Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1
Reactant: CCCCCC(O)c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
TBSOTf (2.9 mL, 12.6 mmol) was added to an ice-cold solution of 4 (3.017 g, 11.7 mmol) and 2,6-lutidine (1.6 mL, 13.7 mmol) in dichloromethane (30 mL). The reaction was stirred for 2 h at room temperature and then 100 mL saturated sodium bicarbonate solution was added. The resulting mixture was extracted with dichloromethane (30 mL) and the dichloromethane layer was washed with 1 M HCl (2×50 mL) and brine (50 mL). The dichloromethane solution was then dried (MgSO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (hexanes) gave compound 5 (3.843 g, 88%).
Reaction SMILES: Cl[CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3].[Na].[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:21]=1[C:22]([OH:24])=[O:23]>CN(C)C=O>[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:21]=1[C:22]([O:24][CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3])=[O:23]
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: CC(Cl)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccnc(C)c1C(=O)OC(C)c1nc2c(c(=O)n(C)c(=O)n2C)n1C

Procedure:
1.54 g of 8-α-chloroethylcaffeine are dissolved in 15 ml of anhydrous dimethylformamide, and 1.75 g of the sodium salt of dry 2,4-dimethylnicotinic acid are then added.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1>>[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][N:4]3[C:8](=[O:9])[C:7]4=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]4[C:5]3=[O:14])[CH2:30][CH2:29]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(C(c2cccnc2)N2CCNCC2)cc1
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccccc2)c2cccnc2)CC1
Yield: 53 %

Procedure:
The title compound was prepared in a yield of 53% in a similar manner to that described in Preparation 1' by reacting N-(2-bromoethyl)phthalimide and 4-[α-(3-pyridyl)benzyl]piperazine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[C:11]1([S:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:7][CH:6]([CH3:8])[C:5]([C:14]1[CH:15]=[CH:16][C:11]([S:17][CH3:18])=[CH:12][CH:13]=1)=[O:9]
Reactant: CC(C)C(=O)Cl
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)C(C)C)cc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
To a suspension of aluminum chloride (136 g, 1.02 mol) in chloroform (1.0 L) cooled to -10° C., was added dropwise isobutyrylchloride (115 mL, 1.10 mol). Then thioanisole (100 mL, 0.85 mol) was added dropwise. Upon completion of addition the reaction was allowed to proceed at r.t. for 1.5 h. The reaction was cooled to 10° C. and quenched by addition of water (750 mL). The organic layer was separated, washed with water (2×500 mL), saturated NaHCO3 solution (2×500 mL), brine (1×500 mL), and then dried over Na2SO4. After concentration in vacuo., the resulting crude product crystallized upon standing under high vacuum for 30 min to give the title compound as a brown solid.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[F:48][C:49]([F:59])([F:58])[C:50]1[N:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:57][CH2:56][C:53]4[CH:54]=[N:55][C:50]([C:49]([F:59])([F:48])[F:58])=[CH:51][CH:52]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(C(F)(F)F)nc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(C(F)(F)F)nc1
Yield: 63 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (6-(trifluoromethyl)pyridin-3-yl)methanamine, the title compound was obtained as a colorless solid in 63% yield: 1H NMR (300 MHz, CDCl3) δ 8.70 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.30-7.23 (m, 2H), 7.08-6.99 (m, 2H), 6.20 (t, J=5.8 Hz, 1H), 6.09 (s, 1H), 4.65 (d, J=5.8 Hz, 2H), 4.43 (s, 2H), 3.85-3.77 (m, 2H), 3.49-3.40 (m, 2H), 2.49 (s, 3H): MS (ES+) m/z 493.2 (M+1).
Reaction SMILES: [C:1]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](O)=[C:16]([Cl:21])[CH:15]=1.ClC1C=C(N)C=CC=1OCC1C=CC=CN=1>>[Cl:21][C:16]1[CH:15]=[C:14]([NH2:13])[CH:19]=[CH:18][C:17]=1[O:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: OCc1nccc2ccccc12
Agent: Nc1ccc(OCc2ccccn2)c(Cl)c1
Product: Nc1ccc(OCc2nccc3ccccc23)c(Cl)c1

