Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH3:31]>ClCCl>[C:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([CH3:31])=[CH2:29]
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Reactant: CC(CBr)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(S(=O)(=O)N2CCN(CC3CCN(c4ccncc4)CC3)C(=O)C2)cc1
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (549 mg) and triethylamine (0.836 ml) in dichloromethane (10 ml) was added dropwise a solution of 4-(2-bromo-1-methylethyl)benzenesulfonyl chloride (893 mg) in dichloromethane (2 ml) at 0° C., and the mixture was stirred at 0 for 1 hour and then at room temperature for 6 hours. The reaction solution was diluted with dichloromethane, washed with water and saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in ethanol (20 ml), and to the solution was added 1 N sodium hydroxide (2 ml). The mixture was stirred at 80° C. for 30 minutes, and to the reaction solution was added ethyl acetate. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9:1→1:1) and washed with water to give colorless crystals of 4-(4-isopropenylbenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (155 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31]OS(C)(=O)=O)[C:6]=2[CH:37]=1.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][CH2:31][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[C:6]=2[CH:37]=1
Reactant: CS(=O)(=O)OCCC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)nc2)c2ccc(Cl)cc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(=O)N2CCCC(CCN3CCCC3)c3cc(Cl)ccc32)cn1)c1ccccc1Cl
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of 7-chloro-5-(2-methanesulfonyloxyethyl)-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) in dimethylformamide (5 ml) are added pyrrolidine (0.09 ml), sodium iodide (0.14 g) and potassium carbonate (0.15 g), and the mixture is stirred at 110° C. for 2 hours. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-[2-(1-pyrrolidinyl)ethyl]-1-[6-(2-chlorobenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (98 mg) as colorless amorphous.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O[CH2:14][C:15]1[CH:20]([C:21]([OH:23])=[O:22])[N:19]2[C:24](=[O:36])[CH:25]([NH:26][C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:18]2[S:17][CH:16]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[C:29]1([CH2:28][C:27]([NH:26][CH:25]2[C:24](=[O:36])[N:19]3[CH:20]([C:21]([OH:23])=[O:22])[C:15]([CH2:14][C:9]4[C:1]([OH:2])=[CH:3][C:4]([OH:5])=[CH:6][C:7]=4[OH:8])=[CH:16][S:17][C@H:18]23)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3c(O)cc(O)cc3O)=CS[C@H]12
Reaction time: 0.5 h

Procedure:
A solution of 0.063 g of phloroglucinol in 0.3 ml of trifluoroacetic acid is mixed with 0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid, and the solution is left to stand for 30 minutes at room temperature and diluted with an equal quantity of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 7-(N-Phenylacetyl-amino)-3-(2,4,6-trihydroxy-benzyl)-ceph-2-em-4ξ-carboxylic acid is thus obtained, showing the following Rf values in a thin layer chromatogram (silica gel): 0.73 (system n-butanol/acetic acid/water, 67:10:23) and 0.55 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:6][C:7](=[O:25])[NH:8][C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]([C:21](=[O:23])[CH3:22])[C@@H:11]([CH3:24])[CH2:10]1)[CH3:5].CC(C)C=O.[NH2:31][CH2:32][CH:33]=O.Cl>CO.C(O)(=O)C>[CH3:5][CH:4]([O:6][C:7](=[O:25])[NH:8][C@H:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[NH:31][CH:32]=[CH:33][N:20]=3)[CH:17]=2)[N:12]([C:21](=[O:23])[CH3:22])[C@@H:11]([CH3:24])[CH2:10]1)[CH3:3]
Reactant: NCC=O
Reactant: CC(=O)N1c2ccc(C#N)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: CC(C)C=O
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1c2ccc(-c3ncc[nH]3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.5 %

Procedure:
Sodium hydride (60% in mineral oil, 50 mg, 1.25 mmol) was added portionwise to a stirred solution of 1-methylethyl[(2S,4R)-1-acetyl-6-cyano-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 57) (350 mg, 1.1 mmol) in dry methanol (10 mL). The resulting mixture was stirred at room temperature for 48 h then was treated with aminoacetaldehyde dimethyl acetaldehyde (233 mg, 2.2 mmol) and acetic acid (1 mL, excess). The resulting mixture was refluxed for 2 h then was cooled to room temperature and treated with HCl (1M in water, 5 mL). The resulting mixture was refluxed for 1 h, cooled to room temperature and most of the methanol was removed in vacuo. The residue was diluted with water (10 mL) and basified by the addition of solid potassium carbonate (CARE: gas evolved). The resulting aqueous phase was extracted with AcOEt (3×10 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 6% MeOH in DCM) followed by trituration of the adduct obtained with Et2O gave 1-methylethyl[(2S,4R)-1-acetyl-6-(1H-imidazol-2-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (14 mg, 0.039 mmol, 3.5%) as an off white solid.
