0 ml of dried pyridine, the solution was left to stand at room temperature for a period of 3 or 4 days, the undissolved matter was filtered off, and the filtrate was concentrated under vacuum to remove the pyridine. The residue was dissolved in 25 ml of an aqueous solution that contained 1 g of sodium acetate, the solution was adjusted to a pH of 7.0 with sodium hydroxide, and washed five times with ether twice the volume of the solution to remove the guanidium salt. The solution was then passed through a column of Dowex 2 (Cl- type: manufactured by Dow Chemical Co.) to remove the unreacted guanosine-3'-monophosphoramidate. The solution was treated with lithium hydroxide to bring its pH to 6.5, concentrated under vacuum, the residue was dissolved in 25 ml of methanol, to which was added 200 ml of acetone to precipitate the crystal of a lithium salt of guanosine-3'-diphosphate. The crystal was passed through a column of Dowex 50 (H+ type) for desalting. The eluate was collected, concentrated under vacuum, and the residue was lyophilized to give guanosine-3'-diphosphate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH3:15].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>CCOCC.O>[Cl:27][CH2:28][C:29]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH3:15])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Cl)cc1NCC1OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1ccc(Cl)cc1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)-2-methyl-5-chloroaniline (8 grams), sodium bicarbonate (7 grams), dioxane (50 ml) and water (4 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. This mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (4.3 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about 1 hour. After this time ether (100 ml) was added to the mixture and the resulting solution was washed with water. The washed solution was then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from hexane to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2-methyl-5-chloroaniline having a melting point of 88° to 89°C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.[OH-].[NH4+]>ClC(Cl)Cl>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[N:6]=[N:7][C:2]([N:27]3[CH2:28][CH2:29][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[CH:19]=4)[CH2:25][CH2:26]3)=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: CCc1ccc(Oc2ccc(Cl)nn2)cc1
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1ccc(Oc2ccc(N3CCN(c4cccc(C)c4)CC3)nn2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A mixture of 4 parts of 6-chloro-3-(4-ethylphenoxy)pyridazine and 6 parts of 1-(3-methylphenyl)piperazine was stirred and heated for 3 hours in an oil bath at 110° C. The whole was alloWed to stand overnight. Concentrate ammonium hydroxide and trichloromethane were added. The precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.7 parts (27%) of 3-(4-ethylphenoxy)-6-[4-(3-methylphenyl)-1-piperazinyl]pyridazine; mp. 106.6° C. (compound 221).
Reaction SMILES: [CH3:1][C:2]([CH3:46])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:45])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:44])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:43])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:42])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:41])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:40])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:39])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:38])=[CH:35]/[CH2:36]O.[CH3:47][O:48][CH:49]1[C:54]([O:55][CH3:56])=[C:53]([OH:57])[CH:52]=[CH:51][C:50]1([OH:59])C.[CH3:60]CCCCC>[N+](C)([O-])=O.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[CH3:56][O:55][C:54]1[C:49]([O:48][CH3:47])=[C:50]([OH:59])[C:51]([CH3:60])=[C:52]([CH2:36]/[CH:35]=[C:34](\[CH3:38])/[CH2:33][CH2:32]/[CH:31]=[C:30](\[CH3:39])/[CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:40])/[CH2:25][CH2:24]/[CH:23]=[C:22](\[CH3:41])/[CH2:21][CH2:20]/[CH:19]=[C:18](\[CH3:42])/[CH2:17][CH2:16]/[CH:15]=[C:14](\[CH3:43])/[CH2:13][CH2:12]/[CH:11]=[C:10](\[CH3:44])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:45])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:46])[CH3:1])[C:53]=1[OH:57]
Reactant: CCCCCC
Reactant: COC1=C(O)C=CC(C)(O)C1OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Product: COc1c(O)c(C)c(C/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CC/C=C(\C)CCC=C(C)C)c(O)c1OC
Temperature: 50 °C