Procedure:
Compound 11A was prepared from 4-amino-2-chloro-phenol 1-isoquinolinyl methanol by a route analogous to that used for the preparation of 1C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:20]([N:22]([CH2:45][CH3:46])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]([Br:35])[CH:30]=[C:31](I)[CH:32]=2)[C:27]([OH:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:26]1=[O:44])[CH3:21].[CH3:47][N:48](C=O)C>CCOC(C)=O.C1(C)C=CC=CC=1.[C-]#N.[C-]#N.[Zn+2]>[CH2:20]([N:22]([CH2:45][CH3:46])[CH2:23][CH2:24][N:25]1[C:33]2[C:28](=[C:29]([Br:35])[CH:30]=[C:31]([C:47]#[N:48])[CH:32]=2)[C:27]([OH:43])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:26]1=[O:44])[CH3:21]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(I)cc21
Agent: [C-]#N
Agent: [Zn+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To Pd2(dba)3CHCl3 (60.1 mg, 5 mol %) and PPh3 (60.9 mg, 20 mol %) under a nitrogen atmosphere was added anhydrous DMF (0.5 mL). The resulting precipitate was stirred at room temperature for 30 minutes during which time the colour changed from red to yellow/orange. To this was added 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-iodooxindole (626.4 mg, 1.16 mmol) dissolved in anhydrous DMF (1.0 mL). To the resulting red solution was then added Zn(CN)2. The resulting precipitate was then heated to 60° C. (bath temperature) and stirring was continued at that temperature for 4 hours. The mixture was allowed to cool to room temperature and diluted with EtOAc:toluene (1:1, 10 mL). The mixture was washed with H2O (6 mL). The aqueous phase was then extracted with EtOAc:toluene (1:1, 5 mL×5). The organic phases were combined and dried (anhydrous MgSO4). After filtration the solvent was removed in vacuo. The orange solid obtained was then purified by flash chromatography (silica gel, eluting 1% to 2% to 3%MeOH in CHCl3) to give the title compound as a light brown/orange solid (462.6 mg, 91%).
Reaction SMILES: [CH2:1]1[C:3]2([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C:4]([NH:6][C:7](=O)[CH:2]12)=O.[CH2:16]([Mg]Br)[CH3:17].O>CCOCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]23[CH2:1][CH:2]2[CH:7]([CH2:16][CH3:17])[NH:6][CH2:4]3)=[CH:10][CH:11]=1
Reactant: CC[Mg]Br
Reactant: O=C1NC(=O)C2(c3ccc(Cl)cc3)CC12
Solvent: CCOCC
Solvent: O
Product: CCC1NCC2(c3ccc(Cl)cc3)CC12
Reaction time: 18 h