Reaction SMILES: CS[S:3][CH3:4].S(Cl)(Cl)(=O)=O.[CH3:10][C:11]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]2[C:12]=1[CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[NH:15]2>ClCCCl.CN(C=O)C.C(OCC)(=O)C>[CH3:10][C:11]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]2[C:12]=1[C:13]([S:3][CH3:4])=[C:14]([C:21]([O:23][CH3:24])=[O:22])[NH:15]2
Reactant: CSSC
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Solvent: CN(C)C=O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1[nH]c2c(C)ccc(C)c2c1SC
Reaction time: 0.33 h
Yield: 105.1 %

Procedure:
Under ice-cooling, 0.89 ml (7.4 mmol) of dimethyl disulfide was dissolved in 20 ml of 1,2-dichloroethane, and 0.53 ml (6.5 mmol) of sulfuryl chloride was added. The reaction mixture was stirred for 20 minutes and a solution of 2.00 g (9.8 imnol) of methyl 4,7-dimethylindole-2-carboxylate in 10 ml of anhydrous DMF was added. The reaction mixture was stirred for 2 hours, then dissolved in ethyl acetate and washed with water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide 1.94 g of white crystals. Yield: 80%
Reaction SMILES: [Cl:1][C:2]1[C:3]([Si](C)(C)C)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=2)[N:7]=1.[Br:22]C(F)(F)C(F)(F)Br>CCCC[N+](CCCC)(CCCC)CCCC.C1C=CC([Sn-](F)(F)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.ClCCl>[Br:22][C:3]1[C:2]([Cl:1])=[N:7][N:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:9][N:10]=[C:5]2[CH:4]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: C[Si](C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccccc1-c1nnc2cc(Br)c(Cl)nn12
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
Tetrabutylammonium difluorotriphenylstannate (6.8 g, 10.8 mmol) was added to a suspension of 6-chloro-3-(2-fluorophenyl)-7-(trimethylsilyl)-1,2,4-triazolo[4,3-b]pyridazine (3.17 g, 9.88 mmol), prepared as in Example 25 Step c), and 1,2-dibromotetrafluoroethane (6.0 ml, 50 mmol) in anhydrous THF (75 ml) and-the mixture was stirred at room temperature under nitrogen for 18 h. The mixture was diluted with dichloromethane (100 ml), filtered and the filtrate was concentrated. Flash column chromatography on silica gel, eluting with 50-100% EtOAc-hexane, gave 7-bromo-6-chloro-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (2.84 g, 88%) as an off-white solid; 1H NMR (360 MHz, CDCl3) δ 7.31 (1H, dd, J=10 and 10 Hz), 7.36 (1H, ddd, J=8, 8 and 1 Hz), 7.57-7.63 (1H, m), 7.87 (1H, ddd, J=7, 7 and 2 Hz), 8.49 (1H, s); MS (ES+) m/e 327/329/331 [MH]+.