Procedure:
In a 50 ml four necked flask equipped with a stirrer, thermometer, gas inlet, and a reflux condenser, under argon atmosphere 0.654 g (96.52%, 1 mmol) of solanesol (nonaprenol, C45) were dissolved in 15 ml of n-hexane. The solution was mixed with 0.983 g (5.0 mmol) of 2,3-dimethoxy-1,4-dihydroxy-toluene (DMDHT) dissolved in 7.6 ml of nitromethane. The catalyst, Sc(OTf)3 (2.5 mg, 0.005 mmol) was then added. The two-phase mixture was heated up to 50° C. (internal temperature) under stirring (400 rpm). After 16 hours reaction time the mixture was cooled down to room temperature (21° C.). The hexane layer was separated and washed two times with 4 ml (total 8 ml) of nitromethane. The hexane phase was evaporated and yielded 0.78 g of crude 2,3-dimethoxy-5-methyl-6-((2E,6E,10E,14E,18E,22E,26E,30E)-3,7,11,15,19,23,27,31,35-nonamethyl-hexatriaconta-2,6,10,14,18,22,26,30,34-nonaenyl)-benzene-1,4-diol (H2-CoQ9), which was purified by column chromatography on 30 g silica (elution with n-hexane/ethyl acetate=99/1, v/v), to give 440 mg of an orange oil consisting of 73.2% H2-CoQ9 and 21% CoQ9 (formed from H2-CoQ9 by partial air oxidation during isolation and HPLC analysis), corresponding to yields of 40.4% H2-CoQ9 and 11.6% CoQ9, sum 52%.
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]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=O)=[CH:11]2)[C:4]=1[CH3:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[CH2:48]([CH2:50][NH2:51])[OH:49]>C(Cl)Cl>[OH:49][CH2:48][CH2:50][NH:51][C:19]([C:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[N:10]([CH2:9][C:5]2[C:4]([CH3:22])=[C:3]([O:2][CH3:1])[N:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:21]
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncccc32)c1C
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ncnc(Cn2cc(C(=O)NCCO)c3ncccc32)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
See FIG. 18(a). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (1 g, 3.35 mmol) was taken in DCM (20 mL) to get a suspension. Triethyl amine (1.394 mL, 10.06 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride (3.991 mL, 6.70 mmol). The reaction mass was stirred at RT for 5 minutes. Ethanol amine (6.02 mL, 10.06 mmol) was added and stirred at RT for 2 h. After completion of the reaction, diluted with DCM and then washed with water and brine solution. The organic layer was separated, dried, evaporated and the crude compound was purified by silica gel chromatography. Yield-45%. ES+MS m/z: 342 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s. 3 H ) 3.37-3.64 (m, 4 H ) 3.94 (s, 3 H ) 4.80 (t, J=4.99 Hz, 1 H ) 5.67 (s, 2 H ) 7.24 (dd, J=8.29, 4.52 Hz, 1 H ) 7.92 (d, J=8.10 Hz, 1 H ) 8.23 (s, 1 H ) 8.41 (s, 1 H ) 8.47 (d, J=4.52 Hz, 1 H ) 8.85 (t, J=5.37 Hz, 1 H ).
Reaction SMILES: NS(O)(=O)=O.ClCCl.[CH3:9][Si:10]([CH3:22])([CH3:21])NS(C1C=CC=CC=1)(=O)=O.[CH3:23][C:24]1[CH2:25][S:26](=[O:46])[C@@H:27]2[CH:34]([NH:35][C:36](=[O:44])[CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:33](=[O:45])[N:28]2[C:29]=1[C:30]([OH:32])=[O:31].[Br:47]N1C(=O)CCC1=O>>[Br:47][CH2:23][C:24]1[CH2:25][S:26](=[O:46])[C@@H:27]2[CH:34]([NH:35][C:36](=[O:44])[CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:33](=[O:45])[N:28]2[C:29]=1[C:30]([O:32][Si:10]([CH3:22])([CH3:21])[CH3:9])=[O:31]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Reactant: C[Si](C)(C)NS(=O)(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 40 %

Procedure:
0.1 mg (1 mmole) of amidosulfonic acid was added to the clear solution obtained by refluxing 75 ml of dichloromethane containing 0.76 g (3.3 mmoles) of N-trimethylsilylbenzenesulfonamide and 350 mg (1.0 mmole) of 3-methyl-7-phenylacetamido-3-cephem-4-carboxylic acid-1-oxide for one and a half hours and the mixture obtained was cooled in an ice-bath. Bromination was carried out in one hour with 0.26 g (1.46 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 40% yield of trimethylsilyl 3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: C(C1[CH:29]=[CH:28][C:6]([CH2:7][C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[C:11](=[O:16])[N:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([O:24]C)=[C:19]([Cl:26])[CH:18]=2)[C:9]3=[O:27])=[CH:5][CH:4]=1)#N.Br.C[CH2:32][O:33][C:34]([CH3:36])=[O:35]>>[CH3:32][O:33][C:34]([C:36]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]23[CH2:15][CH2:14][CH2:13][N:12]2[C:11](=[O:16])[N:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[C:19]([Cl:26])[CH:18]=2)[C:9]3=[O:27])=[CH:28][CH:29]=1)=[O:35]
Reactant: COc1c(Cl)cc(N2C(=O)N3CCCC3(Cc3ccc(C#N)cc3)C2=O)cc1Cl
Reactant: CCOC(C)=O
Agent: Br
Product: COC(=O)c1ccc(CC23CCCN2C(=O)N(c2cc(Cl)c(O)c(Cl)c2)C3=O)cc1

Procedure:
A mixture of the compound from Example 139 (20 mg) and aqueous HBr (5 mL) was heated under reflux for 40 minutes. EtOAc was added and the organic layer was separated. The aqueous layer was extracted with EtOAC. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by preparative TLC (EtOAc). The obtained material was dissolved in MeOH (2 mL) and few drops of SOCl2 were added. The reaction mixture was heated under reflux for 1 hour. The residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated. The product was purified via preparative TLC. MS m/z 449 (MH+). mp. 105.3° C.