Procedure:
To 4.43 g of 1-(p-chlorophenyl)-1,2-cyclopropanedicarboximide in 100 ml of ether is added 16.4 ml of 2M ethylmagnesium bromide. The mixture is allowed to stand at room temperature for 18 hours and then is combined with water. The ether solution is dried over sodium sulfate and evaporated to give 4.05 g of a pink semisolid. Crystallization from ether hexane gives 1-(p-chloropehnyl)-4-ethyl-4-hydroxy-3-azabicyclo[3.1.0]hexan-2-one as colorless crystals, m.p. 154°-157° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:20][C:12]=3[N:13]=[C:14](S(C)(=O)=O)[N:15]=2)=[CH:5][CH:4]=1.[O-:36][CH2:37][CH3:38].[Na+]>O1CCOCC1.C(O)C>[CH2:37]([O:36][C:14]1[N:15]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:35])[F:34])=[CH:8][CH:7]=2)[C:11]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:20][C:12]=2[N:13]=1)[CH3:38]
Reactant: CC[O-]
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1S(C)(=O)=O)C2
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine (150 mg, 0.27 mmol) was suspended in dioxane (5.0 mL) and ethanol (2.0 mL), sodium ethoxide (20 mg, 0.28 mmol) was added and the mixture was stirred at at 80° C. for 2 hrs. Solvent was removed and the residue was purified by flash chromatography over silica gel and then by preparative TLC to obtain the product as a white solid (102 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].CN(C)C=O>CO>[CH3:17][N:18]([CH:20]=[CH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[CH3:19]
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
Into a reaction flask were introduced 89.7 g of methyl 4-methyl-3-nitrobenzoate, 82.1 g of dimethylformamide dimethyl acetal and 200 ml of dimethylformamide (DMF), and the content of the flask was stirred at 120° C. for 6 hours. DMF was distilled off to obtain a red-violet colored solid product. Then, 300 ml of methanol was poured into the flask to wash the crystalline matter, and filtered. Thus, 104.8 g (yield 91%) of methyl 4-dimethylaminovinyl-3-nitrobenzoate was obtained.
Reaction SMILES: Cl.Cl.Cl.[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5].C(N(CC)CC)C.[O:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[C:47](O)=[O:48].Cl.CON(OC)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)(Cl)Cl>[CH2:4]([O:6][CH2:7][C:8]1[N:9]([CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:47]([CH:43]3[CH2:44][CH2:45][CH2:46][O:42]3)=[O:48])[CH2:33][CH2:34]2)[C:10]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:14]=3[N:13]=[C:12]([NH2:26])[C:11]=2[N:27]=1)[CH3:5]
Reactant: O=C(O)C1CCCO1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCNCC1
Agent: CCN=C=NCCCN(OC)OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)C2CCCO2)CC1
Temperature: 4 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A solution of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride (1.0 g, 1.90 mmol) and triethylamine (1.35 mL, 9.50 mmol) in chloroform (80 mL) was cooled to 4° C. 2-Tetrahydrofuroic acid (0.243 g, 2.09 mmol) and 1-(3-dimethoxyaminopropyl)-3-ethylcarbodiimide hydrochloride (0.401 g, 2.09 mmol) were sequentially added, and the reaction was stirred for two hours. The reaction was incomplete as determined by thin layer chromatography (TLC) analysis. The reaction was cooled to 4° C., and 1-hydroxybenzotriazole (0.283 g, 2.09 mmol) was added. The reaction was allowed to warm to ambient temperature, stirred for 16 hours, and then diluted with chloroform (100 mL). The resulting solution was washed sequentially with water (100 mL), 4% aqueous sodium carbonate (2×100 mL), water (200 mL), and brine (150 mL); dried over sodium sulfate; filtered; and concentrated under reduced pressure. The residue was purified by HPFC followed by recrystallization from ethyl acetate to provide 0.68 g of 2-ethoxymethyl-7-(pyridin-3-yl)-1-{[1-(tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]methyl}-1H-imidazo[4,5-c]quinolin-4-amine as a white, crystalline solid, mp 191-192° C.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH:8]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:4][CH:3]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41](O)=[O:42])=[CH:33][CH:32]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:41]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:26]([OH:28])=[O:27])[NH2:8])=[CH:29][CH:30]=2)=[O:42])=[CH:33][CH:32]=1
Reactant: Nc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: N[C@@H](Cc1ccc(NC(=O)c2ccnc3ccccc23)cc1)C(=O)O
Reaction time: 4 h

Procedure:
A 250 mL cylindrical glass vessel equipped with a coarse glass frit was charged with 4-amino-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-phenylalanine (10 g) obtained in Example 62 and a solution prepared from quinoline-4-carboxylic acid (5.2 g, 30 mmol), BOP (13.75 g, 30 mmol) and diisopropylethylamine (6.8 mL) in 70 mL of N-methylpyrrolidinone. The slurry was agitated for 4 hr. The mixture was filtered and washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL). To the washed resin was added a solution of 25% piperidine in N-methylpyrrolidinone (80 mL), the mixture was agitated at room temperature for 20 minutes and filtered. The process was repeated and the resulting slurry was filtered and washed with dichloromethane (2×100 mL), methanol (2×100 mL) and dimethylformamide (2×100 mL). Filtration afforded 4-[(4-quinolinylcarbonyl)amino]-L-phenylalanine on Wang resin suitable for use in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20][CH3:21])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[C:10]1[C:18]2[C:13](=[C:14]([CH2:19][S:20]([CH3:21])=[O:40])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.19 mmol) of the compound from Example 103 were introduced into 14 ml of dichloromethane at 0° C., 47 mg (0.19 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 74 mg (95% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:20](=O)[CH3:21])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=1)=[C:20]([CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.54 g), 2-(4-methanesulfonylbenzyl)-3-oxobutyric acid ethyl ester (0.75 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 20 hours. The mixture was diluted with water and the pH of this solution this solution was adjusted to 3 by the addition of sodium acetate. The resulting precipitate was collected by filtration and dried to afford title compound as a white solid, 1.0 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][O:13][C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[C:10]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[C:11]([CH2:12][O:13][C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)=[C:10]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(COc2ccnn2C)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1OCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl

Procedure:
6.95 g (19 mmol) of methyl 2-chloro-[(1-methylpyrazol-5-yl)oxymethyl]-4-methylsulfonylbenzoate in a mixture of 30 ml of tetrahydrofurane and 30 ml of water are treated at room temperature with 0.93 g of lithium hydroxide for 12 h. The reaction mixture is adjusted to pH4 with 10% strength hydrochloric acid and extracted with methylene chloride. The organic phase is dried and freed from the solvent. Yield: 4.3 g; m.p. 197° C.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.[CH3:18][C:19]1[CH:23]=[C:22]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[S:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH:17]1([CH2:16][N:26]2[CH2:27][CH2:28][N:24]([C:22]3[S:21][C:20]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:19]([CH3:18])[CH:23]=3)[C:25]2=[O:29])[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: BrCC1CC1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)cc1C
Yield: 80 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with (bromomethyl)cyclopropane to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 6.14 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.87-3.79 (m, 2H), 3.72-3.64 (m, 2H), 3.18 (d, J=7.1 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H), 1.02-0.87 (m, 1H), 0.60-0.52 (m, 2H), 0.28-0.21 (m, 2H); MS (ES+) m/z 309.2 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OC1CCNCC1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>C1COCC1>[N+:29]([C:26]1[CH:27]=[CH:28][C:23]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:24][CH:25]=1)([O-:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: OC1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A solution of 2.01 (10 mmol) of N-Boc4-hydroxypiperidine (prepared in a standard fashion starting from commercial 4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solution of 1.23 g (11 mmol) of tBuO K+in 10 ml of dry THF in a three necked flask, under an inert atmosphere, cooled by an ice bath. After agitation for 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of 4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reaction mixture is agitated for 5 hours at 23° C. and finally poured into 25 ml of a water+ice mixture. The product is extracted using 50 ml of ethyl acetate. After decantation, the organic phase is washed twice with 25 ml of water and 25 ml of salt water. The organic solution is dried over magnesium sulphate, followed by filtration and concentration of the filtrate under vacuum to produce a residue which is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and evaporated under vacuum. The expected product is obtained in the form of a pale yellow powder with a yield of 47%. Melting point: 97-98° C.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.[K+].[Br-]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][N:15]1[C:14]2[CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccc(-c3ccccc3)cc2NC1=O
Reactant: Clc1cccc(CBr)c1
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccc(-c3ccccc3)cc2N1Cc1cccc(Cl)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-6-phenyl-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, to afford a white crystalline solid in 27% overall yield, mp 119°-121° C.; IR (KBr) 3517, 1659, 1487, 1435, 1387, 1282, 1260, 1060, 760 cm-1 ; 1H NMR (CDCl3) δ2.22-2.38 (m, 3H), 3.95 (v br s, 2H), 4.90 (dd, J=7.6, 5.5 Hz, 1H), 5.18 (ABq, JAB =17.1 Hz, 2H), 7.04 (d, J=1.9 Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 7.15-7.42 (m, 10H); MH+ at m/z=394; Anal. Calc'd for C23H20 ClNO3 : C, 70.14; H, 5.12; N, 3.56. Found: C, 70.10; H, 5.11; N, 3.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14](=O)[CH3:15])[C:9]2=O)=[CH:5][CH:4]=1.O.[NH2:18][CH2:19][C@H:20]([OH:22])[CH3:21]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]3[CH:13]=[C:14]([CH3:15])[N:18]([CH2:19][C@H:20]([OH:22])[CH3:21])[C:9]=32)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)C(CC(C)=O)C2
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)-c1c(cc(C)n1C[C@@H](C)O)C2
Reaction time: 1.5 h
Yield: 61.4 %

Procedure:
A solution of 1.45 g of (RS)-6-methoxy-2-(2-oxopropyl)-1-indanone and 60 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 90 minutes, during which time the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.05 g (61%) of (R)-1-(7-methoxy-2-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow solid with m.p. 110°.