Reaction SMILES: [C@H:1]12[CH2:14][CH:4]([N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6]1)[CH2:3][NH:2]2.[Cl:15][C:16]1[N:17]=[N:18][C:19](Cl)=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:15][C:16]1[N:17]=[N:18][C:19]([N:2]2[CH2:3][CH:4]3[CH2:14][C@H:1]2[CH2:6][N:5]3[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])=[CH:20][CH:21]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2c1ccc(Cl)nn1

Procedure:
0.397 g (2.0 mmol) of 1,1-dimethylethyl (1S)-2,5-diazabicyclo[2.2.1]heptane-5-carboxylate, 0.328 g (2.2 mmol) of 3,6-dichloropyridazine and 1.3 g (4 mmol) of caesium carbonate in 30 ml of toluene are placed into a 100 ml three-necked round-bottomed flask and the mixture is refluxed for 48 h.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[OH:14][C:15]1[C:10]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:11]=2)[N:9]=[CH:22][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1O

Procedure:
Prepared as in Example 1c from 4-isopropoxyaniline and diethyl 2-(ethoxymethylene)malonate as a yellow solid (20%). MS 276 (MH+).
Reaction SMILES: CCC(C[O:7][C:8](C(N(CC[NH+](C)C)C)=O)([C:15]1[CH:20]=CC=CC=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)CC.[Cl-].C1C2C(=CC=CC=2)C=C1.[Br:40]Br.OO>ClC1C=CC=CC=1Cl.O>[Br:40][C@@H:15]1[CH2:20][C:10]2[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:8]1[OH:7]
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Reactant: BrBr
Agent: C1=Cc2ccccc2C1
Agent: OO
Agent: [Cl-]
Solvent: O
Solvent: Clc1ccccc1Cl
Product: O[C@@H]1c2ccccc2C[C@H]1Br
Temperature: 20 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
100 ml of water and 0.70 g of Triton X-100 were put into a 300-ml 4-mouthed flask, and mixed as 80 ml of ortho-dichlorobenzene and 60.0 g of indene (95 wt %; 0.491 mol) were added. At 20° C., 41.54 g of bromine (0.259 mol) was added with strong stirring and air cooling over approximately 5 minutes. After dropwise addition the temperature of the reaction mixture became 52° C. After mixing at 60° C. for 13 hours, 23.8 g of hydrogen peroxide (35 wt %; 0.245 mol) was added dropwise at the same temperature, requiring 3 hours, followed by mixing for a further 3 hours at 60° C. and then separation into an aqueous layer and a slurry layer. The aqueous layer was extracted with 120 ml of ortho-dichlorobenzene, and the extract layer was bulked with the earlier slurry layer. The warm slurry layer was cooled gradually to 20° C. under stirring, the crystals which came down were isolated by centrifugation and washed with 30 ml of ortho-dichlorobenzene. The wet crystals were dried at 65°-70° C. under decreased pressure to obtain 72.18 g of white crystals of trans-2-bromoindan-1-ol (yield 69.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13]C(N)=O>ClC1C=CC=CC=1C.P(O)(O)O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(N)=O
Agent: OP(O)O
Solvent: Cc1ccccc1Cl
Product: NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
83.5 g (0.5 mol) of 4-nitrobenzoic acid, 33.0 g (0.55 mol) of urea and 0.5 g of phosphorous acid are heated in 250 ml of o-chlorotoluene with stirring at from 150° to 157° C. for 8 h. After cooling to 25° C. the solid is filtered off with suction and washed with 50 ml of o-chlorotoluene. The filter cake is introduced into 250 ml of water, the mixture is adjusted to a pH of 12 using aqueous sodium hydroxide solution, and is subjected to steam distillation. Subsequently the solid is filtered off with suction and dried at 100° C. 74.9 g of 4-nitrobenzamide are obtained having a melting point of from 194 to 195° C. This corresponds to a yield of 90.3% of theory. By acidification of the aqueous mother liquor to pH 2, 3.4 g of 4-nitrobenzoic acid (4.1% of theory) are obtained which can be employed again in a subsequent batch.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 62.3 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine (764 mg, 3.0 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (710 mg, 3.0 mmol) and DIPEA (2.6 mL, 15 mmol) in IPA (8 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in EtOAc) to afford 210 as a white solid (700 mg, 63%). LCMS (Method K): RT 2.94 min [M+H]+ 375.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.89 (1H, br s), 8.61 (1H, br s), 8.20-7.80 (4H, m), 7.79-7.67 (2H, m), 7.52-7.43 (1H, m), 7.20-7.08 (2H, m), 5.86 (1H, br s), 1.63 (3H, d, J=6.82 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:13]2([C:19]([O:21]C)=[O:20])[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:13]2([C:19]([OH:21])=[O:20])[CH2:14][CH2:15][S:16][CH2:17][CH2:18]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)C1(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)CCSCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C2(C(=O)O)CCSCC2)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carbomethoxy-tetrahydrothiopyran (800.0 mg, 1.9 mmol) in methanol (50 mL) is added 1N sodium hydroxide (25 mL). The mixture is heated to reflux for 10 hours, and then solid sodium hydroxide is added (3.0 g, excess) and refluxing is continued for 18 hours. The mixture is concentrated to a volume of approximately 30 mL and acidified with citric acid (pH=5). The mixture is partitioned between ethyl acetate and water. The organic layer is removed, washed with brine, dried (MgSO4), and the solvent is evaporated to give 4-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-carboxytetrahydrothiopyran.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[OH:15]O>C(O)(=O)C>[N+:1]1([O-:15])[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1
Reactant: OO
Reactant: c1cnc2c(c1)ccc1cccnc12
Solvent: CC(=O)O
Product: [O-][n+]1cccc2ccc3cccnc3c21
Temperature: 55 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Referring to scheme 7, a mixture of 30 g [1,10]phenanthroline, 26 g 30% hydrogen peroxide and 200 ml acetic acid was added to a flask, and the mixture was then heated to 50-60° C. and stirred overnight. After completion of reaction, the reaction mixture was cooled to room temperature, and vacuum distillated to remove acetic acid, and then 300 ml CH2Cl2 was added. Next, the solution was filtered to remove solids, and neutralized by adding K2CO3(aq). The organic layer was separated, concentrated, and purified by column chromatography with silca gel (Methanol), so as to obtain solids [1,10]phenanthroline-N-oxide (23 g, yield 70.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)[N:10]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)[N:10]=1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(F)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 50 °C

Procedure:
A solution of the product from Example 104 Step F (0.280 g; 0.541 mmol) in methanol (4 mL) and THF (1 mL) in a round bottom flask was treated with 3N aq. NaOH (1.08 mL; 3.24 mmol) and heated to 50° C. for 2 hours. The volatiles were removed in vacuo, and the reaction was quenched with saturated aq. NaHSO4 solution and extracted with methylene chloride (5×). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford the crude product. NMR and LCMS indicated good purity and the crude product was used without further purification: m/e=504 (M+1).
Reaction SMILES: C(O)=O.[O:4]1CCCO[CH:5]1[CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[F:34][C:33]([F:35])([F:36])[O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][CH:21]2[CH2:20][CH2:19][CH:18]([CH:15]3[CH2:16][CH2:17][CH:12]([CH2:11][CH2:10][CH:5]=[O:4])[CH2:13][CH2:14]3)[CH2:23][CH2:22]2)=[CH:31][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(CCC2CCC(C3CCC(CCC4OCCCO4)CC3)CC2)cc1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=CCCC1CCC(C2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Yield: 94.8 %

Procedure:
Formic acid (3.0 g, 66 mmol) and toluene (20 ml) were added to the above 4-(4-(1,3-dioxan-2-ylethyl)cyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexane (3.25 g, 6.94 mmol), followed by refluxing the mixture for 5 hours, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, and distilling off the solvent, to obtain 3-(4-(4-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexyl)cyclohexyl)propanal (2.70 g, 6.58 mmol). Yield: 94.8%.
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCC(OC2C3C=CC=CC=3CCN3C2=NC(C2C=CC=CC=2)=C3)CC1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[CH2:30]([O:37][C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccccc1
Reactant: CN1CCC(OC2c3cccc(Br)c3CCn3cc(-c4ccccc4)nc32)CC1
Agent: [Cu]I
Agent: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccccc4)nc32)CC1
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Solvent: Cc1ccccc1
Product: CN1CCC(OC2c3cccc(OCc4ccccc4)c3CCn3cc(-c4ccccc4)nc32)CC1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (276 mg, 0, 40 mmole) in anhydrous toluene (5 mL) in a screw-capped vial are added benzyl alcohol (87 mg, 0, 80 mmole), copper(I) iodide (15.3 mg, 0.080 mmole), ground 4A molecular sieves (133 mg), 3,4,7,8-tetramethyl-1,10-phenanthroline (38 mg, 0, 16 mmole) and cesium carbonate (261 mg, 0, 80 mmole). The vial is evacuated and filled with argon. The reaction mixture is stirred at 90° C. for 3 days. Water and ammonia are added to the reaction mixture, and the aqueous phase is extracted three times with dichloromethane. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1°)/0 formic acid (B), focus gradient from 23% (B) to 33% (B) in 10 minutes) to afford 8-benzyloxy-4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 68° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:9].[CH2:10]=[C:11]1O[C:13](=[O:14])[CH2:12]1>C1(C)C=CC=CC=1>[CH3:10][C:11]1[C:6]2[C:5](=[CH:4][C:3]([NH2:9])=[C:2]([Cl:1])[CH:7]=2)[NH:8][C:13](=[O:14])[CH:12]=1
Reactant: C=C1CC(=O)O1
Reactant: Nc1ccc(Cl)c(N)c1
Solvent: Cc1ccccc1
Product: Cc1cc(=O)[nH]c2cc(N)c(Cl)cc12
Temperature: 30 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
28.6 g of 4-chloro-1,3-phenylendiamine are suspended at 22° C. in 400 ml of toluene. 17.6 g of diketene in 100 ml of toluene are added to the grey suspension in the course of 30 minutes at 25±2° C., the suspension briefly passing into solution before the mono-diketenisation product is precipitated in the form of a beige solid. Stirring is then carried out for 6 h at 22° C. Then 5 g of pyridinium para-toluenesulfonate (PPTS) are added and the mixture is boiled under reflux for 16 h. The yellow suspension is cooled to 30° C., with stirring, and then at 30° C. 30 ml of 1 N NaOH are added. A further 100 ml of water are then added. The crude product is filtered at 22° C., washed neutral with H2O and dried overnight at 60° C. in vacuo. 38.5 g (yield: 92%, isomeric ratio of 4-methyl-6-chloro-7-aminoquinolone to 4-methyl-5-amino-6-chloroquinolone>95:5) of a beige solid having a melting point of 350° C. are obtained.
Reaction SMILES: [CH:1]12[CH2:15][CH2:14][O:13][C:12]1([O:16]O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C12CCOC=1CCCCCCCCCC2>>[C:12]1(=[O:16])[O:13][CH2:14][CH2:15][CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: OOC12CCCCCCCCCCC1CCO2
Agent: C1CCCCCC2=C(CCCC1)CCO2
Agent: O=C1CCCCCCCCC/C=C\CCO1
Product: O=C1CCCCCCCCCC=CCCO1

Procedure:
The 13-oxabicyclo[10.3.0]pentadecan-12-yl hydroperoxide used as starting product is a novel compound which was prepared from 13-oxabicyclo[10.3.0]pentadec-1(12)-ene having the following characteristics: